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Does Bupropion and Zanamivir interact?

•Drug A: Bupropion •Drug B: Zanamivir •Severity: MINOR •Description: Zanamivir may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prevention and treatment of influenza A and B. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zanamivir, an antiviral agent, is a neuraminidase inhibitor indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients 7 years and older who have been symptomatic for no more than 2 days. Zanamivir has also been shown to significantly inhibit the human sialidases NEU3 and NEU2 in the micromolar range (Ki 3.7 +/-0.48 and 12.9+/-0.07 microM, respectively), which could account for some of the rare side effects of zanamivir. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The proposed mechanism of action of zanamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. By binding and inhibiting the neuraminidase protein, the drug renders the influenza virus unable to escape its host cell and infect others. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absolute bioavailability is very low following oral administration (2%). Following oral inhalation, bioavailability is 4% to 17%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Zanamivir has limited plasma protein binding (<10%). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Not metabolized •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Unabsorbed drug is excreted in the feces.Zanamivir is renally excreted as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2.5-5.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 2.5 - 10.9 L/h [Following oral inhalation 10 mg] 5.3 L/h [Normal renal function receiving IV single dose of 4 mg or 2 mg] 2.7 L/h [Patients with mild and moderate renal impairement receiving IV single dose of 4 mg or 2 mg] 0.8 L/h [Patients with severe renal impairement receiving IV single dose of 4 mg or 2 mg] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Relenza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zanamivir •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zanamivir is a neuraminidase inhibitor used to treat influenza A and B.

The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Question: Does Bupropion and Zanamivir interact? Information: •Drug A: Bupropion •Drug B: Zanamivir •Severity: MINOR •Description: Zanamivir may decrease the excretion rate of Bupropion which could result in a higher serum level. •Extended Description: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prevention and treatment of influenza A and B. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zanamivir, an antiviral agent, is a neuraminidase inhibitor indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients 7 years and older who have been symptomatic for no more than 2 days. Zanamivir has also been shown to significantly inhibit the human sialidases NEU3 and NEU2 in the micromolar range (Ki 3.7 +/-0.48 and 12.9+/-0.07 microM, respectively), which could account for some of the rare side effects of zanamivir. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The proposed mechanism of action of zanamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. By binding and inhibiting the neuraminidase protein, the drug renders the influenza virus unable to escape its host cell and infect others. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Absolute bioavailability is very low following oral administration (2%). Following oral inhalation, bioavailability is 4% to 17%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Zanamivir has limited plasma protein binding (<10%). •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Not metabolized •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Unabsorbed drug is excreted in the feces.Zanamivir is renally excreted as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2.5-5.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 2.5 - 10.9 L/h [Following oral inhalation 10 mg] 5.3 L/h [Normal renal function receiving IV single dose of 4 mg or 2 mg] 2.7 L/h [Patients with mild and moderate renal impairement receiving IV single dose of 4 mg or 2 mg] 0.8 L/h [Patients with severe renal impairement receiving IV single dose of 4 mg or 2 mg] •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Relenza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zanamivir •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zanamivir is a neuraminidase inhibitor used to treat influenza A and B. Output: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. The severity of the interaction is minor.

Does Bupropion and Zanubrutinib interact?

•Drug A: Bupropion •Drug B: Zanubrutinib •Severity: MAJOR •Description: The metabolism of Zanubrutinib can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate. This is of significant concern if the substrate being out-competed possesses a narrow therapeutic index as there is only a small serum concentration range within which its administration is considered safe and where any increase or change in its serum concentration could consequently result in an increased risk, incidence, and/or severity of adverse effects and toxicity associated with exposure to the given agent . •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zanubrutinib is indicated for the treatment of: Mantle cell lymphoma (MCL) in adults who have received at least one prior therapy. Waldenström’s macroglobulinemia in adults. Relapsed or refractory marginal zone lymphoma (MZL) in adults who have received at least one anti-CD20-based regimen. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults. Refractory or relapsed follicular lymphoma, in combination with obinutuzumab, in adults who have received at least two prior systemic therapies. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zanubrutinib is an immunomodulating agent that decreases the survival of malignant B cells. It inhibits BTK by binding to its active site. It works to inhibit the proliferation and survival of malignant B cells to reduce the tumour size in mantle cell lymphoma. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Bruton's tyrosine kinase (BTK) is a non-receptor kinase and a signalling molecule for the B cell receptors expressed on the peripheral B cell surface. The BCR signalling pathway plays a crucial role in normal B-cell development but also the proliferation and survival of malignant B cells in many B cell malignancies, including mantle-cell lymphoma (MCL). Once activated by upstream Src-family kinases, BTK phosphorylates phospholipase-Cγ (PLCγ), leading to Ca2+ mobilization and activation of NF-κB and MAP kinase pathways. These downstream cascades promote the expression of genes involved in B cell proliferation and survival. The BCR signalling pathway also induces the anti-apoptotic protein Bcl-xL and regulates the integrin α4β1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin via BTK. Apart from the direct downstream signal transduction pathway of B cells, BTK is also involved in chemokine receptor, Toll-like receptor (TLR) and Fc receptor signalling pathways. Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue in the adenosine triphosphate (ATP)–binding pocket of BTK, which is the enzyme's active site. This binding specificity is commonly seen with other BTK inhibitors. Due to this binding profile, zanubrutinib may also bind with varying affinities to related and unrelated ATP-binding kinases that possess a cysteine residue at this position. By blocking the BCR signalling pathway, zanubrutinib inhibits the proliferation, trafficking, chemotaxis, and adhesion of malignant B cells, ultimately leading to reduced tumour size. Zanubrutinib was also shown to downregulate programmed death-ligand 1 (PD-1) expression and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on CD4+ T cells. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration of zanubrutinib 160 mg twice daily and 320 mg once daily, the mean (%CV) zanubrutinib steady-state concentrations were 2,295 (37%) ng·h/mL and 2,180 (41%) ng·h/mL, respectively. The mean Cmax (%CV) was 314 (46%) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily. The Cmax and AUC of zanubrutinib increase in a dose-proportional manner and there is minimal systemic accumulation after repeated dosing. The median Tmax is 2 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The geometric mean (%CV) apparent steady-state Vd is 881 (95%) L. The blood-to­ plasma ratio is about 0.7 to 0.8. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of zanubrutinib is approximately 94%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zanubrutinib is predominantly metabolized by CYP3A4. Its metabolites have not been characterized. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of 320 mg radiolabelled zanubrutinib, approximately 87% of the dose was excreted in the feces and about 8% of the dose was recovered in the urine, where less than 1% of the recovered drug comprised of unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Following administration of a single oral dose of 160 mg or 320 mg of zanubrutinib, the mean half-life is approximately 2 to 4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There is limited data on zanubrutinib overdose. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brukinsa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zanubrutinib is a kinase inhibitor used to treat mantle cell lymphoma, a type of B-cell non-Hodgkin lymphoma, in adults who previously received therapy.

When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate. This is of significant concern if the substrate being out-competed possesses a narrow therapeutic index as there is only a small serum concentration range within which its administration is considered safe and where any increase or change in its serum concentration could consequently result in an increased risk, incidence, and/or severity of adverse effects and toxicity associated with exposure to the given agent . The severity of the interaction is major.

Question: Does Bupropion and Zanubrutinib interact? Information: •Drug A: Bupropion •Drug B: Zanubrutinib •Severity: MAJOR •Description: The metabolism of Zanubrutinib can be decreased when combined with Bupropion. •Extended Description: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate. This is of significant concern if the substrate being out-competed possesses a narrow therapeutic index as there is only a small serum concentration range within which its administration is considered safe and where any increase or change in its serum concentration could consequently result in an increased risk, incidence, and/or severity of adverse effects and toxicity associated with exposure to the given agent . •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zanubrutinib is indicated for the treatment of: Mantle cell lymphoma (MCL) in adults who have received at least one prior therapy. Waldenström’s macroglobulinemia in adults. Relapsed or refractory marginal zone lymphoma (MZL) in adults who have received at least one anti-CD20-based regimen. Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults. Refractory or relapsed follicular lymphoma, in combination with obinutuzumab, in adults who have received at least two prior systemic therapies. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zanubrutinib is an immunomodulating agent that decreases the survival of malignant B cells. It inhibits BTK by binding to its active site. It works to inhibit the proliferation and survival of malignant B cells to reduce the tumour size in mantle cell lymphoma. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Bruton's tyrosine kinase (BTK) is a non-receptor kinase and a signalling molecule for the B cell receptors expressed on the peripheral B cell surface. The BCR signalling pathway plays a crucial role in normal B-cell development but also the proliferation and survival of malignant B cells in many B cell malignancies, including mantle-cell lymphoma (MCL). Once activated by upstream Src-family kinases, BTK phosphorylates phospholipase-Cγ (PLCγ), leading to Ca2+ mobilization and activation of NF-κB and MAP kinase pathways. These downstream cascades promote the expression of genes involved in B cell proliferation and survival. The BCR signalling pathway also induces the anti-apoptotic protein Bcl-xL and regulates the integrin α4β1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin via BTK. Apart from the direct downstream signal transduction pathway of B cells, BTK is also involved in chemokine receptor, Toll-like receptor (TLR) and Fc receptor signalling pathways. Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue in the adenosine triphosphate (ATP)–binding pocket of BTK, which is the enzyme's active site. This binding specificity is commonly seen with other BTK inhibitors. Due to this binding profile, zanubrutinib may also bind with varying affinities to related and unrelated ATP-binding kinases that possess a cysteine residue at this position. By blocking the BCR signalling pathway, zanubrutinib inhibits the proliferation, trafficking, chemotaxis, and adhesion of malignant B cells, ultimately leading to reduced tumour size. Zanubrutinib was also shown to downregulate programmed death-ligand 1 (PD-1) expression and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on CD4+ T cells. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration of zanubrutinib 160 mg twice daily and 320 mg once daily, the mean (%CV) zanubrutinib steady-state concentrations were 2,295 (37%) ng·h/mL and 2,180 (41%) ng·h/mL, respectively. The mean Cmax (%CV) was 314 (46%) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily. The Cmax and AUC of zanubrutinib increase in a dose-proportional manner and there is minimal systemic accumulation after repeated dosing. The median Tmax is 2 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The geometric mean (%CV) apparent steady-state Vd is 881 (95%) L. The blood-to­ plasma ratio is about 0.7 to 0.8. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The plasma protein binding of zanubrutinib is approximately 94%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zanubrutinib is predominantly metabolized by CYP3A4. Its metabolites have not been characterized. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of 320 mg radiolabelled zanubrutinib, approximately 87% of the dose was excreted in the feces and about 8% of the dose was recovered in the urine, where less than 1% of the recovered drug comprised of unchanged parent drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): Following administration of a single oral dose of 160 mg or 320 mg of zanubrutinib, the mean half-life is approximately 2 to 4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): There is limited data on zanubrutinib overdose. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Brukinsa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zanubrutinib is a kinase inhibitor used to treat mantle cell lymphoma, a type of B-cell non-Hodgkin lymphoma, in adults who previously received therapy. Output: When a CYP2B6 substrate is coadministered with another CYP2B6 substrate, both substrates will invariably compete with each other to be metabolized by the limited quantities of CYP2B6 isoenzymes present in the body. When one substrate is subsequently capable of 'out-competing' the other, this other substrate will have its CYP2B6 facilitated metabolism stalled or otherwise decreased for a time, resulting in increased serum concentrations of this substrate. This is of significant concern if the substrate being out-competed possesses a narrow therapeutic index as there is only a small serum concentration range within which its administration is considered safe and where any increase or change in its serum concentration could consequently result in an increased risk, incidence, and/or severity of adverse effects and toxicity associated with exposure to the given agent . The severity of the interaction is major.

Does Bupropion and Ziconotide interact?

•Drug A: Bupropion •Drug B: Ziconotide •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Ziconotide. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ziconotide is indicated for the management of severe chronic pain in patients refractory to other treatments, and for whom intrathecal therapy is warranted. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ziconotide inhibits N-type calcium channels involved in nociceptive signalling, primarily in the dorsal horn of the spinal cord. Although binding is reversible, careful dosing is required to ensure therapeutic effects while minimizing adverse effects, and ziconotide has been described as possessing a narrow therapeutic window. Patients taking ziconontide may experience cognitive and neuropsychiatric symptoms, reduced levels of consciousness, and elevated serum creatine kinase levels. In addition, ziconotide may increase the risk of infection, including serious cases of meningitis. Patients who withdraw from opiates for ziconotide initiation are advised to taper off the dose. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling and include the N-type (Cav2.2) heteromultimeric high-voltage type calcium channels. Chronic pain conditions, including inflammatory and neuropathic pain, often involve the aberrant upregulation of VGCC activity through various cellular mechanisms, which can lead to allodynia and hyperalgesia. Specifically, N-type channel activation in lightly myelinated Aδ- and C-fibres is known to mediate the release of neurotransmitters substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate, which influence downstream neural activation and pain perception. In addition, SP and CGRP induce inflammation, potentially exacerbating pre-existing inflammatory chronic pain. Ziconotide belongs to the ω-conotoxin class of neurotoxic peptides derived from the cone snail Conus magus which are capable of inhibiting N-type VGCCs. Although the exact mechanism is yet to be elucidated, it is thought that ω-conotoxins function through direct occlusion of the ion pore to prevent calcium translocation across the membrane. Additional studies involving expression of chimeric subunits and molecular modelling suggest that insertion of the ziconotide Met residue into a hydrophobic pocket formed by Ile, Phe, and Leu of Cav2.2 increases binding and may be associated with toxic adverse effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Ziconotide administered intrathecally over one hour in doses between 1 and 10 mcg produced calculated AUC values between 83.6-608 ng*h/mL and C max between 16.4-132 ng/mL; these values are approximately dose-proportional. Given the intrathecal administration and low membrane permeability due to its size, ziconotide is expected to remain primarily in the CSF; plasma levels, where detected, remain constant up to nine months following administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In patients administered 1-10 mcg intrathecal ziconotide over one hour, the apparent volume of distribution was calculated as 155 ± 263 mL; this value is roughly equivalent to the expected CSF volume. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an apparent volume of distribution of 30,460 ± 6366 mL. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Ziconotide is roughly 50% bound to human plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Ziconotide is expected to be processed by various peptidases upon entering systemic circulation; no detailed information on ziconotide metabolism has been reported. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): A small fraction of intravenous ziconotide (< 1%) is recovered in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): In patients administered 1-10 mcg intrathecal ziconotide over one hour, the elimination half-life was calculated as 4.6 ± 0.9 hr. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an elimination half-life of 1.3 ± 0.3 hr. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ziconotide CSF clearance is 0.38 ± 0.56 mL/min while plasma clearance is 270 ± 44 mL/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include neurological effects such as ataxia, nystagmus, stupor, sedation, speech difficulties, dizziness, nausea, and vomiting, and may also cause other effects such as hypotension; overdose is not associated with respiratory depression. In case of overdose, symptom-related supportive care up to and including hospitalization is recommended. Ziconotide has no known antidote, but the withdrawal of ziconotide generally allows patients to clear the drug and recover within 24 hours. As ziconotide does not bind to opiate receptors, opioid antagonists are not effective at ameliorating overdose effects. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Prialt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ziconotide is an N-type calcium channel antagonist used to manage patients with severe chronic pain who cannot tolerate, or who have not responded adequately to other treatments such as intrathecal morphine and systemic analgesics.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Ziconotide interact? Information: •Drug A: Bupropion •Drug B: Ziconotide •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Bupropion is combined with Ziconotide. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Ziconotide is indicated for the management of severe chronic pain in patients refractory to other treatments, and for whom intrathecal therapy is warranted. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ziconotide inhibits N-type calcium channels involved in nociceptive signalling, primarily in the dorsal horn of the spinal cord. Although binding is reversible, careful dosing is required to ensure therapeutic effects while minimizing adverse effects, and ziconotide has been described as possessing a narrow therapeutic window. Patients taking ziconontide may experience cognitive and neuropsychiatric symptoms, reduced levels of consciousness, and elevated serum creatine kinase levels. In addition, ziconotide may increase the risk of infection, including serious cases of meningitis. Patients who withdraw from opiates for ziconotide initiation are advised to taper off the dose. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling and include the N-type (Cav2.2) heteromultimeric high-voltage type calcium channels. Chronic pain conditions, including inflammatory and neuropathic pain, often involve the aberrant upregulation of VGCC activity through various cellular mechanisms, which can lead to allodynia and hyperalgesia. Specifically, N-type channel activation in lightly myelinated Aδ- and C-fibres is known to mediate the release of neurotransmitters substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate, which influence downstream neural activation and pain perception. In addition, SP and CGRP induce inflammation, potentially exacerbating pre-existing inflammatory chronic pain. Ziconotide belongs to the ω-conotoxin class of neurotoxic peptides derived from the cone snail Conus magus which are capable of inhibiting N-type VGCCs. Although the exact mechanism is yet to be elucidated, it is thought that ω-conotoxins function through direct occlusion of the ion pore to prevent calcium translocation across the membrane. Additional studies involving expression of chimeric subunits and molecular modelling suggest that insertion of the ziconotide Met residue into a hydrophobic pocket formed by Ile, Phe, and Leu of Cav2.2 increases binding and may be associated with toxic adverse effects. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Ziconotide administered intrathecally over one hour in doses between 1 and 10 mcg produced calculated AUC values between 83.6-608 ng*h/mL and C max between 16.4-132 ng/mL; these values are approximately dose-proportional. Given the intrathecal administration and low membrane permeability due to its size, ziconotide is expected to remain primarily in the CSF; plasma levels, where detected, remain constant up to nine months following administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In patients administered 1-10 mcg intrathecal ziconotide over one hour, the apparent volume of distribution was calculated as 155 ± 263 mL; this value is roughly equivalent to the expected CSF volume. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an apparent volume of distribution of 30,460 ± 6366 mL. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Ziconotide is roughly 50% bound to human plasma proteins. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Ziconotide is expected to be processed by various peptidases upon entering systemic circulation; no detailed information on ziconotide metabolism has been reported. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): A small fraction of intravenous ziconotide (< 1%) is recovered in urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): In patients administered 1-10 mcg intrathecal ziconotide over one hour, the elimination half-life was calculated as 4.6 ± 0.9 hr. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an elimination half-life of 1.3 ± 0.3 hr. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ziconotide CSF clearance is 0.38 ± 0.56 mL/min while plasma clearance is 270 ± 44 mL/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include neurological effects such as ataxia, nystagmus, stupor, sedation, speech difficulties, dizziness, nausea, and vomiting, and may also cause other effects such as hypotension; overdose is not associated with respiratory depression. In case of overdose, symptom-related supportive care up to and including hospitalization is recommended. Ziconotide has no known antidote, but the withdrawal of ziconotide generally allows patients to clear the drug and recover within 24 hours. As ziconotide does not bind to opiate receptors, opioid antagonists are not effective at ameliorating overdose effects. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Prialt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ziconotide is an N-type calcium channel antagonist used to manage patients with severe chronic pain who cannot tolerate, or who have not responded adequately to other treatments such as intrathecal morphine and systemic analgesics. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Zidovudine interact?

•Drug A: Bupropion •Drug B: Zidovudine •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Zidovudine. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used in combination with other antiretroviral agents for the treatment of human immunovirus (HIV) infections. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 30-38% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV. •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age] 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age] 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD 50 is 3084 mg/kg (orally in mice). •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Combivir, Retrovir, Trizivir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azidothymidine Zidovudina Zidovudine Zidovudinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zidovudine is a dideoxynucleoside used in the treatment of HIV infection.

Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Zidovudine interact? Information: •Drug A: Bupropion •Drug B: Zidovudine •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Zidovudine. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used in combination with other antiretroviral agents for the treatment of human immunovirus (HIV) infections. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 30-38% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT). •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV. •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age] 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age] 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD 50 is 3084 mg/kg (orally in mice). •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Combivir, Retrovir, Trizivir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azidothymidine Zidovudina Zidovudine Zidovudinum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zidovudine is a dideoxynucleoside used in the treatment of HIV infection. Output: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Does Bupropion and Zileuton interact?

•Drug A: Bupropion •Drug B: Zileuton •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Zileuton. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zileuton is an asthma drug that differs chemically and pharmacologically from other antiasthmatic agents. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Current data indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Due to the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5-lipoxygenase activity may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and almost completely absorbed. The absolute bioavailability is unknown. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.2 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 93% bound to plasma proteins, primarily to albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. The urinary excretion of the inactive N-dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent oral cl=7 mL/min/kg •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Minimum oral lethal dose of zileuton in various preparations was 500-4000 mg/kg in mice and 300-1000 mg/kg in rats (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively). •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zyflo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Leutrol Zileuton Zileutón Zileutonum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zileuton is a leukotriene synthesis inhibitor used in the prophylaxis and treatment of chronic asthma.

Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Question: Does Bupropion and Zileuton interact? Information: •Drug A: Bupropion •Drug B: Zileuton •Severity: MINOR •Description: The metabolism of Bupropion can be decreased when combined with Zileuton. •Extended Description: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zileuton is an asthma drug that differs chemically and pharmacologically from other antiasthmatic agents. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Current data indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Due to the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5-lipoxygenase activity may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly and almost completely absorbed. The absolute bioavailability is unknown. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.2 L/kg •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 93% bound to plasma proteins, primarily to albumin. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. The urinary excretion of the inactive N-dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose. •Half-life (Drug A): 24 hours •Half-life (Drug B): 2.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent oral cl=7 mL/min/kg •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Minimum oral lethal dose of zileuton in various preparations was 500-4000 mg/kg in mice and 300-1000 mg/kg in rats (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively). •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zyflo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Leutrol Zileuton Zileutón Zileutonum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zileuton is a leukotriene synthesis inhibitor used in the prophylaxis and treatment of chronic asthma. Output: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects. The severity of the interaction is minor.

Does Bupropion and Ziprasidone interact?

•Drug A: Bupropion •Drug B: Ziprasidone •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Ziprasidone. •Extended Description: Ziprasidone is associated with central nervous system (CNS) adverse effects such as drowsiness and dizziness; therefore, concomitant administration with other CNS depressants may exacerbate the associated adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): In its oral form, ziprasidone is approved for the treatment of schizophrenia, as monotherapy for acute treatment of manic or mixed episodes related to bipolar I disorder, and as adjunctive therapy to lithium or valproate for maintenance treatment of bipolar I disorder. The injectable formulation is approved only for treatment of acute agitation in schizophrenia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ziprasidone is classified as a "second generation" or "atypical" antipsychotic and is a dopamine and 5HT2A receptor antagonist with a unique receptor binding profile. As previously mentioned, ziprasidone has a very high 5-HT2A/D2 affinity ratio, binds to multiple serotonin receptors in addition to 5-HT2A, and blocks monoamine transporters which prevents 5HT and NE reuptake. On the other hand, ziprasidone has a low affinity for muscarinic cholinergic M1, histamine H1, and alpha1-adrenergic receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of ziprasidone are differentiated from other antispychotics based on its preference and affinity for certain receptors. Ziprasidone binds to serotonin-2A (5-HT2A) and dopamine D2 receptors in a similar fashion to other atypical antipsychotics; however, one key difference is that ziprasidone has a higher 5-HT2A/D2 receptor affinity ratio when compared to other antipsychotics such as olanzapine, quetiapine, risperidone, and aripiprazole. Ziprasidone offers enhanced modulation of mood, notable negative symptom relief, overall cognitive improvement and reduced motor dysfunction which is linked to it's potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in brain tissue. Ziprasidone can bind moderately to norepinephrine and serotonin reuptake sites which may contribute to its antidepressant and anxiolytic activity. Patient's taking ziprasidone will likely experience a lower incidence of orthostatic hypotension, cognitive disturbance, sedation, weight gain, and disruption in prolactin levels since ziprasidone has a lower affinity for histamine H1, muscarinic M1, and alpha1-adrenoceptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): In the absence of food, ziprasidone's oral bioavailability is 60%, and absorption may reach 100% if ziprasidone is taken with a meal containing at least 500 kcal. The difference in bioavailability has little to do with the fat content of the food and appears to be related to the bulk of the meal since more absorption occurs the longer ziprasidone remains in the stomach. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean apparent volume of distribution of Ziprasidone is 1.5 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Ziprasidone is extensively protein bound with over 99% of the drug bound to plasma proteins, primarily albumin and alpha1-acid glycoprotein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted unchanged in the urine. The primary reductive pathway is catalyzed by aldehyde oxidase, while 2 other less prominent oxidative pathways are catalyzed by CYP3A4. Ziprasidone is unlikely to interact with other medications metabolized by CYP3A4 since only 1/3 of the antipsychotic is metabolized by the CYP3A4 system. There are 12 identified ziprasidone metabolites (abbreviations italicized): Ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid ( OX-COOH ), OX-COOH glucuronide, 3-(piperazine-1-yl)-1,2-benzisothiazole ( BITP ), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-Methyl-dihydro-ziprasidone, S-Methyl-dihydro-ziprasidone-sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one ( OX-P ), and dihydro-ziprasidone-sulfone. As suggested by the quantity of metabolites, ziprasidone is metabolized through several different pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, and oxidative N-dealkylation of ziprasidone produces OX-COOH and BITP. OX-COOH undergoes phase II metabolism to yield a glucuronidated metabolite while BITP is sequentially oxidized into BITP sulfoxide, BITP sulfone, then BITP sulfone lactam. Ziprasidone can also undergo reductive cleavage and methylation to produce S-Methyl-dihydro-ziprasidone and then further oxidation to produce S-Methyl-dihydro-ziprasidone-sulfoxide. Finally dearylation of ziprasidone produces OX-P, and the process of hydration and oxidation transforms the parent drug into dihydro-ziprasidone-sulfone. Although CYP3A4 and aldehyde oxidase are the primary enzymes involved in ziprasidone metabolism, the pathways associated with each enzyme have not been specified. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half life of ziprasidone is 6-7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent systemic clearance is 7.5 mL/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The most common adverse reactions reported with ziprasidone include somnolence, respiratory tract infections, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting, headache and nausea. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Geodon, Zeldox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ziprasidone is an atypical antipsychotic used to manage schizophrenia, bipolar mania, and agitation in patients with schizophrenia.

Ziprasidone is associated with central nervous system (CNS) adverse effects such as drowsiness and dizziness; therefore, concomitant administration with other CNS depressants may exacerbate the associated adverse effects. The severity of the interaction is moderate.

Question: Does Bupropion and Ziprasidone interact? Information: •Drug A: Bupropion •Drug B: Ziprasidone •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Ziprasidone. •Extended Description: Ziprasidone is associated with central nervous system (CNS) adverse effects such as drowsiness and dizziness; therefore, concomitant administration with other CNS depressants may exacerbate the associated adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): In its oral form, ziprasidone is approved for the treatment of schizophrenia, as monotherapy for acute treatment of manic or mixed episodes related to bipolar I disorder, and as adjunctive therapy to lithium or valproate for maintenance treatment of bipolar I disorder. The injectable formulation is approved only for treatment of acute agitation in schizophrenia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Ziprasidone is classified as a "second generation" or "atypical" antipsychotic and is a dopamine and 5HT2A receptor antagonist with a unique receptor binding profile. As previously mentioned, ziprasidone has a very high 5-HT2A/D2 affinity ratio, binds to multiple serotonin receptors in addition to 5-HT2A, and blocks monoamine transporters which prevents 5HT and NE reuptake. On the other hand, ziprasidone has a low affinity for muscarinic cholinergic M1, histamine H1, and alpha1-adrenergic receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The effects of ziprasidone are differentiated from other antispychotics based on its preference and affinity for certain receptors. Ziprasidone binds to serotonin-2A (5-HT2A) and dopamine D2 receptors in a similar fashion to other atypical antipsychotics; however, one key difference is that ziprasidone has a higher 5-HT2A/D2 receptor affinity ratio when compared to other antipsychotics such as olanzapine, quetiapine, risperidone, and aripiprazole. Ziprasidone offers enhanced modulation of mood, notable negative symptom relief, overall cognitive improvement and reduced motor dysfunction which is linked to it's potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in brain tissue. Ziprasidone can bind moderately to norepinephrine and serotonin reuptake sites which may contribute to its antidepressant and anxiolytic activity. Patient's taking ziprasidone will likely experience a lower incidence of orthostatic hypotension, cognitive disturbance, sedation, weight gain, and disruption in prolactin levels since ziprasidone has a lower affinity for histamine H1, muscarinic M1, and alpha1-adrenoceptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): In the absence of food, ziprasidone's oral bioavailability is 60%, and absorption may reach 100% if ziprasidone is taken with a meal containing at least 500 kcal. The difference in bioavailability has little to do with the fat content of the food and appears to be related to the bulk of the meal since more absorption occurs the longer ziprasidone remains in the stomach. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean apparent volume of distribution of Ziprasidone is 1.5 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Ziprasidone is extensively protein bound with over 99% of the drug bound to plasma proteins, primarily albumin and alpha1-acid glycoprotein. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted unchanged in the urine. The primary reductive pathway is catalyzed by aldehyde oxidase, while 2 other less prominent oxidative pathways are catalyzed by CYP3A4. Ziprasidone is unlikely to interact with other medications metabolized by CYP3A4 since only 1/3 of the antipsychotic is metabolized by the CYP3A4 system. There are 12 identified ziprasidone metabolites (abbreviations italicized): Ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid ( OX-COOH ), OX-COOH glucuronide, 3-(piperazine-1-yl)-1,2-benzisothiazole ( BITP ), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-Methyl-dihydro-ziprasidone, S-Methyl-dihydro-ziprasidone-sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one ( OX-P ), and dihydro-ziprasidone-sulfone. As suggested by the quantity of metabolites, ziprasidone is metabolized through several different pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, and oxidative N-dealkylation of ziprasidone produces OX-COOH and BITP. OX-COOH undergoes phase II metabolism to yield a glucuronidated metabolite while BITP is sequentially oxidized into BITP sulfoxide, BITP sulfone, then BITP sulfone lactam. Ziprasidone can also undergo reductive cleavage and methylation to produce S-Methyl-dihydro-ziprasidone and then further oxidation to produce S-Methyl-dihydro-ziprasidone-sulfoxide. Finally dearylation of ziprasidone produces OX-P, and the process of hydration and oxidation transforms the parent drug into dihydro-ziprasidone-sulfone. Although CYP3A4 and aldehyde oxidase are the primary enzymes involved in ziprasidone metabolism, the pathways associated with each enzyme have not been specified. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug. •Half-life (Drug A): 24 hours •Half-life (Drug B): The half life of ziprasidone is 6-7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent systemic clearance is 7.5 mL/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): The most common adverse reactions reported with ziprasidone include somnolence, respiratory tract infections, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting, headache and nausea. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Geodon, Zeldox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Ziprasidone is an atypical antipsychotic used to manage schizophrenia, bipolar mania, and agitation in patients with schizophrenia. Output: Ziprasidone is associated with central nervous system (CNS) adverse effects such as drowsiness and dizziness; therefore, concomitant administration with other CNS depressants may exacerbate the associated adverse effects. The severity of the interaction is moderate.

Does Bupropion and Zolmitriptan interact?

•Drug A: Bupropion •Drug B: Zolmitriptan •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zolmitriptan is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zolmitriptan is indicated for the acute treatment of migraine with or without auras in patients aged 18 and over. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zolmitriptan, like other triptans, is a serotonin (5-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT 1B and 5-HT 1D receptor subtypes. It is through the downstream effects of 5-HT 1B/1D activation that triptans are proposed to provide acute relief of migraines. Zolmitriptan is also a vasoconstrictor, leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions. In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome. Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Migraines are complex physiological events characterized by unilateral throbbing headaches combined with photophobia and other aversions to sensory input. Migraine attacks are generally divided into phases: the premonitory phase, which typically involves irritability, fatigue, yawning, and stiff neck; the headache phase, which lasts for between four and 72 hours; and the postdrome phase, which lasts for up to a day following resolution of pain and whose symptoms are similar to those of the premonitory phase. In addition, neurological deficits, collectively termed migraine aura, may precede the headache phase. The underlying pathophysiology of migraines is a matter of active research but involves both neurological and vascular components. The head pain associated with migraine is thought to be a consequence of activation of the nociceptive nerves comprising the trigeminocervical complex (TCC). Terminals of nociceptive nerves that innervate the dura matter release vasoactive peptides, such as calcitonin gene-related peptide (CGRP), resulting in cranial vasodilation. Finally, when present, migraine aura appears to correlate with a transient wave(s) of cortical depolarization, termed cortical spreading depression (CSD). Triptans, including zolmitriptan, are proposed to act in three ways. The main mechanism is through modulation of nociceptive nerve signalling in the central nervous system through 5-HT 1B/1D receptors throughout the TCC and associated areas of the brain. In addition, triptans can enhance vasoconstriction, both through direct 5-HT 1B -mediated dilation of cranial blood vessels, as well as through 5-HT 1D -mediated suppression of CGRP release. Although triptans are classically described solely in terms of their effects on 5-HT 1B/1D receptors, they also act as 5-HT 1F agonists as well. This 5-HT subtype is also found throughout the TCC, but is not present appreciably in cerebral vasculature; the significance of triptan-mediated 5-HT 1F activation is currently not well described. Additionally, CSD that initiates in the ipsilateral parietal region may exert its effects in a manner that relies on 5-HT 1B/1D receptor activation, suggesting that triptans may have some effect on CSD-mediated symptoms. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Zolmitriptan tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. The dosing kinetics are linear over a range of 2.5 to 50 mg with 75% of the eventual C max being attained within 1 hour of dosing. The median T max for the tablet form is 1.5 hours, while for the orally disintegrating tablet form, it is 3 hours. The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the C max was between 16 and 25.2 ng/mL. Zolmitriptan administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa. The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery. The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Zolmitriptan has a volume of distribution between 7 and 8.4 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Zolmitriptan and its active N-desmethyl metabolite remain approximately 25% bound to plasma proteins over a concentration range of 10-1000 ng/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors like cimetidine suggest that it is likely metabolized by CYP1A2, as well as by monoamine oxidase (MAO). Zolmitriptan metabolism results in three major metabolites: an active N-desmethyl metabolite (183C91) as well as inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%). Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged. •Half-life (Drug A): 24 hours •Half-life (Drug B): Zolmitriptan has a mean elimination half-life of approximately three hours following oral or nasal administration. Its active N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life. •Clearance (Drug A): No clearance available •Clearance (Drug B): Zolmitriptan has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Toxicity information regarding zolmitriptan is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as cardiovascular symptoms due to excessive vasoconstriction and activation of serotonergic receptors. Patients receiving a single 50 mg oral dose of zolmitriptan often experienced sedation. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zomig •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zolmitriptan Zolmitriptán Zolmitriptanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zolmitriptan is a member of the triptan class of 5-HT(1B/1D/1F) receptor agonist drugs used for the acute treatment of migraine with or without aura in adults.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Zolmitriptan interact? Information: •Drug A: Bupropion •Drug B: Zolmitriptan •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zolmitriptan is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zolmitriptan is indicated for the acute treatment of migraine with or without auras in patients aged 18 and over. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zolmitriptan, like other triptans, is a serotonin (5-hydroxytryptamine; 5-HT) receptor agonist, with enhanced specificity for the 5-HT 1B and 5-HT 1D receptor subtypes. It is through the downstream effects of 5-HT 1B/1D activation that triptans are proposed to provide acute relief of migraines. Zolmitriptan is also a vasoconstrictor, leading to possible adverse cardiovascular effects such as myocardial ischemia/infarction, arrhythmias, cerebral and subarachnoid hemorrhage, stroke, gastrointestinal ischemia, and peripheral vasospastic reactions. In addition, chest/throat/neck/jaw pain, tightness, and/or pressure has been reported, along with the possibility of medication overuse headaches and serotonin syndrome. Patients with phenylketonuria should be advised that ZOMIG-ZMT contains phenylalanine. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Migraines are complex physiological events characterized by unilateral throbbing headaches combined with photophobia and other aversions to sensory input. Migraine attacks are generally divided into phases: the premonitory phase, which typically involves irritability, fatigue, yawning, and stiff neck; the headache phase, which lasts for between four and 72 hours; and the postdrome phase, which lasts for up to a day following resolution of pain and whose symptoms are similar to those of the premonitory phase. In addition, neurological deficits, collectively termed migraine aura, may precede the headache phase. The underlying pathophysiology of migraines is a matter of active research but involves both neurological and vascular components. The head pain associated with migraine is thought to be a consequence of activation of the nociceptive nerves comprising the trigeminocervical complex (TCC). Terminals of nociceptive nerves that innervate the dura matter release vasoactive peptides, such as calcitonin gene-related peptide (CGRP), resulting in cranial vasodilation. Finally, when present, migraine aura appears to correlate with a transient wave(s) of cortical depolarization, termed cortical spreading depression (CSD). Triptans, including zolmitriptan, are proposed to act in three ways. The main mechanism is through modulation of nociceptive nerve signalling in the central nervous system through 5-HT 1B/1D receptors throughout the TCC and associated areas of the brain. In addition, triptans can enhance vasoconstriction, both through direct 5-HT 1B -mediated dilation of cranial blood vessels, as well as through 5-HT 1D -mediated suppression of CGRP release. Although triptans are classically described solely in terms of their effects on 5-HT 1B/1D receptors, they also act as 5-HT 1F agonists as well. This 5-HT subtype is also found throughout the TCC, but is not present appreciably in cerebral vasculature; the significance of triptan-mediated 5-HT 1F activation is currently not well described. Additionally, CSD that initiates in the ipsilateral parietal region may exert its effects in a manner that relies on 5-HT 1B/1D receptor activation, suggesting that triptans may have some effect on CSD-mediated symptoms. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Zolmitriptan tablets have a mean absolute oral bioavailability of approximately 40%, with food having no effect on the rate or extent of absorption. The dosing kinetics are linear over a range of 2.5 to 50 mg with 75% of the eventual C max being attained within 1 hour of dosing. The median T max for the tablet form is 1.5 hours, while for the orally disintegrating tablet form, it is 3 hours. The AUC across studies was in the range of 84.4-173.8 ng/mL*h while the C max was between 16 and 25.2 ng/mL. Zolmitriptan administered as a nasal spray is detected in the plasma within 2-5 minutes, compared to 10-15 minutes for the tablet form; the faster kinetics likely reflect fast absorption across the nasal mucosa. The bioavailability compared to the tablet is 102%, and plasma zolmitriptan concentration is maintained for 4-6 hours after intranasal delivery. The active N-desmethyl metabolite of zolmitriptan has a mean plasma concentration that is roughly two-thirds of zolmitriptan, regardless of dosage route or concentration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Zolmitriptan has a volume of distribution between 7 and 8.4 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Zolmitriptan and its active N-desmethyl metabolite remain approximately 25% bound to plasma proteins over a concentration range of 10-1000 ng/mL. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zolmitriptan is metabolized in the liver, and studies using cytochrome P450 inhibitors like cimetidine suggest that it is likely metabolized by CYP1A2, as well as by monoamine oxidase (MAO). Zolmitriptan metabolism results in three major metabolites: an active N-desmethyl metabolite (183C91) as well as inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zolmitriptan is primarily excreted in urine (approximately 65%) and feces (approximately 30%). Within urine, the most common form is the indole acetic acid metabolite (31%), followed by the N-oxide (7%), and N-desmethyl (4%) metabolites; the majority of zolmitriptan recovered in feces remains unchanged. •Half-life (Drug A): 24 hours •Half-life (Drug B): Zolmitriptan has a mean elimination half-life of approximately three hours following oral or nasal administration. Its active N-desmethyl metabolite has a slightly longer (approximately 3.5 hours) half-life. •Clearance (Drug A): No clearance available •Clearance (Drug B): Zolmitriptan has a clearance of 31.5 mL/min/kg for oral tablets and 25.9 mL/min/kg for nasal administration; one-sixth of the clearance is renal. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Toxicity information regarding zolmitriptan is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as cardiovascular symptoms due to excessive vasoconstriction and activation of serotonergic receptors. Patients receiving a single 50 mg oral dose of zolmitriptan often experienced sedation. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zomig •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zolmitriptan Zolmitriptán Zolmitriptanum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zolmitriptan is a member of the triptan class of 5-HT(1B/1D/1F) receptor agonist drugs used for the acute treatment of migraine with or without aura in adults. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Zolpidem interact?

•Drug A: Bupropion •Drug B: Zolpidem •Severity: MODERATE •Description: Bupropion may increase the central nervous system depressant (CNS depressant) activities of Zolpidem. •Extended Description: Zolpidem is known to exert CNS depressant effects. Administering CNS depressants with zolpidem may lead to profound CNS depression due to additive effects , . In addition, “sleep-driving” and other complex behaviors may occur with zolpidem use while the patient is not fully awake. The risk of these behaviors increases with the use of other CNS depressants and alcohol . •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): This drug is indicated for the short-term treatment of insomnia in adults characterized by difficulties with sleep initiation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Effects on the central nervous system (CNS) This drug has CNS depressant effects, which may include somnolence, decreased alertness, sedation, drowsiness, dizziness, and other changes in psychomotor function. Due to the above effects, the FDA has recommended an initial dose of zolpidem (immediate-acting) is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. Refer to product labeling for detailed information,. Effects on memory Controlled studies in adults using objective measures of memory demonstrated no significant evidence of next-day memory impairment after the administration of zolpidem. On the contrary, in a clinical study involving the administration of zolpidem doses of 10 and 20 mg, a marked reduction in a next-morning recall of information relayed to subjects during peak drug effect (90 minutes after dosing) was observed. These subjects experienced a condition known as anterograde amnesia. Subjective evidence from adverse event data has suggested that anterograde amnesia may occur after zolpidem administration, mainly at doses above 10 mg. Effects on psychomotor function This drug may cause decreased psychomotor performance. Additive psychomotor effects may occur with other drugs that cause depression of psychomotor function, including alcohol. Patients taking zolpidem should be cautioned against participating in hazardous activities or occupations requiring complete mental alertness or motor coordination, including operating machinery or driving a motor vehicle after ingesting the drug. Potential impairment of the performance of the above types of activities may also occur the day after zolpidem ingestion, especially at higher doses and ingestion of the extended-release form,. Effects on insomnia and sleep stages Evidence suggests that this drug is associated with minimal rebound insomnia. During clinical trials with patients using zolpidem on an ‘as-needed’ basis, zolpidem use resulted in global improvements in sleep. Zolpidem has been demonstrated to decrease sleep latency (the time it takes to fall asleep) for up to 35 days in controlled clinical studies. In studies measuring the percentage of sleep time spent in each sleep stage, zolpidem has primarily been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was measured as similar to placebo with only minor and inconsistent changes in REM (paradoxical) sleep at the recommended dose. Next-day residual effects In 2013, the FDA issued a statement warning that patients who take zolpidem extended-release (Ambien CR)―either 6.25 mg or 12.5 mg―should not drive or participate in other activities requiring full mental alertness the day after taking the drug, due to the fact that zolpidem concentrations can remain increased the next day, and impair the ability to perform these activities,. Patients may decrease their risk of next-morning impairment by taking the lowest dose of their insomnia medicine that treats their symptoms, according to the FDA. Specific dosing recommendations for both men and women are included in this statement. This information is also available on product labeling,. Rebound effects There was no polysomnographic (objective) evidence of rebound insomnia at normal doses, in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate. Subjective evidence of impaired sleep in the elderly on the first post-treatment night was observed at doses higher than the recommended 5mg dose for elderly patients. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic substance with a chemical structure that is not related to the structure benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs exerting hypnotic effects. It interacts with a GABA-BZ receptor complex and shares various pharmacological properties with the benzodiazepine class of drugs. Subunit binding of the GABAA receptor chloride channel macromolecular complex is thought to lead to the sedative, anticonvulsant, anxiolytic, and myorelaxant drug effects of zolpidem. The main regulatory site of the GABAA receptor complex can be found on its alpha (α) subunit and is called the benzodiazepine (BZ) or omega (ω) receptor. At least three different subtypes of the (ω) receptor have been identified to this date. In contrast to benzodiazepine drugs, which are found to modulate all benzodiazepine receptor subtypes in a non-selective fashion, zolpidem binds the (BZ1) receptor specifically with a potent affinity for the alpha 1/alpha 5 subunits (in vitro). More recent studies suggest that zolpidem binds primarily to the alpha 1, 2, and 3 subunits of the GABA receptor,,, and not the alpha 5 subunit. The ( BZ1 ) receptor is found primarily on the Lamina IV of the brain sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. Specific and selective binding of zolpidem on the (BZ1) receptor is not considered absolute, however, this binding could potentially explain the relative lack of myorelaxant and anticonvulsant activity in animal studies in addition to the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Zolpidem is rapidly absorbed from the gastrointestinal tract. In a single-dose crossover study in 45 healthy subjects given 5 and 10 mg zolpidem tartrate tablets, the average peak zolpidem concentrations (Cmax) were 59 and 121 ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both doses. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.54 to 0.68 L/kg (in humans). In patients with long term renal insufficiency who were not yet on hemodialysis, the volume of distribution was found to increase significantly, AUC increased by 60%, and half-life nearly doubled. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 92.5 ± 0.1% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9,. Although zolpidem is heavily metabolized, all three metabolites are inactive. The major metabolic routes in humans are oxidation of the methyl group on the phenyl ring or the methyl group on the imidazopyridine moiety, to produce carboxylic acids (metabolites I and II), and hydroxylation of one of the imidazopyridine groups (to produce metabolite X). Another less common pathway is by the oxidation of the methyl groups on the substituted amide. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated mainly by renal excretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): The average zolpidem elimination half-life was 2.6 and 2.5 hours, for the 5 and 10 mg tablets, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): In a clinical trial, after a 20mg dose, total clearance of zolpidem 0.24 to 0.27 ml/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral (male rat) LD 50 = 695 mg/kg. Overdose Symptoms of overdose include impairment of consciousness ranging from somnolence to light coma, in addition to cardiorespiratory collapse resulting in fatal outcomes have been reported. Withdrawal effects Following rapid decreases in dose or abrupt discontinuation of zolpidem and other sedative/hypnotics, reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs have been made. Carcinogenesis Zolpidem was administered to rats and mice over a span of 2 years at dietary dosages of 4, 18, and 80 mg/kg/day. In mice, these doses are considered 26 to 520 times or 2 to 35 times the maximum 10 mg human dose, respectively. In rats, these doses are 43 to 876 times or 6 to 115 times the maximum 10 mg human dose. No evidence of carcinogenicity was seen in mice. Renal liposarcomas were observed in 4/100 rats (3 males, 1 female) receiving 80 mg/kg/day, and a renal lipoma was observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and liposarcoma for zolpidem were similar to those seen in historical control cases, and the tumor findings are presumed to be a spontaneous occurrence, not causally related to zolpidem. Mutagenesis Zolpidem did not show mutagenic activity in several tests including the Ames test, genotoxicity in mouse lymphoma cells in vitro, chromosomal aberrations in cultured human lymphocytes, abnormal DNA synthesis in rat hepatocytes in vitro, and the micronucleus test performed in mice. Impairment of fertility In a rat reproduction study, the high dose (100 mg base/kg) of zolpidem lead to irregular estrus cycles and prolonged precoital intervals, however, there was no effect on male or female fertility after daily oral doses comparable to 5 to 130 times the recommended human dose. No effects on any other fertility parameters were observed. Use in pregnancy This drug is considered a pregnancy category C drug. There are currently no sufficient conclusive studies completed in pregnant women to determine the safety of zolpidem use during pregnancy. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Use in nursing From 0.004% to 0.019% of the total administered zolpidem dose is excreted into milk. The effect of zolpidem on the nursing infant is unknown at this time. Caution should be observed when zolpidem is administered to a nursing mother. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Ambien, Edluar, Intermezzo, Tovalt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zolpidem Zolpidemum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zolpidem is a sedative hypnotic used for the short-term treatment of insomnia to improve sleep latency.

Zolpidem is known to exert CNS depressant effects. Administering CNS depressants with zolpidem may lead to profound CNS depression due to additive effects , . In addition, “sleep-driving” and other complex behaviors may occur with zolpidem use while the patient is not fully awake. The risk of these behaviors increases with the use of other CNS depressants and alcohol . The severity of the interaction is moderate.

Question: Does Bupropion and Zolpidem interact? Information: •Drug A: Bupropion •Drug B: Zolpidem •Severity: MODERATE •Description: Bupropion may increase the central nervous system depressant (CNS depressant) activities of Zolpidem. •Extended Description: Zolpidem is known to exert CNS depressant effects. Administering CNS depressants with zolpidem may lead to profound CNS depression due to additive effects , . In addition, “sleep-driving” and other complex behaviors may occur with zolpidem use while the patient is not fully awake. The risk of these behaviors increases with the use of other CNS depressants and alcohol . •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): This drug is indicated for the short-term treatment of insomnia in adults characterized by difficulties with sleep initiation. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Effects on the central nervous system (CNS) This drug has CNS depressant effects, which may include somnolence, decreased alertness, sedation, drowsiness, dizziness, and other changes in psychomotor function. Due to the above effects, the FDA has recommended an initial dose of zolpidem (immediate-acting) is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. Refer to product labeling for detailed information,. Effects on memory Controlled studies in adults using objective measures of memory demonstrated no significant evidence of next-day memory impairment after the administration of zolpidem. On the contrary, in a clinical study involving the administration of zolpidem doses of 10 and 20 mg, a marked reduction in a next-morning recall of information relayed to subjects during peak drug effect (90 minutes after dosing) was observed. These subjects experienced a condition known as anterograde amnesia. Subjective evidence from adverse event data has suggested that anterograde amnesia may occur after zolpidem administration, mainly at doses above 10 mg. Effects on psychomotor function This drug may cause decreased psychomotor performance. Additive psychomotor effects may occur with other drugs that cause depression of psychomotor function, including alcohol. Patients taking zolpidem should be cautioned against participating in hazardous activities or occupations requiring complete mental alertness or motor coordination, including operating machinery or driving a motor vehicle after ingesting the drug. Potential impairment of the performance of the above types of activities may also occur the day after zolpidem ingestion, especially at higher doses and ingestion of the extended-release form,. Effects on insomnia and sleep stages Evidence suggests that this drug is associated with minimal rebound insomnia. During clinical trials with patients using zolpidem on an ‘as-needed’ basis, zolpidem use resulted in global improvements in sleep. Zolpidem has been demonstrated to decrease sleep latency (the time it takes to fall asleep) for up to 35 days in controlled clinical studies. In studies measuring the percentage of sleep time spent in each sleep stage, zolpidem has primarily been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was measured as similar to placebo with only minor and inconsistent changes in REM (paradoxical) sleep at the recommended dose. Next-day residual effects In 2013, the FDA issued a statement warning that patients who take zolpidem extended-release (Ambien CR)―either 6.25 mg or 12.5 mg―should not drive or participate in other activities requiring full mental alertness the day after taking the drug, due to the fact that zolpidem concentrations can remain increased the next day, and impair the ability to perform these activities,. Patients may decrease their risk of next-morning impairment by taking the lowest dose of their insomnia medicine that treats their symptoms, according to the FDA. Specific dosing recommendations for both men and women are included in this statement. This information is also available on product labeling,. Rebound effects There was no polysomnographic (objective) evidence of rebound insomnia at normal doses, in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate. Subjective evidence of impaired sleep in the elderly on the first post-treatment night was observed at doses higher than the recommended 5mg dose for elderly patients. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic substance with a chemical structure that is not related to the structure benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs exerting hypnotic effects. It interacts with a GABA-BZ receptor complex and shares various pharmacological properties with the benzodiazepine class of drugs. Subunit binding of the GABAA receptor chloride channel macromolecular complex is thought to lead to the sedative, anticonvulsant, anxiolytic, and myorelaxant drug effects of zolpidem. The main regulatory site of the GABAA receptor complex can be found on its alpha (α) subunit and is called the benzodiazepine (BZ) or omega (ω) receptor. At least three different subtypes of the (ω) receptor have been identified to this date. In contrast to benzodiazepine drugs, which are found to modulate all benzodiazepine receptor subtypes in a non-selective fashion, zolpidem binds the (BZ1) receptor specifically with a potent affinity for the alpha 1/alpha 5 subunits (in vitro). More recent studies suggest that zolpidem binds primarily to the alpha 1, 2, and 3 subunits of the GABA receptor,,, and not the alpha 5 subunit. The ( BZ1 ) receptor is found primarily on the Lamina IV of the brain sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. Specific and selective binding of zolpidem on the (BZ1) receptor is not considered absolute, however, this binding could potentially explain the relative lack of myorelaxant and anticonvulsant activity in animal studies in addition to the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Zolpidem is rapidly absorbed from the gastrointestinal tract. In a single-dose crossover study in 45 healthy subjects given 5 and 10 mg zolpidem tartrate tablets, the average peak zolpidem concentrations (Cmax) were 59 and 121 ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both doses. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.54 to 0.68 L/kg (in humans). In patients with long term renal insufficiency who were not yet on hemodialysis, the volume of distribution was found to increase significantly, AUC increased by 60%, and half-life nearly doubled. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 92.5 ± 0.1% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9,. Although zolpidem is heavily metabolized, all three metabolites are inactive. The major metabolic routes in humans are oxidation of the methyl group on the phenyl ring or the methyl group on the imidazopyridine moiety, to produce carboxylic acids (metabolites I and II), and hydroxylation of one of the imidazopyridine groups (to produce metabolite X). Another less common pathway is by the oxidation of the methyl groups on the substituted amide. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated mainly by renal excretion. •Half-life (Drug A): 24 hours •Half-life (Drug B): The average zolpidem elimination half-life was 2.6 and 2.5 hours, for the 5 and 10 mg tablets, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): In a clinical trial, after a 20mg dose, total clearance of zolpidem 0.24 to 0.27 ml/min/kg. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Oral (male rat) LD 50 = 695 mg/kg. Overdose Symptoms of overdose include impairment of consciousness ranging from somnolence to light coma, in addition to cardiorespiratory collapse resulting in fatal outcomes have been reported. Withdrawal effects Following rapid decreases in dose or abrupt discontinuation of zolpidem and other sedative/hypnotics, reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs have been made. Carcinogenesis Zolpidem was administered to rats and mice over a span of 2 years at dietary dosages of 4, 18, and 80 mg/kg/day. In mice, these doses are considered 26 to 520 times or 2 to 35 times the maximum 10 mg human dose, respectively. In rats, these doses are 43 to 876 times or 6 to 115 times the maximum 10 mg human dose. No evidence of carcinogenicity was seen in mice. Renal liposarcomas were observed in 4/100 rats (3 males, 1 female) receiving 80 mg/kg/day, and a renal lipoma was observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and liposarcoma for zolpidem were similar to those seen in historical control cases, and the tumor findings are presumed to be a spontaneous occurrence, not causally related to zolpidem. Mutagenesis Zolpidem did not show mutagenic activity in several tests including the Ames test, genotoxicity in mouse lymphoma cells in vitro, chromosomal aberrations in cultured human lymphocytes, abnormal DNA synthesis in rat hepatocytes in vitro, and the micronucleus test performed in mice. Impairment of fertility In a rat reproduction study, the high dose (100 mg base/kg) of zolpidem lead to irregular estrus cycles and prolonged precoital intervals, however, there was no effect on male or female fertility after daily oral doses comparable to 5 to 130 times the recommended human dose. No effects on any other fertility parameters were observed. Use in pregnancy This drug is considered a pregnancy category C drug. There are currently no sufficient conclusive studies completed in pregnant women to determine the safety of zolpidem use during pregnancy. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Use in nursing From 0.004% to 0.019% of the total administered zolpidem dose is excreted into milk. The effect of zolpidem on the nursing infant is unknown at this time. Caution should be observed when zolpidem is administered to a nursing mother. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Ambien, Edluar, Intermezzo, Tovalt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zolpidem Zolpidemum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zolpidem is a sedative hypnotic used for the short-term treatment of insomnia to improve sleep latency. Output: Zolpidem is known to exert CNS depressant effects. Administering CNS depressants with zolpidem may lead to profound CNS depression due to additive effects , . In addition, “sleep-driving” and other complex behaviors may occur with zolpidem use while the patient is not fully awake. The risk of these behaviors increases with the use of other CNS depressants and alcohol . The severity of the interaction is moderate.

Does Bupropion and Zonisamide interact?

•Drug A: Bupropion •Drug B: Zonisamide •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zonisamide is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zonisamide capsules are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. Zonisamide oral suspension is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): By stopping the spread of seizure discharges, zonisamide prevents the extensor component of tonic convulsion, restricts the spread of focal seizures and prevents the propagation of seizures from the cortex to subcortical structures. In animal models, zonisamide was effective against tonic extension seizures but ineffective against clonic seizures. It also increased the threshold for generalized seizures and reduced the duration of cortical focal seizures. Aside from its antiepileptic effects, zonisamide is capable of activating neuroprotective mechanisms. It inhibits nitric oxide synthase and ​​reduces ischemia-induced memory impairment and lipid peroxidation. The use of zonisamide may lead to potentially fatal reactions. Severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia have been reported in patients treated with sulfonamides such as zonisamide. Zonisamide may also lead to the development of serious hematological events, drug reaction with eosinophilia and systemic symptoms (DRESS) and multi-organ hypersensitivity, acute myopia and secondary angle closure glaucoma, as well as suicidal behaviour and ideation. Zonisamide is a carbonic anhydrase inhibitor, which may lead to metabolic acidosis in patients treated with this drug. Its therapeutic effects due to this pharmacological action are unknown. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action by which zonisamide controls seizures has not been fully established. However, its antiepileptic properties may be due to its effects on sodium and calcium channels. Zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents, stabilizing neuronal membranes and suppressing neuronal hypersynchronization. It affects T-type calcium currents, but has no effect on L-type calcium currents. Zonisamide suppresses synaptically-driven electrical activity by altering the synthesis, release, and degradation of neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptamine 5-HT ), and acetylcholine. Furthermore, it binds to the GABA/benzodiazepine receptor ionophore complex without producing changes in chloride flux. In vitro studies have suggested that zonisamide does not affect postsynaptic GABA or glutamate responses, nor the neuronal or glial uptake of [ H]-GABA. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Between 200 and 400 mg, zonisamide follows a dose-proportional pharmacokinetic profile. At concentrations higher than 800 mg, the C max and AUC increase in a disproportional manner, possibly due to zonisamide binding red blood cells. In healthy volunteers given 200 to 400 mg of zonisamide orally, peak plasma concentrations (C max ) range between 2 and 5 µg/mL and are reached within 2–6 hours (T max ). In healthy volunteers given 100 mg of zonisamide oral suspension, the T max ranged from 0.5 to 5 hours. Zonisamide has a high oral bioavailability (95%). The T max of zonisamide was delayed by food intake (4-6 hours); however, food has no effect on its bioavailability. Steady state is achieved 14 days after a stable dose is reached. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following a 400 mg oral dose, zonisamide has an apparent volume of distribution (V/F) of 1.45 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): At concentrations between 1.0 and 7.0 μg/mL, zonisamide is approximately 40% bound to human plasma proteins. The concentration of zonisamide is 8-fold higher in red blood cells than in plasma due to its ability to bind extensively to erythrocytes. The presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine does not affect zonisamide protein binding. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zonisamide metabolites are generated mainly by principally reductive and conjugative mechanisms. Oxidation reactions play a minor role in the metabolism of zonisamide. Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and reduced to form the open ring metabolite, 2–sulfamoylacetylphenol (SMAP). The reduction of zonisamide to SMAP is mediated by CYP3A4. Zonisamide does not induce liver enzymes or its own metabolism. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zonisamide is mainly excreted as the parent drug and the glucuronide of a metabolite. Urine is the main route of zonisamide excretion, and only a small portion of this drug is excreted in feces. Following multiple doses of radiolabeled zonisamide, 62% of the dose was recovered in the urine, and 3% in feces by day 10. Of the excreted dose of zonisamide, 35% was recovered unchanged, 15% as N-acetyl zonisamide, and 50% as the glucuronide of 2–sulfamoylacetylphenol (SMAP). •Half-life (Drug A): 24 hours •Half-life (Drug B): In plasma, the elimination half-life of zonisamide is approximately 63 hours. In red blood cells, it is approximately 105 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients not taking enzyme-inducing antiepilepsy drugs (AEDs), the plasma clearance of oral zonisamide is approximately 0.30-0.35 mL/min/kg. In patients treated with AEDs, this value increases to 0.5 mL/min/kg. Renal clearance is approximately 3.5 mL/min after a single-dose of zonisamide. In red blood cells, the clearance of an oral dose of zonisamide is 2 mL/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Information on daily doses over 800 mg/day of zonisamide is limited. During clinical development, three patients ingested unknown amounts of zonisamide as suicide attempts, and all of them were hospitalized with central nervous system symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; 31 hours after zonisamide ingestion, plasma level was 100.1 µg/mL. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later. There are no specific antidotes for zonisamide overdosage. In case of a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. Due to its long half-life and low protein binding, renal dialysis may be effective in treating zonisamide overdose; however, the effectiveness of this procedure has not been formally studied. In vivo studies found no evidence of carcinogenicity at zonisamide doses equivalent to or higher than the maximum recommended human dose (MRHD). In an in vitro chromosomal aberration assay in CHL cells, zonisamide displayed mutagenicity. Signs of reproductive toxicity were also detected in rats treated with a dose 0.5 times the MRHD. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zonegran, Zonisade •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zonisamida Zonisamide Zonisamidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zonisamide is a sulfonamide anticonvulsant used to treat partial seizures.

Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Question: Does Bupropion and Zonisamide interact? Information: •Drug A: Bupropion •Drug B: Zonisamide •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zonisamide is combined with Bupropion. •Extended Description: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zonisamide capsules are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. Zonisamide oral suspension is indicated as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): By stopping the spread of seizure discharges, zonisamide prevents the extensor component of tonic convulsion, restricts the spread of focal seizures and prevents the propagation of seizures from the cortex to subcortical structures. In animal models, zonisamide was effective against tonic extension seizures but ineffective against clonic seizures. It also increased the threshold for generalized seizures and reduced the duration of cortical focal seizures. Aside from its antiepileptic effects, zonisamide is capable of activating neuroprotective mechanisms. It inhibits nitric oxide synthase and ​​reduces ischemia-induced memory impairment and lipid peroxidation. The use of zonisamide may lead to potentially fatal reactions. Severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia have been reported in patients treated with sulfonamides such as zonisamide. Zonisamide may also lead to the development of serious hematological events, drug reaction with eosinophilia and systemic symptoms (DRESS) and multi-organ hypersensitivity, acute myopia and secondary angle closure glaucoma, as well as suicidal behaviour and ideation. Zonisamide is a carbonic anhydrase inhibitor, which may lead to metabolic acidosis in patients treated with this drug. Its therapeutic effects due to this pharmacological action are unknown. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action by which zonisamide controls seizures has not been fully established. However, its antiepileptic properties may be due to its effects on sodium and calcium channels. Zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents, stabilizing neuronal membranes and suppressing neuronal hypersynchronization. It affects T-type calcium currents, but has no effect on L-type calcium currents. Zonisamide suppresses synaptically-driven electrical activity by altering the synthesis, release, and degradation of neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptamine 5-HT ), and acetylcholine. Furthermore, it binds to the GABA/benzodiazepine receptor ionophore complex without producing changes in chloride flux. In vitro studies have suggested that zonisamide does not affect postsynaptic GABA or glutamate responses, nor the neuronal or glial uptake of [ H]-GABA. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Between 200 and 400 mg, zonisamide follows a dose-proportional pharmacokinetic profile. At concentrations higher than 800 mg, the C max and AUC increase in a disproportional manner, possibly due to zonisamide binding red blood cells. In healthy volunteers given 200 to 400 mg of zonisamide orally, peak plasma concentrations (C max ) range between 2 and 5 µg/mL and are reached within 2–6 hours (T max ). In healthy volunteers given 100 mg of zonisamide oral suspension, the T max ranged from 0.5 to 5 hours. Zonisamide has a high oral bioavailability (95%). The T max of zonisamide was delayed by food intake (4-6 hours); however, food has no effect on its bioavailability. Steady state is achieved 14 days after a stable dose is reached. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following a 400 mg oral dose, zonisamide has an apparent volume of distribution (V/F) of 1.45 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): At concentrations between 1.0 and 7.0 μg/mL, zonisamide is approximately 40% bound to human plasma proteins. The concentration of zonisamide is 8-fold higher in red blood cells than in plasma due to its ability to bind extensively to erythrocytes. The presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine does not affect zonisamide protein binding. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zonisamide metabolites are generated mainly by principally reductive and conjugative mechanisms. Oxidation reactions play a minor role in the metabolism of zonisamide. Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and reduced to form the open ring metabolite, 2–sulfamoylacetylphenol (SMAP). The reduction of zonisamide to SMAP is mediated by CYP3A4. Zonisamide does not induce liver enzymes or its own metabolism. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Zonisamide is mainly excreted as the parent drug and the glucuronide of a metabolite. Urine is the main route of zonisamide excretion, and only a small portion of this drug is excreted in feces. Following multiple doses of radiolabeled zonisamide, 62% of the dose was recovered in the urine, and 3% in feces by day 10. Of the excreted dose of zonisamide, 35% was recovered unchanged, 15% as N-acetyl zonisamide, and 50% as the glucuronide of 2–sulfamoylacetylphenol (SMAP). •Half-life (Drug A): 24 hours •Half-life (Drug B): In plasma, the elimination half-life of zonisamide is approximately 63 hours. In red blood cells, it is approximately 105 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients not taking enzyme-inducing antiepilepsy drugs (AEDs), the plasma clearance of oral zonisamide is approximately 0.30-0.35 mL/min/kg. In patients treated with AEDs, this value increases to 0.5 mL/min/kg. Renal clearance is approximately 3.5 mL/min after a single-dose of zonisamide. In red blood cells, the clearance of an oral dose of zonisamide is 2 mL/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Information on daily doses over 800 mg/day of zonisamide is limited. During clinical development, three patients ingested unknown amounts of zonisamide as suicide attempts, and all of them were hospitalized with central nervous system symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; 31 hours after zonisamide ingestion, plasma level was 100.1 µg/mL. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later. There are no specific antidotes for zonisamide overdosage. In case of a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. Due to its long half-life and low protein binding, renal dialysis may be effective in treating zonisamide overdose; however, the effectiveness of this procedure has not been formally studied. In vivo studies found no evidence of carcinogenicity at zonisamide doses equivalent to or higher than the maximum recommended human dose (MRHD). In an in vitro chromosomal aberration assay in CHL cells, zonisamide displayed mutagenicity. Signs of reproductive toxicity were also detected in rats treated with a dose 0.5 times the MRHD. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zonegran, Zonisade •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zonisamida Zonisamide Zonisamidum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zonisamide is a sulfonamide anticonvulsant used to treat partial seizures. Output: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death.2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. The severity of the interaction is moderate.

Does Bupropion and Zopiclone interact?

•Drug A: Bupropion •Drug B: Zopiclone •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Zopiclone. •Extended Description: The co-administration of ethanol with zopiclone increased the risk of adverse effects such as complex sleep behaviors (sleep driving, eating food, making phone calls, leaving the house), and also increases the CNS depressant effects of zopiclone. This may result in profound sedation or respiratory depression. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the short-term treatment of insomnia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zopiclone is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA B Z) receptor complex. Subunit modulation of the GABA B Z receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zopiclone binds selectively to the brain alpha subunit of the GABA A omega-1 receptor. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABA B Z receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 45% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agent. Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Imovane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zopiclona Zopiclone Zopiclonum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zopiclone is a nonbenzodiazepine hypnotic used for the short-term management of insomnia.

The co-administration of ethanol with zopiclone increased the risk of adverse effects such as complex sleep behaviors (sleep driving, eating food, making phone calls, leaving the house), and also increases the CNS depressant effects of zopiclone. This may result in profound sedation or respiratory depression. The severity of the interaction is moderate.

Question: Does Bupropion and Zopiclone interact? Information: •Drug A: Bupropion •Drug B: Zopiclone •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Bupropion is combined with Zopiclone. •Extended Description: The co-administration of ethanol with zopiclone increased the risk of adverse effects such as complex sleep behaviors (sleep driving, eating food, making phone calls, leaving the house), and also increases the CNS depressant effects of zopiclone. This may result in profound sedation or respiratory depression. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): For the short-term treatment of insomnia. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zopiclone is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA B Z) receptor complex. Subunit modulation of the GABA B Z receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zopiclone binds selectively to the brain alpha subunit of the GABA A omega-1 receptor. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABA B Z receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): Approximately 45% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 24 hours •Half-life (Drug B): Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agent. Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Imovane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zopiclona Zopiclone Zopiclonum •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zopiclone is a nonbenzodiazepine hypnotic used for the short-term management of insomnia. Output: The co-administration of ethanol with zopiclone increased the risk of adverse effects such as complex sleep behaviors (sleep driving, eating food, making phone calls, leaving the house), and also increases the CNS depressant effects of zopiclone. This may result in profound sedation or respiratory depression. The severity of the interaction is moderate.

Does Bupropion and Zuclopenthixol interact?

•Drug A: Bupropion •Drug B: Zuclopenthixol •Severity: MAJOR •Description: The metabolism of Zuclopenthixol can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used in the management of acute psychoses such as mania or schizophrenia. However, the use of zuclopenthixol acetate in psychiatric emergencies as an alternative to standard treatments (haloperidol, clotiapine, etc.) should be cautioned, since well executed and documented trials of zuclopenthixol acetate for this use have yet to be conducted. Zuclopenthixol acetate is not intended for long-term use. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zuclopenthixol is a thioxanthene with therapeutic actions similar to the phenothiazine antipsychotics. It is an antagonist at D1 and D2 dopamine receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zuclopenthixol is a typical antipsychotic neuroleptic drug of the thioxanthene class. It mainly acts by antagonism of D1 and D2 dopamine receptors. Zuclopenthixol also has high affinity for alpha1-adrenergic and 5-HT2 receptors. It has weaker histamine H1 receptor blocking activity, and even lower affinity for muscarinic cholinergic and alpha2-adrenergic receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Upon reaching the body water phase, the decanoate ester is slowly released from the oil depot, which is resultantly hydrolyzed to the active substance, zuclopenthixol. The decanoate ester provides a means of slow release since zuclopenthixol itself is a short-acting drug. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 20 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 98-99% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The metabolism of zuclopenthixol is mainly by sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of pharmacological activity. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Primarily in the feces with approximately 10% in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): 20 hours (range 12-28 hours) for the tablet form, 19 days for the depot form. •Clearance (Drug A): No clearance available •Clearance (Drug B): approximately 0.9 L/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Although there have not been any cases of overdosage reported, the symptoms are likely to be somnolence, coma, extrapyramidal symptoms, convulsions, hypotension, shock, or hyper- or hypothermia. Neuroleptic malignant syndrome may occur. Zuclopenthixol may potentiate anticholinergic effects of concurrent medications. Zuclopenthixol has a demonstrated antiemetic effect in animals, and may mask signs of toxicity due to other drug overdoses, or may mask symptoms of disease. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Clopixol, Clopixol Acuphase, Clopixol Depot •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zuclopenthixol Zuclopenthixolum Zuclopentixol •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zuclopenthixol is an antipsychotic indicated for the management of schizophrenia. The acuphase formulation is indicated for initial treatment of acute psychosis or exacerbation of psychosis, while the depot formulation is best for maintenance.

The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Question: Does Bupropion and Zuclopenthixol interact? Information: •Drug A: Bupropion •Drug B: Zuclopenthixol •Severity: MAJOR •Description: The metabolism of Zuclopenthixol can be decreased when combined with Bupropion. •Extended Description: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Used in the management of acute psychoses such as mania or schizophrenia. However, the use of zuclopenthixol acetate in psychiatric emergencies as an alternative to standard treatments (haloperidol, clotiapine, etc.) should be cautioned, since well executed and documented trials of zuclopenthixol acetate for this use have yet to be conducted. Zuclopenthixol acetate is not intended for long-term use. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): Zuclopenthixol is a thioxanthene with therapeutic actions similar to the phenothiazine antipsychotics. It is an antagonist at D1 and D2 dopamine receptors. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): Zuclopenthixol is a typical antipsychotic neuroleptic drug of the thioxanthene class. It mainly acts by antagonism of D1 and D2 dopamine receptors. Zuclopenthixol also has high affinity for alpha1-adrenergic and 5-HT2 receptors. It has weaker histamine H1 receptor blocking activity, and even lower affinity for muscarinic cholinergic and alpha2-adrenergic receptors. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Upon reaching the body water phase, the decanoate ester is slowly released from the oil depot, which is resultantly hydrolyzed to the active substance, zuclopenthixol. The decanoate ester provides a means of slow release since zuclopenthixol itself is a short-acting drug. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 20 L/kg. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): 98-99% •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): The metabolism of zuclopenthixol is mainly by sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of pharmacological activity. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Primarily in the feces with approximately 10% in the urine. •Half-life (Drug A): 24 hours •Half-life (Drug B): 20 hours (range 12-28 hours) for the tablet form, 19 days for the depot form. •Clearance (Drug A): No clearance available •Clearance (Drug B): approximately 0.9 L/min. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Although there have not been any cases of overdosage reported, the symptoms are likely to be somnolence, coma, extrapyramidal symptoms, convulsions, hypotension, shock, or hyper- or hypothermia. Neuroleptic malignant syndrome may occur. Zuclopenthixol may potentiate anticholinergic effects of concurrent medications. Zuclopenthixol has a demonstrated antiemetic effect in animals, and may mask signs of toxicity due to other drug overdoses, or may mask symptoms of disease. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Clopixol, Clopixol Acuphase, Clopixol Depot •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Zuclopenthixol Zuclopenthixolum Zuclopentixol •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zuclopenthixol is an antipsychotic indicated for the management of schizophrenia. The acuphase formulation is indicated for initial treatment of acute psychosis or exacerbation of psychosis, while the depot formulation is best for maintenance. Output: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. The severity of the interaction is major.

Does Bupropion and Zuranolone interact?

•Drug A: Bupropion •Drug B: Zuranolone •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zuranolone is combined with Bupropion. •Extended Description: Since zuranolone is a GABAA positive allosteric modulator, it can enhance inhibitory conductance in the nervous system. Therefore, the co-administration of zuranolone with another central nervous system depressant can exacerbate nervous system depression, leading to impairment of psychomotor performance or other CNS depression-associated side effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zuranolone is indicated for the treatment of postpartum depression (PPD) in adults. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): At two times the maximum recommended dose, zuranolone does not cause clinically significant QTc interval prolongation. Co-administration of repeated 50 mg daily doses of zuranolone with alcohol or alprazolam led to impairment in psychomotor performance. Zuranolone exhibited an EC 50 of 430 nM and 118 nM at the α1β2γ2 and α4β3δ GABA A receptors respectively, the two most abundant synaptic and extrasynaptic receptors in the brain. Therefore, zuranolone can potentiate both phasic and tonic postsynaptic currents associated with modulation of the synaptic and extrasynaptic GABA A receptors respectively. Since tonic current can produce a larger inhibitory effect compared to phasic current, the ability of zuranolone to modulate the tonic current provides a greater opportunity to enhance GABA conductance. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of zuranolone in the treatment of PPD is not fully understood but is thought to be related to its positive allosteric modulation of GABA A receptors. Unlike benzodiazepines, another class of GABA A positive modulators, zuranolone binds to the α/β subunit interface presented in all GABA A receptors instead of the α/γ subunit interface. Therefore, zuranolone can bind to both synaptic GABA A receptors, composed of 2α2βγ subunits, and extrasynaptic GABA A receptors, composed of 2α2βδ subunits. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (T max ). The absolute bioavailability of zuranolone was not evaluated. Zuranolone exposure (C max and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times the recommended dosage of zuranolone) with a moderate-fat meal (700 calories; 30% fat). Once-daily administration of Zuranolone resulted in an accumulation of approximately 1.5-fold in systemic exposures and a steady state was achieved in 3 to 5 days. Following administration of 30 mg of zuranolone to healthy subjects, the C max increased by approximately 3.5-fold, and the AUC last increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The C max increased by approximately 4.3-fold and the AUC last increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions. The T max was not impacted by food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of zuranolone following oral administration is greater than 500 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58. Plasma protein binding is greater than 99.5%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in the adult population. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance (CL/F) of zuranolone is 33 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Based on findings from animal studies, zuranolone may cause fetal harm. Advise pregnant women of the potential risk to a fetus. Available data on zuranolone use in pregnant women from the clinical development program are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animals, oral administration of zuranolone to pregnant rats during organogenesis resulted in developmental toxicity, including embryofetal death and fetal malformations, with a no adverse effect level (NOAEL) associated with maternal plasma exposures 7 times greater than in humans at the maximum recommended human dose (MRHD) of 50 mg. Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including, perinatal mortality, at maternal exposures similar to that in humans at the MRHD. Developmental toxicity was observed at doses that were also maternally toxic. Neuronal death was observed in rats exposed to zuranolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth. Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction. Abuse is the intentional non-therapeutic use of a drug, even once, for its desired psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Individuals with a history of drug abuse or substance use disorders may be at a greater risk of these outcomes with zuranolone. In a human abuse potential study, single oral doses of 30 mg, 60 mg, and 90 mg of zuranolone (0.6 times, 1.2 times, and 1.8 times the recommended daily dose, respectively) were compared to single oral doses of alprazolam (1.5 mg and 3 mg) and placebo in healthy, non-dependent individuals with a history of recreational CNS depressant use. The study demonstrated that zuranolone has dose-dependent abuse potential comparable to alprazolam and greater abuse potential than placebo on positive subjective measures of “drug liking,” “overall drug liking,” “take drug again,” “high,” and “good drug effects.” In the human abuse potential study, dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, were reported with zuranolone use. Zuranolone may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7th-day subjects received 50 mg or 100 mg ) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. These adverse reactions indicate a potential for physical dependence on zuranolone. These adverse reactions were mild-to-moderate in severity. The risk of developing physical dependence and a subsequent withdrawal syndrome upon abrupt zuranolone discontinuation for individuals who take a higher-than-recommended dosage and/or use zuranolone for a longer duration than recommended has not been evaluated in clinical studies. However, convulsions were observed in a dog upon abrupt zuranolone discontinuation after dogs were administered zuranolone for 14 days at doses that produced exposures higher than the maximum recommended human dose. There was a case of intentional overdose with zuranolone reported during premarketing clinical trials. The patient took 330 mg (6.5 times the maximum recommended dose) of zuranolone and was reported to be in an altered state of consciousness. The event resolved the next day, following treatment with intravenous fluids. Overdosage with zuranolone may result in excessive CNS depressant effects such as somnolence and disturbance in consciousness. There is no specific antidote for zuranolone overdosage. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Oral administration of zuranolone in a 26-week carcinogenicity study in transgenic mice (0, 10, 30, or 100 mg/kg/day), and in a 104-week carcinogenicity study in rats (0, 2, 6, or 20 mg/kg/day in males and 0, 0.2, 0.6, or 1.5 mg/kg/day in females) was not associated with increases in tumors in either species. Plasma exposures (AUC) in rats at the highest dose tested were approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 50 mg. Zuranolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosome aberration assay in Chinese hamster ovary cells, and an in vivo bone marrow micronucleus assay in rats. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zurzuvae •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zuranolone is a neuroactive steroid drug used to treat postpartum depression

Since zuranolone is a GABAA positive allosteric modulator, it can enhance inhibitory conductance in the nervous system. Therefore, the co-administration of zuranolone with another central nervous system depressant can exacerbate nervous system depression, leading to impairment of psychomotor performance or other CNS depression-associated side effects. The severity of the interaction is moderate.

Question: Does Bupropion and Zuranolone interact? Information: •Drug A: Bupropion •Drug B: Zuranolone •Severity: MODERATE •Description: The risk or severity of CNS depression can be increased when Zuranolone is combined with Bupropion. •Extended Description: Since zuranolone is a GABAA positive allosteric modulator, it can enhance inhibitory conductance in the nervous system. Therefore, the co-administration of zuranolone with another central nervous system depressant can exacerbate nervous system depression, leading to impairment of psychomotor performance or other CNS depression-associated side effects. •Indication (Drug A): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Indication (Drug B): Zuranolone is indicated for the treatment of postpartum depression (PPD) in adults. •Pharmacodynamics (Drug A): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Pharmacodynamics (Drug B): At two times the maximum recommended dose, zuranolone does not cause clinically significant QTc interval prolongation. Co-administration of repeated 50 mg daily doses of zuranolone with alcohol or alprazolam led to impairment in psychomotor performance. Zuranolone exhibited an EC 50 of 430 nM and 118 nM at the α1β2γ2 and α4β3δ GABA A receptors respectively, the two most abundant synaptic and extrasynaptic receptors in the brain. Therefore, zuranolone can potentiate both phasic and tonic postsynaptic currents associated with modulation of the synaptic and extrasynaptic GABA A receptors respectively. Since tonic current can produce a larger inhibitory effect compared to phasic current, the ability of zuranolone to modulate the tonic current provides a greater opportunity to enhance GABA conductance. •Mechanism of action (Drug A): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Mechanism of action (Drug B): The mechanism of action of zuranolone in the treatment of PPD is not fully understood but is thought to be related to its positive allosteric modulation of GABA A receptors. Unlike benzodiazepines, another class of GABA A positive modulators, zuranolone binds to the α/β subunit interface presented in all GABA A receptors instead of the α/γ subunit interface. Therefore, zuranolone can bind to both synaptic GABA A receptors, composed of 2α2βγ subunits, and extrasynaptic GABA A receptors, composed of 2α2βδ subunits. •Absorption (Drug A): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Absorption (Drug B): Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (T max ). The absolute bioavailability of zuranolone was not evaluated. Zuranolone exposure (C max and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times the recommended dosage of zuranolone) with a moderate-fat meal (700 calories; 30% fat). Once-daily administration of Zuranolone resulted in an accumulation of approximately 1.5-fold in systemic exposures and a steady state was achieved in 3 to 5 days. Following administration of 30 mg of zuranolone to healthy subjects, the C max increased by approximately 3.5-fold, and the AUC last increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The C max increased by approximately 4.3-fold and the AUC last increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions. The T max was not impacted by food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of zuranolone following oral administration is greater than 500 L. •Protein binding (Drug A): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Protein binding (Drug B): The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58. Plasma protein binding is greater than 99.5%. •Metabolism (Drug A): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Metabolism (Drug B): Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone. •Route of elimination (Drug A): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Route of elimination (Drug B): Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone. •Half-life (Drug A): 24 hours •Half-life (Drug B): The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in the adult population. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance (CL/F) of zuranolone is 33 L/h. •Toxicity (Drug A): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Toxicity (Drug B): Based on findings from animal studies, zuranolone may cause fetal harm. Advise pregnant women of the potential risk to a fetus. Available data on zuranolone use in pregnant women from the clinical development program are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animals, oral administration of zuranolone to pregnant rats during organogenesis resulted in developmental toxicity, including embryofetal death and fetal malformations, with a no adverse effect level (NOAEL) associated with maternal plasma exposures 7 times greater than in humans at the maximum recommended human dose (MRHD) of 50 mg. Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including, perinatal mortality, at maternal exposures similar to that in humans at the MRHD. Developmental toxicity was observed at doses that were also maternally toxic. Neuronal death was observed in rats exposed to zuranolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth. Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction. Abuse is the intentional non-therapeutic use of a drug, even once, for its desired psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Individuals with a history of drug abuse or substance use disorders may be at a greater risk of these outcomes with zuranolone. In a human abuse potential study, single oral doses of 30 mg, 60 mg, and 90 mg of zuranolone (0.6 times, 1.2 times, and 1.8 times the recommended daily dose, respectively) were compared to single oral doses of alprazolam (1.5 mg and 3 mg) and placebo in healthy, non-dependent individuals with a history of recreational CNS depressant use. The study demonstrated that zuranolone has dose-dependent abuse potential comparable to alprazolam and greater abuse potential than placebo on positive subjective measures of “drug liking,” “overall drug liking,” “take drug again,” “high,” and “good drug effects.” In the human abuse potential study, dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, were reported with zuranolone use. Zuranolone may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7th-day subjects received 50 mg or 100 mg ) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. These adverse reactions indicate a potential for physical dependence on zuranolone. These adverse reactions were mild-to-moderate in severity. The risk of developing physical dependence and a subsequent withdrawal syndrome upon abrupt zuranolone discontinuation for individuals who take a higher-than-recommended dosage and/or use zuranolone for a longer duration than recommended has not been evaluated in clinical studies. However, convulsions were observed in a dog upon abrupt zuranolone discontinuation after dogs were administered zuranolone for 14 days at doses that produced exposures higher than the maximum recommended human dose. There was a case of intentional overdose with zuranolone reported during premarketing clinical trials. The patient took 330 mg (6.5 times the maximum recommended dose) of zuranolone and was reported to be in an altered state of consciousness. The event resolved the next day, following treatment with intravenous fluids. Overdosage with zuranolone may result in excessive CNS depressant effects such as somnolence and disturbance in consciousness. There is no specific antidote for zuranolone overdosage. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Oral administration of zuranolone in a 26-week carcinogenicity study in transgenic mice (0, 10, 30, or 100 mg/kg/day), and in a 104-week carcinogenicity study in rats (0, 2, 6, or 20 mg/kg/day in males and 0, 0.2, 0.6, or 1.5 mg/kg/day in females) was not associated with increases in tumors in either species. Plasma exposures (AUC) in rats at the highest dose tested were approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 50 mg. Zuranolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosome aberration assay in Chinese hamster ovary cells, and an in vivo bone marrow micronucleus assay in rats. •Brand Names (Drug A): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Brand Names (Drug B): Zurzuvae •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. •Summary (Drug B): Zuranolone is a neuroactive steroid drug used to treat postpartum depression Output: Since zuranolone is a GABAA positive allosteric modulator, it can enhance inhibitory conductance in the nervous system. Therefore, the co-administration of zuranolone with another central nervous system depressant can exacerbate nervous system depression, leading to impairment of psychomotor performance or other CNS depression-associated side effects. The severity of the interaction is moderate.

Does Buserelin and Acarbose interact?

•Drug A: Buserelin •Drug B: Acarbose •Severity: MODERATE •Description: The therapeutic efficacy of Acarbose can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e.g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e.g. sucrose) into smaller monosaccharides (e.g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i.e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Precose •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Acarbose interact? Information: •Drug A: Buserelin •Drug B: Acarbose •Severity: MODERATE •Description: The therapeutic efficacy of Acarbose can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e.g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e.g. sucrose) into smaller monosaccharides (e.g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i.e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Precose •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Adenosine interact?

•Drug A: Buserelin •Drug B: Adenosine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Adenosine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy in patients unable to adequately exercise. It is also indicated to convert sinus rhythm of paroxysmal supraventricular tachycardia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy and also indicated for conversion of sinus rhythm of paroxysmal supraventricular tachycardia. Adenosine has a short duration of action as the half life is <10 seconds, and a wide therapeutic window. Patients should be counselled regarding the risk of cardiovascular side effects, bronchoconstriction, seizures, and hypersensitivity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Agonism of adenosine receptors A1 and A2 reduces conduction time in the atrioventricular node of the heart. Conduction time is decreased by inducing potassium efflux and inhibiting calcium influx through channels in nerve cells, leading to hyperpolarization and and increased threshold for calcium dependent action potentials. Decreased conduction time leads to an antiarrhythmic effect. Inhibition of calcium influx, reduces the activity of adenylate cyclase, relaxing vascular smooth muscle. Relaxed vascular smooth muscle leads to increased blood flow through normal coronary arteries but not stenotic arteries, allowing thallium-201 to be more readily uptaken in normal coronary arteries. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Data regarding the absorption of adenosine are not readily available. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Data regarding the volume of distribution of adenosine are not readily available. •Protein binding (Drug A): 15% •Protein binding (Drug B): Adenosine is bound to albumin in plasma, however data regarding the extent of binding are not readily available. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Adenosine can be phosphorylated by adenosine kinase to form adenosine monophosphate. From there, it is phosphorylated again by adenylate kinase 1 to form adenosine diphosphate, and again by nucleoside diphosphate kinase A or B to form adenosine triphosphate. Alternatively, adenosine can be deaminated by adenosine deaminase to form inosine. Iosine is phosphorylated by purine nucleoside phosphorylase to form hypoxanthine. Hypoxanthine undergoes oxidation by xanthine dehydrogenase twice to form the metabolites xanthine, followed by uric acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Adenosine is predominantly eliminated in the urine as uric acid. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of adenosine in blood is less than 10 seconds. •Clearance (Drug A): No clearance available •Clearance (Drug B): Data regarding the clearance of adenosine are not readily available. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose of adenosine may present with asystole, heart block, or cardiac ischemia; though the effects are generally short lived. Patients experiencing an overdose should be treated with symptomatic and supportive care, which may include a slow intravenous injection of theophylline. The LD 50 in mice is >20 g/kg subcutaneously, 500mg/kg intraperitoneally, and 39.6 µg/kg subcutaneously. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Adenocard, Viva-drops Lubricating Eye Drops •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ade-Rib Adenin riboside Adenine Deoxyribonucleoside Adenogesic Adenosin Adenosina Adénosine Adenosine Adenosinum beta-D-Adenosine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Adenosine is a medication used in myocardial perfusion scintigraphy and to treat supraventricular tachycardia.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Adenosine interact? Information: •Drug A: Buserelin •Drug B: Adenosine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Adenosine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy in patients unable to adequately exercise. It is also indicated to convert sinus rhythm of paroxysmal supraventricular tachycardia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy and also indicated for conversion of sinus rhythm of paroxysmal supraventricular tachycardia. Adenosine has a short duration of action as the half life is <10 seconds, and a wide therapeutic window. Patients should be counselled regarding the risk of cardiovascular side effects, bronchoconstriction, seizures, and hypersensitivity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Agonism of adenosine receptors A1 and A2 reduces conduction time in the atrioventricular node of the heart. Conduction time is decreased by inducing potassium efflux and inhibiting calcium influx through channels in nerve cells, leading to hyperpolarization and and increased threshold for calcium dependent action potentials. Decreased conduction time leads to an antiarrhythmic effect. Inhibition of calcium influx, reduces the activity of adenylate cyclase, relaxing vascular smooth muscle. Relaxed vascular smooth muscle leads to increased blood flow through normal coronary arteries but not stenotic arteries, allowing thallium-201 to be more readily uptaken in normal coronary arteries. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Data regarding the absorption of adenosine are not readily available. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Data regarding the volume of distribution of adenosine are not readily available. •Protein binding (Drug A): 15% •Protein binding (Drug B): Adenosine is bound to albumin in plasma, however data regarding the extent of binding are not readily available. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Adenosine can be phosphorylated by adenosine kinase to form adenosine monophosphate. From there, it is phosphorylated again by adenylate kinase 1 to form adenosine diphosphate, and again by nucleoside diphosphate kinase A or B to form adenosine triphosphate. Alternatively, adenosine can be deaminated by adenosine deaminase to form inosine. Iosine is phosphorylated by purine nucleoside phosphorylase to form hypoxanthine. Hypoxanthine undergoes oxidation by xanthine dehydrogenase twice to form the metabolites xanthine, followed by uric acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Adenosine is predominantly eliminated in the urine as uric acid. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of adenosine in blood is less than 10 seconds. •Clearance (Drug A): No clearance available •Clearance (Drug B): Data regarding the clearance of adenosine are not readily available. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose of adenosine may present with asystole, heart block, or cardiac ischemia; though the effects are generally short lived. Patients experiencing an overdose should be treated with symptomatic and supportive care, which may include a slow intravenous injection of theophylline. The LD 50 in mice is >20 g/kg subcutaneously, 500mg/kg intraperitoneally, and 39.6 µg/kg subcutaneously. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Adenocard, Viva-drops Lubricating Eye Drops •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ade-Rib Adenin riboside Adenine Deoxyribonucleoside Adenogesic Adenosin Adenosina Adénosine Adenosine Adenosinum beta-D-Adenosine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Adenosine is a medication used in myocardial perfusion scintigraphy and to treat supraventricular tachycardia. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ajmaline interact?

•Drug A: Buserelin •Drug B: Ajmaline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ajmaline is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use as an antiarrhythmic agent. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ajmaline is a class 1A antiarrhythmic agent. By interfering with the sodium channels, this drug allows for improvement in abnormal rhythms of the heart •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The class I antiarrhythmic agents interfere with the sodium channel. A class IA agent lengthens the action potential (right shift) which brings about improvement in abnormal heart rhythms. This drug in particular has a high affinity for the Nav 1.5 sodium channel. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ajmalin Ajmaline •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ajmaline is an antiarrhythmic used to manage a variety of forms of tachycardias.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ajmaline interact? Information: •Drug A: Buserelin •Drug B: Ajmaline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ajmaline is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use as an antiarrhythmic agent. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ajmaline is a class 1A antiarrhythmic agent. By interfering with the sodium channels, this drug allows for improvement in abnormal rhythms of the heart •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The class I antiarrhythmic agents interfere with the sodium channel. A class IA agent lengthens the action potential (right shift) which brings about improvement in abnormal heart rhythms. This drug in particular has a high affinity for the Nav 1.5 sodium channel. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ajmalin Ajmaline •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ajmaline is an antiarrhythmic used to manage a variety of forms of tachycardias. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Alfuzosin interact?

•Drug A: Buserelin •Drug B: Alfuzosin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Alfuzosin is used to treat the signs and symptoms of benign prostatic hyperplasia (BPH). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): By selectively inhibiting alpha adrenergic receptors in the lower urinary tract, alfuzosin causes smooth muscle relaxation in the bladder neck and prostate, improving urine flow, thereby reducing BPH symptoms. Additionally, alfuzosin reduces the vasoconstrictor effect of catecholamines (epinephrine and norepinephrine), leading to peripheral vasodilation. This leads to a risk of postural hypotension/syncope, and prescribing information warns that caution should be exercised in patients who take nitrates, antihypertensives, or have experienced decreased blood pressure after using other medications. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alpha(1)-adrenoreceptors are found in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra; their activation may lead to contraction of smooth muscle and urinary symptoms in patients with BPH. Alfuzosin selectively binds to and inhibits alpha(1)-adrenergic receptors in the lower urinary tract. This leads to the relaxation of smooth muscle in both the prostate and bladder neck, resulting in the improvement in urine flow and a reduction of urinary symptoms. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Alfuzosin is readily absorbed in the gastrointestinal tract and the absolute bioavailability under fed conditions is 49%. In patients over 75 years of age, alfuzosin is absorbed more rapidly and peak plasma levels are higher. One source mentions a bioavailability of 64%. After multiple doses under fed conditions, Cmax is achieved in 8 hours. Cmax and AUC0-24 values are about 13.6 ng/mL and 194 ng·h/mL, respectively. Steady-state plasma concentrations are achieved after the second dose and are 1.2 to 1.6 times higher than after a single dose. With the extended-release formulation, alfuzosin release is sustained over 20 hours with a rate of dissolution ranging between 2 and 12 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of alfuzosin after intravenous administration in healthy volunteers is about 3.2 L/kg. Alfuzosin distributes heavily to the tissues of the prostate. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein biding of alfuzosin is moderate and ranges from 82% to 90%. Alfuzosin is 68.2% bound to human serum albumin and 52.5% bound to human serum alpha-glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Alfuzosin undergoes extensive hepatic metabolism; only 11% of the administered dose is detected unchanged in the urine. Alfuzosin is metabolism occurs via three metabolic pathways: oxidation, O-demethylations, and N-dealkylation. Metabolites of alfuzosin are not pharmacologically active and CYP3A4 is main hepatic cytochrome enzyme responsible for its metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): It is partially metabolised and excreted mainly in the bile and faeces. Following oral administration of a radiolabeled alfuzosin solution, the detection of radioactivity after one week was 69% in the feces and 24% in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The apparent elimination half-life of alfuzosin after oral administration is about 10 hours. The terminal half-life is 3-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Exercise caution if renal clearance is < 30 mL/min. The clearance of alfuzosin is increased in renal insufficiency (with or without dialysis), due to an increase in the free fraction. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 of alfuzosin is 2300 mg/kg in male mice and 1950 mg/kg in female mice. An overdose of alfuzosin can cause hypotension. Cardiovascular support should be initiated immediately. The patient should be kept in the supine position to aid in restoring pressure and managing heart rate. Fluid resuscitation should also be considered in severe cases; sometimes, vasopressors are required. Renal function should be monitored frequently. Dialysis may not be of benefit to alfuzosin protein binding of up to 90%. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Uroxatral, Xatral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alfuzosin Alfuzosina Alfuzosine Alfuzosinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Alfuzosin is an alpha-1 adrenergic antagonist used in the symptomatic management of benign prostatic hypertrophy (BPH).

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Alfuzosin interact? Information: •Drug A: Buserelin •Drug B: Alfuzosin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Alfuzosin is used to treat the signs and symptoms of benign prostatic hyperplasia (BPH). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): By selectively inhibiting alpha adrenergic receptors in the lower urinary tract, alfuzosin causes smooth muscle relaxation in the bladder neck and prostate, improving urine flow, thereby reducing BPH symptoms. Additionally, alfuzosin reduces the vasoconstrictor effect of catecholamines (epinephrine and norepinephrine), leading to peripheral vasodilation. This leads to a risk of postural hypotension/syncope, and prescribing information warns that caution should be exercised in patients who take nitrates, antihypertensives, or have experienced decreased blood pressure after using other medications. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alpha(1)-adrenoreceptors are found in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra; their activation may lead to contraction of smooth muscle and urinary symptoms in patients with BPH. Alfuzosin selectively binds to and inhibits alpha(1)-adrenergic receptors in the lower urinary tract. This leads to the relaxation of smooth muscle in both the prostate and bladder neck, resulting in the improvement in urine flow and a reduction of urinary symptoms. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Alfuzosin is readily absorbed in the gastrointestinal tract and the absolute bioavailability under fed conditions is 49%. In patients over 75 years of age, alfuzosin is absorbed more rapidly and peak plasma levels are higher. One source mentions a bioavailability of 64%. After multiple doses under fed conditions, Cmax is achieved in 8 hours. Cmax and AUC0-24 values are about 13.6 ng/mL and 194 ng·h/mL, respectively. Steady-state plasma concentrations are achieved after the second dose and are 1.2 to 1.6 times higher than after a single dose. With the extended-release formulation, alfuzosin release is sustained over 20 hours with a rate of dissolution ranging between 2 and 12 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of alfuzosin after intravenous administration in healthy volunteers is about 3.2 L/kg. Alfuzosin distributes heavily to the tissues of the prostate. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein biding of alfuzosin is moderate and ranges from 82% to 90%. Alfuzosin is 68.2% bound to human serum albumin and 52.5% bound to human serum alpha-glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Alfuzosin undergoes extensive hepatic metabolism; only 11% of the administered dose is detected unchanged in the urine. Alfuzosin is metabolism occurs via three metabolic pathways: oxidation, O-demethylations, and N-dealkylation. Metabolites of alfuzosin are not pharmacologically active and CYP3A4 is main hepatic cytochrome enzyme responsible for its metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): It is partially metabolised and excreted mainly in the bile and faeces. Following oral administration of a radiolabeled alfuzosin solution, the detection of radioactivity after one week was 69% in the feces and 24% in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The apparent elimination half-life of alfuzosin after oral administration is about 10 hours. The terminal half-life is 3-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Exercise caution if renal clearance is < 30 mL/min. The clearance of alfuzosin is increased in renal insufficiency (with or without dialysis), due to an increase in the free fraction. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 of alfuzosin is 2300 mg/kg in male mice and 1950 mg/kg in female mice. An overdose of alfuzosin can cause hypotension. Cardiovascular support should be initiated immediately. The patient should be kept in the supine position to aid in restoring pressure and managing heart rate. Fluid resuscitation should also be considered in severe cases; sometimes, vasopressors are required. Renal function should be monitored frequently. Dialysis may not be of benefit to alfuzosin protein binding of up to 90%. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Uroxatral, Xatral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alfuzosin Alfuzosina Alfuzosine Alfuzosinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Alfuzosin is an alpha-1 adrenergic antagonist used in the symptomatic management of benign prostatic hypertrophy (BPH). Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Alimemazine interact?

•Drug A: Buserelin •Drug B: Alimemazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Alimemazine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used to prevent and relieve allergic conditions which cause pruritus (itching) and urticaria (some allergic skin reactions). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Trimeprazine (also known as Alimemazine) is a tricyclic antihistamine, similar in structure to the phenothiazine antipsychotics, but differing in the ring-substitution and chain characteristics. Trimeprazine is in the same class of drugs as chlorpromazine (Thorazine) and trifluoperazine (Stelazine); however, unlike the other drugs in this class, trimeprazine is not used clinically as an anti-psychotic. It acts as an anti-histamine, a sedative, and an anti-emetic (anti-nausea). Trimeprazine is used principally as an anti-emetic, to prevent motion sickness or as an anti-histamine in combination with other medications in cough and cold preparations. Tricyclic antihistamines are also structurally-related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of these two drug classes and also the poor tolerability profile of tricyclic H 1 -antihistamines. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Trimeprazine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed in the digestive tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose clumsiness or unsteadiness, seizures, severe drowsiness, flushing or redness of face, hallucinations, muscle spasms (especially of neck and back), restlessness, shortness of breath, shuffling walk, tic-like (jerky) movements of head and face, trembling and shaking of hands, and insomnia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Panectyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Alimemazine is an antihistamine agent used to prevent and relieve allergic conditions which cause pruritus and other allergic skin conditions, including urticaria.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Alimemazine interact? Information: •Drug A: Buserelin •Drug B: Alimemazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Alimemazine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used to prevent and relieve allergic conditions which cause pruritus (itching) and urticaria (some allergic skin reactions). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Trimeprazine (also known as Alimemazine) is a tricyclic antihistamine, similar in structure to the phenothiazine antipsychotics, but differing in the ring-substitution and chain characteristics. Trimeprazine is in the same class of drugs as chlorpromazine (Thorazine) and trifluoperazine (Stelazine); however, unlike the other drugs in this class, trimeprazine is not used clinically as an anti-psychotic. It acts as an anti-histamine, a sedative, and an anti-emetic (anti-nausea). Trimeprazine is used principally as an anti-emetic, to prevent motion sickness or as an anti-histamine in combination with other medications in cough and cold preparations. Tricyclic antihistamines are also structurally-related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of these two drug classes and also the poor tolerability profile of tricyclic H 1 -antihistamines. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Trimeprazine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed in the digestive tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose clumsiness or unsteadiness, seizures, severe drowsiness, flushing or redness of face, hallucinations, muscle spasms (especially of neck and back), restlessness, shortness of breath, shuffling walk, tic-like (jerky) movements of head and face, trembling and shaking of hands, and insomnia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Panectyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Alimemazine is an antihistamine agent used to prevent and relieve allergic conditions which cause pruritus and other allergic skin conditions, including urticaria. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Alogliptin interact?

•Drug A: Buserelin •Drug B: Alogliptin •Severity: MODERATE •Description: The therapeutic efficacy of Alogliptin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Peak inhibition of DPP-4 occurs within 2-3 hours after a single-dose administration to healthy subjects. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Alogliptin also demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-hour period following a standardized meal. Alogliptin does not affect the QTc interval. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4), which normally degrades the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 ( GLP-1). The inhibition of DPP-4 increases the amount of active plasma incretins which helps with glycemic control. GIP and GLP-1 stimulate glucose dependent secretion of insulin in pancreatic beta cells. GLP-1 has the additional effects of suppressing glucose dependent glucagon secretion, inducing satiety, reducing food intake, and reducing gastric emptying. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes. When single, oral doses up to 800 mg in healthy subjects and type 2 diabetes patients are given, the peak plasma alogliptin concentration (median Tmax) occurred 1 to 2 hours after dosing. Accumulation of aloglipin is minimal. The absolute bioavailability of NESINA is approximately 100%. Food does not affect the absorption of alogliptin. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. •Protein binding (Drug A): 15% •Protein binding (Drug B): Alogliptin is 20% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Alogliptin does not undergo extensive metabolism. Two minor metabolites that were detected are N-demethylated alogliptin (<1% of parent compound) and N-acetylated alogliptin (<6% of parent compound). The N-demethylated metabolite is active and an inhibitor of DPP-4. The N-acetylated metabolite is inactive. Cytochrome enzymes that are involved with the metabolism of alogliptin are CYP2D6 and CYP3A4 but the extent to which this occurs is minimal. Approximately 10-20% of the dose is hepatically metabolized by cytochrome enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal excretion (76%) and feces (13%). 60% to 71% of the dose is excreted as unchanged drug in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Terminal half-life = 21 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance = 9.6 L/h (this value indicates some active renal tubular secretion); Systemic clearance = 14.0 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Common adverse reactions (reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache, and upper respiratory tract infection. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Incresync, Kazano, Nesina, Oseni •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat hyperglycemia in patients with type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Alogliptin interact? Information: •Drug A: Buserelin •Drug B: Alogliptin •Severity: MODERATE •Description: The therapeutic efficacy of Alogliptin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Peak inhibition of DPP-4 occurs within 2-3 hours after a single-dose administration to healthy subjects. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Alogliptin also demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-hour period following a standardized meal. Alogliptin does not affect the QTc interval. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4), which normally degrades the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 ( GLP-1). The inhibition of DPP-4 increases the amount of active plasma incretins which helps with glycemic control. GIP and GLP-1 stimulate glucose dependent secretion of insulin in pancreatic beta cells. GLP-1 has the additional effects of suppressing glucose dependent glucagon secretion, inducing satiety, reducing food intake, and reducing gastric emptying. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes. When single, oral doses up to 800 mg in healthy subjects and type 2 diabetes patients are given, the peak plasma alogliptin concentration (median Tmax) occurred 1 to 2 hours after dosing. Accumulation of aloglipin is minimal. The absolute bioavailability of NESINA is approximately 100%. Food does not affect the absorption of alogliptin. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. •Protein binding (Drug A): 15% •Protein binding (Drug B): Alogliptin is 20% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Alogliptin does not undergo extensive metabolism. Two minor metabolites that were detected are N-demethylated alogliptin (<1% of parent compound) and N-acetylated alogliptin (<6% of parent compound). The N-demethylated metabolite is active and an inhibitor of DPP-4. The N-acetylated metabolite is inactive. Cytochrome enzymes that are involved with the metabolism of alogliptin are CYP2D6 and CYP3A4 but the extent to which this occurs is minimal. Approximately 10-20% of the dose is hepatically metabolized by cytochrome enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal excretion (76%) and feces (13%). 60% to 71% of the dose is excreted as unchanged drug in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Terminal half-life = 21 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance = 9.6 L/h (this value indicates some active renal tubular secretion); Systemic clearance = 14.0 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Common adverse reactions (reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache, and upper respiratory tract infection. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Incresync, Kazano, Nesina, Oseni •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat hyperglycemia in patients with type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Amantadine interact?

•Drug A: Buserelin •Drug B: Amantadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amantadine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the chemoprophylaxis, prophylaxis, and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Also for the treatment of parkinsonism and drug-induced extrapyramidal reactions. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amantadine is an antiviral drug which also acts as an antiparkinson agent, for which it is usually combined with L-DOPA when L-DOPA responses decline (probably due to tolerance). It is a derivate of adamantane, like a similar drug rimantadine. The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. It has been shown to cause an increase in dopamine release in the animal brain, and does not possess anticholinergic activity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of its antiparkinsonic effect is not fully understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated. The drug interferes with a viral protein, M2 (an ion channel), which is needed for the viral particle to become "uncoated" once it is taken inside the cell by endocytosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Amantadine is well absorbed orally from the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 3 to 8 L/kg [healthy subjects] •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No appreciable metabolism, although negligible amounts of an acetyl metabolite have been identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Mean half-lives ranged from 10 to 14 hours, however renal function impairment causes a severe increase in half life to 7 to 10 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.2 - 0.3 L/hr/kg 0.10 +/- 0.04 L/hr/kg [healthy, elderly male] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 2 grams. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including ARDS) have been reported. Renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, aggressive behavior, hypertonia, hyperkinesia, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucination, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Gocovri, Osmolex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amantadina Amantadine Amantadinum Amantidine Aminoadamantane •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amantadine is a medication used to treat dyskinesia in Parkinson's patients receiving levodopa, as well as extrapyramidal side effects of medications.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Amantadine interact? Information: •Drug A: Buserelin •Drug B: Amantadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amantadine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the chemoprophylaxis, prophylaxis, and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Also for the treatment of parkinsonism and drug-induced extrapyramidal reactions. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amantadine is an antiviral drug which also acts as an antiparkinson agent, for which it is usually combined with L-DOPA when L-DOPA responses decline (probably due to tolerance). It is a derivate of adamantane, like a similar drug rimantadine. The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. It has been shown to cause an increase in dopamine release in the animal brain, and does not possess anticholinergic activity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of its antiparkinsonic effect is not fully understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated. The drug interferes with a viral protein, M2 (an ion channel), which is needed for the viral particle to become "uncoated" once it is taken inside the cell by endocytosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Amantadine is well absorbed orally from the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 3 to 8 L/kg [healthy subjects] •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No appreciable metabolism, although negligible amounts of an acetyl metabolite have been identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Mean half-lives ranged from 10 to 14 hours, however renal function impairment causes a severe increase in half life to 7 to 10 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.2 - 0.3 L/hr/kg 0.10 +/- 0.04 L/hr/kg [healthy, elderly male] •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 2 grams. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including ARDS) have been reported. Renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, aggressive behavior, hypertonia, hyperkinesia, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucination, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Gocovri, Osmolex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amantadina Amantadine Amantadinum Amantidine Aminoadamantane •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amantadine is a medication used to treat dyskinesia in Parkinson's patients receiving levodopa, as well as extrapyramidal side effects of medications. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ambroxol interact?

•Drug A: Buserelin •Drug B: Ambroxol •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Ambroxol. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ambroxol is indicated for secretolytic therapy in bronchoplmonary disease with abnormal mucus secretion and transport. It allows the mucus to be more easily cleared and ease a patient's breathing. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ambroxol is a mucolytic agent. Excessive Nitric oxide (NO) is associated with inflammatory and some other disturbances of airways function. NO enhances the activation of soluble guanylate cyclase and cGMP accumulation. Ambroxol has been shown to inhibit the NO-dependent activation of soluble guanylate cyclase. It is also possible that the inhibition of NO-dependent activation of soluble guanylate cyclase can suppress the excessive mucus secretion, therefore it lowers the phlegm viscosity and improves the mucociliary transport of bronchial secretions. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapid and almost complete. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 90% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7-12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambroxol Ambroxolum Bisolvon metabolite vIII Bromhexine metabolite vIII Bromhexine-metabolite vIII •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ambroxol is a medication indicated for airway secretion clearance therapy.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Ambroxol interact? Information: •Drug A: Buserelin •Drug B: Ambroxol •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Ambroxol. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ambroxol is indicated for secretolytic therapy in bronchoplmonary disease with abnormal mucus secretion and transport. It allows the mucus to be more easily cleared and ease a patient's breathing. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ambroxol is a mucolytic agent. Excessive Nitric oxide (NO) is associated with inflammatory and some other disturbances of airways function. NO enhances the activation of soluble guanylate cyclase and cGMP accumulation. Ambroxol has been shown to inhibit the NO-dependent activation of soluble guanylate cyclase. It is also possible that the inhibition of NO-dependent activation of soluble guanylate cyclase can suppress the excessive mucus secretion, therefore it lowers the phlegm viscosity and improves the mucociliary transport of bronchial secretions. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapid and almost complete. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 90% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7-12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambroxol Ambroxolum Bisolvon metabolite vIII Bromhexine metabolite vIII Bromhexine-metabolite vIII •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ambroxol is a medication indicated for airway secretion clearance therapy. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Amifampridine interact?

•Drug A: Buserelin •Drug B: Amifampridine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Amifampridine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients. Nevertheless, at the current time only the Firdapse brand of amifampridine is indicated for the treatment of LEMS in both adult and pediatric patients, while the Ruzurgi brand of amifampridine is indicated for the treatment of LEMS only in patients aged 6 to less than 17 years. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Administration of amifampridine to patients with LES in clinical trials resulted in improvement of the compound muscle action potential (CMAP), muscle function, and quantitative myasthenia gravis (QMG) score. One case of a slight prolongation of the QTc interval in male patient with LEMS and euthyroid Hashimoto’s disease treated with 90 mg of amifampridine in combination with 100 mg azathioprine was reported. In vitro, amifampridine was shown to modulate cardiac conduction and induce phasic contractions in different arteries from several species. In addition, it stimulated potassium-evoked dopamine and noradrenaline release in rat hippocampal slices and upregulate acetylcholine release in the brain. It may also potentiate adrenergic and cholinergic neuromuscular transmission in the gatrointestinal tract. In a single pharmacokinetic study, no effect was observed of amifampridine phosphate on cardiac repolarization as assessed using the QTc interval. There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Amifampridine is a symptomatic treatment that increases acetylcholine concentrations at the neuromuscular junction. It selectively blocks presynaptic fast voltage-gated potassium channels, thereby prolonging cell membrane depolarization and action potential, and augmenting calcium transport into the nerve endings. Increased intracellular calcium enhances the exocytosis of acetylcholine-containing vesicles and enhances impulse transmission at central, autonomic, and neuromuscular synapses. Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours. A single oral dose of 20 mg amifampridine in fasted individuals resulted in mean peak plasma concentrations (Cmax) ranging from 16 to 137 ng/mL. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine. Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax). It is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios. Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype. The NAT enzymes are highly polymorphic that results in variable slow acetylator (SA) and rapid acetylator (RA) phenotypes. Slow acetylators are more prone to increased systemic exposure to amifampridine, and may require higher doses for therapeutic efficacy. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In healthy volunteers, the volume of distribution for plasma amifampridine indicated that RUZURGI is a drug with a moderate to a high volume of distribution. After a 2 mg/kg infusion in rats, the volume of distribution at steady-state was 2.8 ± 0.7 L/kg. Drug concentrations were highest in organs of excretion, including the liver, kidney, and the gastrointestinal tract, and some tissues of glandular function, such as lacrimal, salivary, mucous, pituitary, and thyroid glands. Concentrations in tissues are generally similar to or greater than concentrations in plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro human plasma protein binding of amifampridine and 3-N-acetyl amifampridine was 25.3% and 43.3%, respectively. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours. About 19% of the total renally-excreted dose is in the parent drug form, and about 74-81.7% of the dose is in its metabolite form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average elimination half-life of amifampridine was 3.6 to 4.2 hours and 4.1 to 4.8 hours for the 3-N-acetyl amifampridine metabolite. •Clearance (Drug A): No clearance available •Clearance (Drug B): Overall clearance of amifampridine is both metabolic and renal; it is primarily cleared from the plasma via metabolism by N-acetylation. Following oral administration of a single 20 or 30 mg dose of RUZURGI to healthy volunteers, amifampridine apparent oral clearance (CL/F) was 149 to 214 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The approximate oral LD50 was >25mg/kg in rats and 100 mg/kg in mice. The approximate intravenous LD50 was 25 mg/kg in both rats and mice. Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively. There is limited clinical experienced with amifampridine overdose. The manifestations of acute drug overdose may include abdominal pain, and should be responded with discontinuation of treatment and initiation of supportive care with close monitoring of viral signs. There is no specific antidote known for amifampridine. In vitro, amifampridine showed no clinically relevant carcinogenic or genotoxic potential. However, in a 2-year rat study, amifampridine caused small but statistically significant dose-related increases in the incidence of Schwannomas in both genders and of endometrial carcinomas in females. At doses higher than the recommended daily dose for humans, amifampridine caused a dose-related increase in the percentage of pregnant rats with stillborn offspring. Effects on the central and autonomic nervous system, increased liver and kidney weights and cardiac effects (second degree atrioventricular block) were seen in a repeat-dose toxicity studies in rats and dogs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Firdapse, Ruzurgi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3,4 diaminopyridine 3,4-DAP 3,4-Diaminopyridine 3,4-Pyridinediamine 4,5-Diaminopyridine Amifampridine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amifampridine is a voltage gated potassium channel blocker used to treat Lambert-Eaton myasthenic syndrome.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Amifampridine interact? Information: •Drug A: Buserelin •Drug B: Amifampridine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Amifampridine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients. Nevertheless, at the current time only the Firdapse brand of amifampridine is indicated for the treatment of LEMS in both adult and pediatric patients, while the Ruzurgi brand of amifampridine is indicated for the treatment of LEMS only in patients aged 6 to less than 17 years. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Administration of amifampridine to patients with LES in clinical trials resulted in improvement of the compound muscle action potential (CMAP), muscle function, and quantitative myasthenia gravis (QMG) score. One case of a slight prolongation of the QTc interval in male patient with LEMS and euthyroid Hashimoto’s disease treated with 90 mg of amifampridine in combination with 100 mg azathioprine was reported. In vitro, amifampridine was shown to modulate cardiac conduction and induce phasic contractions in different arteries from several species. In addition, it stimulated potassium-evoked dopamine and noradrenaline release in rat hippocampal slices and upregulate acetylcholine release in the brain. It may also potentiate adrenergic and cholinergic neuromuscular transmission in the gatrointestinal tract. In a single pharmacokinetic study, no effect was observed of amifampridine phosphate on cardiac repolarization as assessed using the QTc interval. There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Amifampridine is a symptomatic treatment that increases acetylcholine concentrations at the neuromuscular junction. It selectively blocks presynaptic fast voltage-gated potassium channels, thereby prolonging cell membrane depolarization and action potential, and augmenting calcium transport into the nerve endings. Increased intracellular calcium enhances the exocytosis of acetylcholine-containing vesicles and enhances impulse transmission at central, autonomic, and neuromuscular synapses. Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours. A single oral dose of 20 mg amifampridine in fasted individuals resulted in mean peak plasma concentrations (Cmax) ranging from 16 to 137 ng/mL. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine. Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax). It is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios. Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype. The NAT enzymes are highly polymorphic that results in variable slow acetylator (SA) and rapid acetylator (RA) phenotypes. Slow acetylators are more prone to increased systemic exposure to amifampridine, and may require higher doses for therapeutic efficacy. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In healthy volunteers, the volume of distribution for plasma amifampridine indicated that RUZURGI is a drug with a moderate to a high volume of distribution. After a 2 mg/kg infusion in rats, the volume of distribution at steady-state was 2.8 ± 0.7 L/kg. Drug concentrations were highest in organs of excretion, including the liver, kidney, and the gastrointestinal tract, and some tissues of glandular function, such as lacrimal, salivary, mucous, pituitary, and thyroid glands. Concentrations in tissues are generally similar to or greater than concentrations in plasma. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro human plasma protein binding of amifampridine and 3-N-acetyl amifampridine was 25.3% and 43.3%, respectively. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours. About 19% of the total renally-excreted dose is in the parent drug form, and about 74-81.7% of the dose is in its metabolite form. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average elimination half-life of amifampridine was 3.6 to 4.2 hours and 4.1 to 4.8 hours for the 3-N-acetyl amifampridine metabolite. •Clearance (Drug A): No clearance available •Clearance (Drug B): Overall clearance of amifampridine is both metabolic and renal; it is primarily cleared from the plasma via metabolism by N-acetylation. Following oral administration of a single 20 or 30 mg dose of RUZURGI to healthy volunteers, amifampridine apparent oral clearance (CL/F) was 149 to 214 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The approximate oral LD50 was >25mg/kg in rats and 100 mg/kg in mice. The approximate intravenous LD50 was 25 mg/kg in both rats and mice. Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively. There is limited clinical experienced with amifampridine overdose. The manifestations of acute drug overdose may include abdominal pain, and should be responded with discontinuation of treatment and initiation of supportive care with close monitoring of viral signs. There is no specific antidote known for amifampridine. In vitro, amifampridine showed no clinically relevant carcinogenic or genotoxic potential. However, in a 2-year rat study, amifampridine caused small but statistically significant dose-related increases in the incidence of Schwannomas in both genders and of endometrial carcinomas in females. At doses higher than the recommended daily dose for humans, amifampridine caused a dose-related increase in the percentage of pregnant rats with stillborn offspring. Effects on the central and autonomic nervous system, increased liver and kidney weights and cardiac effects (second degree atrioventricular block) were seen in a repeat-dose toxicity studies in rats and dogs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Firdapse, Ruzurgi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3,4 diaminopyridine 3,4-DAP 3,4-Diaminopyridine 3,4-Pyridinediamine 4,5-Diaminopyridine Amifampridine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amifampridine is a voltage gated potassium channel blocker used to treat Lambert-Eaton myasthenic syndrome. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Amiodarone interact?

•Drug A: Buserelin •Drug B: Amiodarone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Amiodarone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amiodarona Amiodarone Amiodaronum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amiodarone is a class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Amiodarone interact? Information: •Drug A: Buserelin •Drug B: Amiodarone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Amiodarone. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amiodarona Amiodarone Amiodaronum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amiodarone is a class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Amisulpride interact?

•Drug A: Buserelin •Drug B: Amisulpride •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amisulpride is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Intravenous amisulpride is indicated in adults for the prevention of postoperative nausea and vomiting, either alone or in combination with an antiemetic of a different class. It is also indicated for the treatment of postoperative nausea and vomiting in patients who have received anti-emetic prophylaxis with an agent of a different class or have not received prophylaxis. Oral amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders, characterized by positive symptoms with delusions, hallucinations, thought disorders, hostility and suspicious behavior; or primarily negative symptoms (deficit syndrome) with blunted affect, emotional and social withdrawal. Amisulpride also controls secondary negative symptoms in productive conditions as well as affective disorders such as depressive mood or retardation. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amisulpride is a selective dopamine D2 and D3 receptor antagonist with no affinity towards other dopamine receptor subtypes. Amisulpride is an atypical antipsychotic agent that works as an antagonist at dopamine receptors in the limbic system. Since it works preferentially in the limbic system, amisulpride is less likely to be associated with extrapyramidal adverse effects than other atypical antipsychotic agents. Amisulpride has no affinity for serotonin, alpha-adrenergic, H1-histamine, cholinergic, and sigma receptors. In clinical trials, amisulpride improved reduced secondary negative symptoms, affective symptoms, and psychomotor retardation in patients with acute exacerbation of schizophrenia. Notably, amisulpride has a differential target binding profile at different doses: at low doses, amisulpride selectively binds to presynaptic dopamine autoreceptors. At high doses, it preferentially binds to post-synaptic dopamine receptors. This explains how amisulpride reduces negative symptoms at low doses and mediates antipsychotic effects at high doses. One study alluded that the antinociceptive effects of amisulpride are mediated through opioid receptor acvitation and D2 receptor antagonism. The actions of amisulpride at opioid receptors may explain its pro-convulsant properties. Amisulpride is also an antiemetic agent that prevents and alleviates postoperative nausea and vomiting. It primarily works by blocking dopamine signalling in the chemoreceptor trigger zone, which is a brain area that relays stimuli to the vomiting center. In clinical trials comprising Caucasian and Japanese subjects, amisulpride caused dose- and concentration-dependent prolongation of the QT interval; thus, intravenous infusion under a strict dosing regimen and close monitoring of patients with pre-existing cardiovascular conditions are recommended. Amisulpride increases plasma prolactin levels, leading to an association with benign pituitary tumours such as prolactinoma. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dopamine is an essential and critical neurotransmitter produced in the substantia nigra and ventral tegmental regions of the brain. Dopaminergic projection function in the nigrostriatal, mesolimbic, and mesocortical systems. Hyperactive dopamine transmission in the mesolimbic areas, or dopamine dysregulation in various major brain regions, is understood as the key driver of positive and negative symptoms of schizophrenia. Many antipsychotic agents act as D2 receptor antagonists, as with amisulpride. Amisulpride is a selective dopamine D2 and D3 receptor antagonist. It has high preferential activity towards dopamine receptors in the limbic system rather than the striatum, leading to a lower risk of extrapyramidal side effects than other atypical antipsychotic agents. At low doses, amisulpride reduces negative symptoms of schizophrenia by blocking pre-synaptic dopamine D2 and D3 receptors, increasing the levels of dopamine in the synaptic cleft and facilitating dopaminergic transmission. At higher doses, amisulpride blocks postsynaptic receptors, inhibiting dopaminergic hyperactivity: this explains the drug improving positive symptoms. Amisulpride also works as an antagonist at 5-HT 7A receptors and 5-HT 2A receptors, which may be related to its antidepressant effects. The chemoreceptor trigger zone (CTZ), also commonly known as the area postrema (AP), is an important brain region located within the dorsal surface of the medulla oblongata. CTZ is involved in emesis: it contains receptors, such as dopamine receptors, that are activated in response to emetic agents in the blood and relay information to the vomiting center, which is responsible for inducing the vomiting reflex. Amisulpride is an antiemetic agent that works to limit signals that promote nausea and vomiting. Amisulpride binds to D2 and D3 receptors in the CTZ, leading to reduced dopaminergic signalling into the vomiting center. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, amisulpride is rapidly absorbed with absolute bioavailability of 48%. Amisulpride has two absorption peaks, with one rapidly achieved within one hour post-dose and a second peak occurring between three to four hours post-dose. Following oral administration of a 50 mg dose, two peak plasma concentrations were 39 ± 3 and 54 ± 4 ng/mL. Following intravenous administration, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases by 50% within approximately 15 minutes. The AUC(0-∞) increases dose-proportionally in the dose range from 5 mg to 40 mg, which is about four times the maximum recommended dose. In healthy patients receiving intravenous amisulpride, the mean (SD) Cmax was 200 (139) ng/mL at the dose of 5 mg and 451 (230) ng/mL at the dose of 10 mg. The AUC ranged from 136 to 154 ng x h/mL in the dose range of 5 mg to 10 mg. In patients undergoing surgery, the mean (SD) Cmax ranged from 127 (62) to 161 (58) ng/mL at the dose of 5 mg. At the dose of 10 mg, it was 285 (446) ng/mL. The AUC ranged from 204 to 401 ng x h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following oral administration, the volume of distribution is 5.8 L/kg. Following intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 L in surgical patients and 171 L in healthy subjects. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding ranges from 25% to 30% in the concentration range from 37 to 1850 ng/mL. Amisulpride distributes into erythrocytes. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amisulpride undergoes minimal metabolism and its metabolites in plasma are largely undetectable. Two identified metabolites, formed by de-ethylation and oxidation, are pharmacologically inactive and account for approximately 4% of the dose. Metabolites remain largely uncharacterized. Metabolism of amisulpride does not involve cytochrome P450 enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following intravenous administration, about 74% of amisulpride is excreted in urine, where 58% of the recovered dose was excreted as unchanged amisulpride. About 23% of the dose is excreted in feces, with 20% of the excreted dose as unchanged parent drug. Following intravenous administration, about four metabolites were identified in urine and feces, accounting for less than 7% of the total dose administered. About 22 to 25% of orally administered amisulpride is excreted in urine, mostly as the unchanged parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elimination is biphasic. The elimination half-life of amisulpride is approximately 12 hours after an oral dose. The mean elimination half-life is approximately four to five hours in both healthy subjects and patients undergoing surgery receiving intravenous amisulpride. •Clearance (Drug A): No clearance available •Clearance (Drug B): The plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects following intravenous administration. Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In mice, oral LD 50 is 1024 mg/kg, intraperitoneal LD 50 is 175 mg/kg, and subcutaneous LD 50 is 224 mg/kg. The Lowest published toxic dose (TDLo) following subcutaneous administration is 0.24 mg/kg in rats. The oral TDLo in men is 4.3 mg/kg. Oral doses of amisulpride above 1200 mg/day are associated with adverse effects related to dopamine-2 (D2) antagonism. Cardiovascular adverse reactions include prolongation of the QT interval, torsades de pointes, bradycardia, and hypotension. Neuropsychiatric adverse reactions include sedation, coma, seizures, and dystonic and extrapyramidal reactions. As there is no specific antidote for amisulpride overdosage, management includes cardiac monitoring and treatment of severe extrapyramidal symptoms. Drug elimination with the use of hemodialysis is effective. Severe extrapyramidal effects may be managed with anticholinergic drugs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Barhemsys •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aminosultopride Amisulprida Amisulpride Amisulpridum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amisulpride is a dopamine D2 receptor antagonist used in the treatment of acute and chronic schizophrenia, and in the prevention and treatment of postoperative nausea and vomiting in adults.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Amisulpride interact? Information: •Drug A: Buserelin •Drug B: Amisulpride •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amisulpride is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Intravenous amisulpride is indicated in adults for the prevention of postoperative nausea and vomiting, either alone or in combination with an antiemetic of a different class. It is also indicated for the treatment of postoperative nausea and vomiting in patients who have received anti-emetic prophylaxis with an agent of a different class or have not received prophylaxis. Oral amisulpride is indicated for the treatment of acute and chronic schizophrenic disorders, characterized by positive symptoms with delusions, hallucinations, thought disorders, hostility and suspicious behavior; or primarily negative symptoms (deficit syndrome) with blunted affect, emotional and social withdrawal. Amisulpride also controls secondary negative symptoms in productive conditions as well as affective disorders such as depressive mood or retardation. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amisulpride is a selective dopamine D2 and D3 receptor antagonist with no affinity towards other dopamine receptor subtypes. Amisulpride is an atypical antipsychotic agent that works as an antagonist at dopamine receptors in the limbic system. Since it works preferentially in the limbic system, amisulpride is less likely to be associated with extrapyramidal adverse effects than other atypical antipsychotic agents. Amisulpride has no affinity for serotonin, alpha-adrenergic, H1-histamine, cholinergic, and sigma receptors. In clinical trials, amisulpride improved reduced secondary negative symptoms, affective symptoms, and psychomotor retardation in patients with acute exacerbation of schizophrenia. Notably, amisulpride has a differential target binding profile at different doses: at low doses, amisulpride selectively binds to presynaptic dopamine autoreceptors. At high doses, it preferentially binds to post-synaptic dopamine receptors. This explains how amisulpride reduces negative symptoms at low doses and mediates antipsychotic effects at high doses. One study alluded that the antinociceptive effects of amisulpride are mediated through opioid receptor acvitation and D2 receptor antagonism. The actions of amisulpride at opioid receptors may explain its pro-convulsant properties. Amisulpride is also an antiemetic agent that prevents and alleviates postoperative nausea and vomiting. It primarily works by blocking dopamine signalling in the chemoreceptor trigger zone, which is a brain area that relays stimuli to the vomiting center. In clinical trials comprising Caucasian and Japanese subjects, amisulpride caused dose- and concentration-dependent prolongation of the QT interval; thus, intravenous infusion under a strict dosing regimen and close monitoring of patients with pre-existing cardiovascular conditions are recommended. Amisulpride increases plasma prolactin levels, leading to an association with benign pituitary tumours such as prolactinoma. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dopamine is an essential and critical neurotransmitter produced in the substantia nigra and ventral tegmental regions of the brain. Dopaminergic projection function in the nigrostriatal, mesolimbic, and mesocortical systems. Hyperactive dopamine transmission in the mesolimbic areas, or dopamine dysregulation in various major brain regions, is understood as the key driver of positive and negative symptoms of schizophrenia. Many antipsychotic agents act as D2 receptor antagonists, as with amisulpride. Amisulpride is a selective dopamine D2 and D3 receptor antagonist. It has high preferential activity towards dopamine receptors in the limbic system rather than the striatum, leading to a lower risk of extrapyramidal side effects than other atypical antipsychotic agents. At low doses, amisulpride reduces negative symptoms of schizophrenia by blocking pre-synaptic dopamine D2 and D3 receptors, increasing the levels of dopamine in the synaptic cleft and facilitating dopaminergic transmission. At higher doses, amisulpride blocks postsynaptic receptors, inhibiting dopaminergic hyperactivity: this explains the drug improving positive symptoms. Amisulpride also works as an antagonist at 5-HT 7A receptors and 5-HT 2A receptors, which may be related to its antidepressant effects. The chemoreceptor trigger zone (CTZ), also commonly known as the area postrema (AP), is an important brain region located within the dorsal surface of the medulla oblongata. CTZ is involved in emesis: it contains receptors, such as dopamine receptors, that are activated in response to emetic agents in the blood and relay information to the vomiting center, which is responsible for inducing the vomiting reflex. Amisulpride is an antiemetic agent that works to limit signals that promote nausea and vomiting. Amisulpride binds to D2 and D3 receptors in the CTZ, leading to reduced dopaminergic signalling into the vomiting center. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, amisulpride is rapidly absorbed with absolute bioavailability of 48%. Amisulpride has two absorption peaks, with one rapidly achieved within one hour post-dose and a second peak occurring between three to four hours post-dose. Following oral administration of a 50 mg dose, two peak plasma concentrations were 39 ± 3 and 54 ± 4 ng/mL. Following intravenous administration, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases by 50% within approximately 15 minutes. The AUC(0-∞) increases dose-proportionally in the dose range from 5 mg to 40 mg, which is about four times the maximum recommended dose. In healthy patients receiving intravenous amisulpride, the mean (SD) Cmax was 200 (139) ng/mL at the dose of 5 mg and 451 (230) ng/mL at the dose of 10 mg. The AUC ranged from 136 to 154 ng x h/mL in the dose range of 5 mg to 10 mg. In patients undergoing surgery, the mean (SD) Cmax ranged from 127 (62) to 161 (58) ng/mL at the dose of 5 mg. At the dose of 10 mg, it was 285 (446) ng/mL. The AUC ranged from 204 to 401 ng x h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following oral administration, the volume of distribution is 5.8 L/kg. Following intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 L in surgical patients and 171 L in healthy subjects. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding ranges from 25% to 30% in the concentration range from 37 to 1850 ng/mL. Amisulpride distributes into erythrocytes. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amisulpride undergoes minimal metabolism and its metabolites in plasma are largely undetectable. Two identified metabolites, formed by de-ethylation and oxidation, are pharmacologically inactive and account for approximately 4% of the dose. Metabolites remain largely uncharacterized. Metabolism of amisulpride does not involve cytochrome P450 enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following intravenous administration, about 74% of amisulpride is excreted in urine, where 58% of the recovered dose was excreted as unchanged amisulpride. About 23% of the dose is excreted in feces, with 20% of the excreted dose as unchanged parent drug. Following intravenous administration, about four metabolites were identified in urine and feces, accounting for less than 7% of the total dose administered. About 22 to 25% of orally administered amisulpride is excreted in urine, mostly as the unchanged parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Elimination is biphasic. The elimination half-life of amisulpride is approximately 12 hours after an oral dose. The mean elimination half-life is approximately four to five hours in both healthy subjects and patients undergoing surgery receiving intravenous amisulpride. •Clearance (Drug A): No clearance available •Clearance (Drug B): The plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects following intravenous administration. Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In mice, oral LD 50 is 1024 mg/kg, intraperitoneal LD 50 is 175 mg/kg, and subcutaneous LD 50 is 224 mg/kg. The Lowest published toxic dose (TDLo) following subcutaneous administration is 0.24 mg/kg in rats. The oral TDLo in men is 4.3 mg/kg. Oral doses of amisulpride above 1200 mg/day are associated with adverse effects related to dopamine-2 (D2) antagonism. Cardiovascular adverse reactions include prolongation of the QT interval, torsades de pointes, bradycardia, and hypotension. Neuropsychiatric adverse reactions include sedation, coma, seizures, and dystonic and extrapyramidal reactions. As there is no specific antidote for amisulpride overdosage, management includes cardiac monitoring and treatment of severe extrapyramidal symptoms. Drug elimination with the use of hemodialysis is effective. Severe extrapyramidal effects may be managed with anticholinergic drugs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Barhemsys •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aminosultopride Amisulprida Amisulpride Amisulpridum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amisulpride is a dopamine D2 receptor antagonist used in the treatment of acute and chronic schizophrenia, and in the prevention and treatment of postoperative nausea and vomiting in adults. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Amitriptyline interact?

•Drug A: Buserelin •Drug B: Amitriptyline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Amitriptyline. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): This drug in indicated for the following conditions: Major depressive disorder in adults Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Effects in pain and depression Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. Cardiovascular and Anticholinergic Effects Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. Effects on seizure threshold This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk. •Protein binding (Drug A): 15% •Protein binding (Drug B): Very highly protein bound (95%) in plasma and tissues. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, nortriptyline. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same pharmacologic profile as nortriptyline but are significantly weaker. Demethylnortriptyline and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Toxicity Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg. Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent. Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others,. Use in pregnancy For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits. Use in breastfeeding Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. Effects on fertility Animal studies have shown reproductive toxicity. No data on the effects of amitriptyline on human fertility are available. Mutagenesis and carcinogenesis The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Elavil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amitriptilina Amitriptylin Amitriptyline Amitriptylinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amitriptyline is a tricyclic antidepressant indicated in the treatment of depressive illness, either endogenous or psychotic, and to relieve depression associated anxiety.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Amitriptyline interact? Information: •Drug A: Buserelin •Drug B: Amitriptyline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Amitriptyline. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): This drug in indicated for the following conditions: Major depressive disorder in adults Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Effects in pain and depression Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. Cardiovascular and Anticholinergic Effects Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. Effects on seizure threshold This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk. •Protein binding (Drug A): 15% •Protein binding (Drug B): Very highly protein bound (95%) in plasma and tissues. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, nortriptyline. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same pharmacologic profile as nortriptyline but are significantly weaker. Demethylnortriptyline and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Toxicity Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg. Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent. Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others,. Use in pregnancy For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits. Use in breastfeeding Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. Effects on fertility Animal studies have shown reproductive toxicity. No data on the effects of amitriptyline on human fertility are available. Mutagenesis and carcinogenesis The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Elavil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amitriptilina Amitriptylin Amitriptyline Amitriptylinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amitriptyline is a tricyclic antidepressant indicated in the treatment of depressive illness, either endogenous or psychotic, and to relieve depression associated anxiety. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Amodiaquine interact?

•Drug A: Buserelin •Drug B: Amodiaquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amodiaquine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment of acute malarial attacks in non-immune subjects. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, dizziness and nausea. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of plasmodicidal action of amodiaquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 5.2 ± 1.7 (range 0.4 to 5.5) minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 (mouse, intraperitoneal) 225 mg/kg, LD 50 (mouse, oral) 550 mg/kg. Symptoms of overdose include headache, drowsiness, visual disturbances, vomiting, hypokalaemia, cardiovascular collapse and cardiac and respiratory arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, broadening of the QRS complex, and progressive bradycardia leading to ventricular fibrillation and/or arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amodiaquine is an antimalarial drug.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Amodiaquine interact? Information: •Drug A: Buserelin •Drug B: Amodiaquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amodiaquine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment of acute malarial attacks in non-immune subjects. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, dizziness and nausea. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of plasmodicidal action of amodiaquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 5.2 ± 1.7 (range 0.4 to 5.5) minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 (mouse, intraperitoneal) 225 mg/kg, LD 50 (mouse, oral) 550 mg/kg. Symptoms of overdose include headache, drowsiness, visual disturbances, vomiting, hypokalaemia, cardiovascular collapse and cardiac and respiratory arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, broadening of the QRS complex, and progressive bradycardia leading to ventricular fibrillation and/or arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amodiaquine is an antimalarial drug. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Amoxapine interact?

•Drug A: Buserelin •Drug B: Amoxapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amoxapine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. May also be used to treat depression accompanied by anxiety or agitation. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzodiazepines, dibenzocycloheptenes, and dibenzoxepines. It has a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of nor-epinephirine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Amoxapine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations occur within 1-2 hours of oral administration of a single dose. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Widely distributed in body tissues with highest concentrations found in lungs, spleen, kidneys, heart, and brain. Lower concentrations can be detected in testes and muscle. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro tests show that amoxapine binding to human plasma proteins is approximately 90%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amoxapine is almost completely metabolized in the liver to its major metabolite, 8-hydroxyamoxapine, and a minor metabolite, 7-hydroxyamoxapine. Both metabolites are phamacologically inactive and have half-lives of approximately 30 and 6.5 hours, respectively. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 60-69% of a single orally administered dose of amoxapine is excreted in urine, principally as conjugated metabolites. 7-18% of the dose is excrete feces mainly as unconjugated metabolites. Less than 5% of the dose is excreted as unchanged drug in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases. Renal failure may develop two to five days after toxic overdose in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amoxapin Amoxapina Amoxapine Amoxapinum Amoxepine Desmethylloxapin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amoxapine is a tricyclic antidepressant used in the treatment of neurotic or reactive depressive disorders and endogenous or psychotic depression.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Amoxapine interact? Information: •Drug A: Buserelin •Drug B: Amoxapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Amoxapine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. May also be used to treat depression accompanied by anxiety or agitation. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzodiazepines, dibenzocycloheptenes, and dibenzoxepines. It has a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of nor-epinephirine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Amoxapine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations occur within 1-2 hours of oral administration of a single dose. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Widely distributed in body tissues with highest concentrations found in lungs, spleen, kidneys, heart, and brain. Lower concentrations can be detected in testes and muscle. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro tests show that amoxapine binding to human plasma proteins is approximately 90%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amoxapine is almost completely metabolized in the liver to its major metabolite, 8-hydroxyamoxapine, and a minor metabolite, 7-hydroxyamoxapine. Both metabolites are phamacologically inactive and have half-lives of approximately 30 and 6.5 hours, respectively. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 60-69% of a single orally administered dose of amoxapine is excreted in urine, principally as conjugated metabolites. 7-18% of the dose is excrete feces mainly as unconjugated metabolites. Less than 5% of the dose is excreted as unchanged drug in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases. Renal failure may develop two to five days after toxic overdose in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amoxapin Amoxapina Amoxapine Amoxapinum Amoxepine Desmethylloxapin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Amoxapine is a tricyclic antidepressant used in the treatment of neurotic or reactive depressive disorders and endogenous or psychotic depression. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Anagrelide interact?

•Drug A: Buserelin •Drug B: Anagrelide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Anagrelide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis. It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells. The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week. Evidence from animal studies suggests anagrelide may impair female fertility. Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating therapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy. This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1. Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition. While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count). Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12, and may be of value in the treatment of gastrointestinal stromal tumours. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, the bioavailability of anagrelide is approximately 70%. Given on an empty stomach, the C max is reached within 1 hour (T max ) of administration. Co-administration with food slightly lowers the C max and increases the AUC, but not to a clinically significant extent. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The t 1/2 of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively. Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose. Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding. Employ symptomatic and supportive measures if clinically indicated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Agrylin, Xagrid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Anagrelide is a platelet-reducing agent used to treat thrombocythemia, and its related complications, secondary to myeloproliferative neoplasms.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Anagrelide interact? Information: •Drug A: Buserelin •Drug B: Anagrelide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Anagrelide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis. It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells. The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week. Evidence from animal studies suggests anagrelide may impair female fertility. Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating therapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy. This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1. Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition. While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count). Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12, and may be of value in the treatment of gastrointestinal stromal tumours. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following oral administration, the bioavailability of anagrelide is approximately 70%. Given on an empty stomach, the C max is reached within 1 hour (T max ) of administration. Co-administration with food slightly lowers the C max and increases the AUC, but not to a clinically significant extent. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The t 1/2 of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively. Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose. Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding. Employ symptomatic and supportive measures if clinically indicated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Agrylin, Xagrid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Anagrelide is a platelet-reducing agent used to treat thrombocythemia, and its related complications, secondary to myeloproliferative neoplasms. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Apomorphine interact?

•Drug A: Buserelin •Drug B: Apomorphine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Apomorphine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced Parkinson's disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Apomorfina Apomorphin Apomorphine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Apomorphine is a morphine derivative D2 dopamine agonist used to treat hypomobile "off" episodes of advanced Parkinson's disease.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Apomorphine interact? Information: •Drug A: Buserelin •Drug B: Apomorphine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Apomorphine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced Parkinson's disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Apomorfina Apomorphin Apomorphine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Apomorphine is a morphine derivative D2 dopamine agonist used to treat hypomobile "off" episodes of advanced Parkinson's disease. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Arformoterol interact?

•Drug A: Buserelin •Drug B: Arformoterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Arformoterol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Arformoterol is indicated in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Arformoterol, the active (R,R)-enantiomer of formoterol, is a selective long-acting β2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a β2-agonist than the (R,R)-enantiomer. Arformoterol seems to have little or no effect on β1-adrenergic receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): While it is recognized that β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, data indicate that there are also β2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects. The pharmacologic effects of β2-adrenoceptor agonist drugs, including arformoterol, are at least in part attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of the release of proinflammatory mediators from cells, especially from mast cells. In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-response. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In patients with COPD, the mean peak plasma concentration (C max ) and AUC 0-12h following twice daily administration for 14 days were 4.3 pg/mL and 34.5 pg.hr/mL, respectively. The time to peak plasma concentration (T max ) was approximately 0.5 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following the administration of a single oral dose of arformoterol to eight healthy subjects, 63% of the administered dose was recovered in the urine and 11% in the feces within 48 hours. After 14 days, a total of 89% of the total dose had been recovered - 67% in the urine and 22% in the feces - with approximately 1% remaining unchanged in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy male subjects, the clearance of a single oral dose of arformoterol was 8.9 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): A death was reported in dogs after a single oral dose of 5 mg/kg (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose. Arformoterol should not be used more often or at higher doses than recommended, or conjunction with other medications containing long-acting beta 2 -agonists. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Brovana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Arformoterol •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Arformoterol is a beta-2 adrenergic agonist and bronchodilator used for long-term, symptomatic treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Arformoterol interact? Information: •Drug A: Buserelin •Drug B: Arformoterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Arformoterol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Arformoterol is indicated in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Arformoterol, the active (R,R)-enantiomer of formoterol, is a selective long-acting β2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a β2-agonist than the (R,R)-enantiomer. Arformoterol seems to have little or no effect on β1-adrenergic receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): While it is recognized that β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, data indicate that there are also β2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects. The pharmacologic effects of β2-adrenoceptor agonist drugs, including arformoterol, are at least in part attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of the release of proinflammatory mediators from cells, especially from mast cells. In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-response. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In patients with COPD, the mean peak plasma concentration (C max ) and AUC 0-12h following twice daily administration for 14 days were 4.3 pg/mL and 34.5 pg.hr/mL, respectively. The time to peak plasma concentration (T max ) was approximately 0.5 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following the administration of a single oral dose of arformoterol to eight healthy subjects, 63% of the administered dose was recovered in the urine and 11% in the feces within 48 hours. After 14 days, a total of 89% of the total dose had been recovered - 67% in the urine and 22% in the feces - with approximately 1% remaining unchanged in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy male subjects, the clearance of a single oral dose of arformoterol was 8.9 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): A death was reported in dogs after a single oral dose of 5 mg/kg (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose. Arformoterol should not be used more often or at higher doses than recommended, or conjunction with other medications containing long-acting beta 2 -agonists. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Brovana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Arformoterol •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Arformoterol is a beta-2 adrenergic agonist and bronchodilator used for long-term, symptomatic treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Aripiprazole lauroxil interact?

•Drug A: Buserelin •Drug B: Aripiprazole lauroxil •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Aripiprazole lauroxil. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic disorders. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin levels. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •Clearance (Drug A): No clearance available •Clearance (Drug B): In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aristada •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Aripiprazole lauroxil is an antipsychotic used to treat schizophrenia in adults.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Aripiprazole lauroxil interact? Information: •Drug A: Buserelin •Drug B: Aripiprazole lauroxil •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Aripiprazole lauroxil. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic disorders. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin levels. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): 15% •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •Clearance (Drug A): No clearance available •Clearance (Drug B): In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aristada •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Aripiprazole lauroxil is an antipsychotic used to treat schizophrenia in adults. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Aripiprazole interact?

•Drug A: Buserelin •Drug B: Aripiprazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Aripiprazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-1 receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Abilify •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's syndrome.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Aripiprazole interact? Information: •Drug A: Buserelin •Drug B: Aripiprazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Aripiprazole is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-1 receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Abilify •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's syndrome. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Arsenic trioxide interact?

•Drug A: Buserelin •Drug B: Arsenic trioxide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Arsenic trioxide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 75% bound •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and excreted in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Trisenox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Arsenic trioxide interact? Information: •Drug A: Buserelin •Drug B: Arsenic trioxide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Arsenic trioxide. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 75% bound •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and excreted in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Trisenox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Articaine interact?

•Drug A: Buserelin •Drug B: Articaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Articaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Articadent, Astracaine, Orabloc, Septanest, Septocaine, Ultacan, Ultracaine, Zorcaine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Articaine is a local anesthetic used for inducing local, infiltrative, or conductive anesthesia in both simple and complex dental procedures.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Articaine interact? Information: •Drug A: Buserelin •Drug B: Articaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Articaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Articadent, Astracaine, Orabloc, Septanest, Septocaine, Ultacan, Ultracaine, Zorcaine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Articaine is a local anesthetic used for inducing local, infiltrative, or conductive anesthesia in both simple and complex dental procedures. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Asenapine interact?

•Drug A: Buserelin •Drug B: Asenapine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Asenapine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used for treatment in psychosis, schizophrenia and schizoaffective disorders, manic disorders, and bipolar disorders as monotherapy or in combination. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Asenapine is a serotonin, dopamine, noradrenaline, and histamine antagonist in which asenapine possess more potent activity with serotonin receptors than dopamine. Sedation in patients is associated with asenapine's antagonist activity at histamine receptors. Its lower incidence of extrapyramidal effects are associated with the upregulation of D1 receptors. This upregulation occurs due to asenapine's dose-dependent effects on glutamate transmission in the brain. It does not have any significant activity with muscarinic, cholinergic receptors therefore symptoms associated with anticholinergic drug activity like dry mouth or constipation are not expected to be observed. Asenapine has a higher affinity for all aforementioned receptors compared to first-generation and second-generation antipsychotics except for 5-HT1A and 5-HT1B receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Asenapine is an atypical antipsychotic multireceptor neuroleptic drug which shows strong 5HT2A (serotonin) and D2 (dopamine) receptor antagonism, which has been shown to enhance dopamine (DA) and acetylcholine (Ach) efflux in rat brains. Asenapine may improve cognitive function and negative symptoms in patients with schizophrenia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cmax, single 5 mg dose = 4 ng/mL (within 1 hour); Bioavailability, sublingual administration = 35%; Bioavailability, oral administration (swallowed) = <2%; Time to steady state, 5 mg = 3 days; Peak plasma concentration occurs within 0.5 to 1.5 hours. Doubling dose of asenapine results in 1.7-fold increase in maximum concentration and exposure. Drinking water within 2-5 minutes post administration of asenapine results in a decrease in exposure. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 20-25 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 95% protein bound •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Asenapine is oxidized via CYP1A2 and undergoes direct glucuronidation via UGT1A4. Oxidation via CYP1A2 is asenapine's primary mode of metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urine (50%) and feces (50%) •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 24 hours (range of 13.4 - 39.2 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Saphris, Secuado, Sycrest •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Asenapine is an atypical antipsychotic used to treat patients with bipolar I disorder and patients with schizophrenia.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Asenapine interact? Information: •Drug A: Buserelin •Drug B: Asenapine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Asenapine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Used for treatment in psychosis, schizophrenia and schizoaffective disorders, manic disorders, and bipolar disorders as monotherapy or in combination. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Asenapine is a serotonin, dopamine, noradrenaline, and histamine antagonist in which asenapine possess more potent activity with serotonin receptors than dopamine. Sedation in patients is associated with asenapine's antagonist activity at histamine receptors. Its lower incidence of extrapyramidal effects are associated with the upregulation of D1 receptors. This upregulation occurs due to asenapine's dose-dependent effects on glutamate transmission in the brain. It does not have any significant activity with muscarinic, cholinergic receptors therefore symptoms associated with anticholinergic drug activity like dry mouth or constipation are not expected to be observed. Asenapine has a higher affinity for all aforementioned receptors compared to first-generation and second-generation antipsychotics except for 5-HT1A and 5-HT1B receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Asenapine is an atypical antipsychotic multireceptor neuroleptic drug which shows strong 5HT2A (serotonin) and D2 (dopamine) receptor antagonism, which has been shown to enhance dopamine (DA) and acetylcholine (Ach) efflux in rat brains. Asenapine may improve cognitive function and negative symptoms in patients with schizophrenia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cmax, single 5 mg dose = 4 ng/mL (within 1 hour); Bioavailability, sublingual administration = 35%; Bioavailability, oral administration (swallowed) = <2%; Time to steady state, 5 mg = 3 days; Peak plasma concentration occurs within 0.5 to 1.5 hours. Doubling dose of asenapine results in 1.7-fold increase in maximum concentration and exposure. Drinking water within 2-5 minutes post administration of asenapine results in a decrease in exposure. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 20-25 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 95% protein bound •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Asenapine is oxidized via CYP1A2 and undergoes direct glucuronidation via UGT1A4. Oxidation via CYP1A2 is asenapine's primary mode of metabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urine (50%) and feces (50%) •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 24 hours (range of 13.4 - 39.2 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Saphris, Secuado, Sycrest •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Asenapine is an atypical antipsychotic used to treat patients with bipolar I disorder and patients with schizophrenia. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Astemizole interact?

•Drug A: Buserelin •Drug B: Astemizole •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Astemizole. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Astemizole is a second generation H 1 -receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Astemizole competes with histamine for binding at H 1 -receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H 1 -receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H 3 -receptors, producing adverse effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 96.7% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Almost completely metabolized in the liver and primarily excreted in the feces. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 1 day •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =2052mg/kg in mice •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Astemizol Astémizole Astemizole Astemizolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Astemizole is a second generation antihistamine used to treat allergy symptoms.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Astemizole interact? Information: •Drug A: Buserelin •Drug B: Astemizole •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Astemizole. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Astemizole is a second generation H 1 -receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Astemizole competes with histamine for binding at H 1 -receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H 1 -receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H 3 -receptors, producing adverse effects. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 96.7% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Almost completely metabolized in the liver and primarily excreted in the feces. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 1 day •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): LD 50 =2052mg/kg in mice •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Astemizol Astémizole Astemizole Astemizolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Astemizole is a second generation antihistamine used to treat allergy symptoms. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Atazanavir interact?

•Drug A: Buserelin •Drug B: Atazanavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Atazanavir is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Atazanavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 3 months of age and older weighing at least 5kg. Atazanavir is also indicated in combination with cobicistat and other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35kg. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Atazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture for 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Atazanavir is rapidly absorbed with a T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C max values over the dose range of 200 to 800 mg once daily. A steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C max relative to the fasting state. Administration of atazanavir with either a light or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C max by approximately 25% compared to the fasting state. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In patients with HIV infection, the volume of distribution of atazanavir was estimated to be 88.3 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single 400-mg dose of C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drugs accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose). •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with HIV infection, the clearance of atazanavir was estimated to be 12.9 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Evotaz, Reyataz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atazanavir Atazanavirum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Atazanavir is an antiviral protease inhibitor used in combination with other antiretrovirals for the treatment of HIV.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Atazanavir interact? Information: •Drug A: Buserelin •Drug B: Atazanavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Atazanavir is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Atazanavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 3 months of age and older weighing at least 5kg. Atazanavir is also indicated in combination with cobicistat and other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35kg. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Atazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture for 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Atazanavir is rapidly absorbed with a T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C max values over the dose range of 200 to 800 mg once daily. A steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C max relative to the fasting state. Administration of atazanavir with either a light or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C max by approximately 25% compared to the fasting state. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): In patients with HIV infection, the volume of distribution of atazanavir was estimated to be 88.3 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single 400-mg dose of C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drugs accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose). •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with HIV infection, the clearance of atazanavir was estimated to be 12.9 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Evotaz, Reyataz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atazanavir Atazanavirum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Atazanavir is an antiviral protease inhibitor used in combination with other antiretrovirals for the treatment of HIV. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Atomoxetine interact?

•Drug A: Buserelin •Drug B: Atomoxetine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Atomoxetine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine has been shown to specifically increase norepinephrine and dopamine within the prefrontal cortex, which results in improved ADHD symptoms. Due to atomoxetine's noradrenergic activity, it also has effects on the cardiovascular system such as increased blood pressure and tachycardia. Sudden deaths, stroke, and myocardial infarction have been reported in patients taking atomoxetine at usual doses for ADHD. Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Although the role of atomoxetine in these cases is unknown, consideration should be given to not treating patients with clinically significant cardiac abnormalities. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. Atomoxetine capsules increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). All pediatric patients being treated with atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Postmarketing reports indicate that atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atomoxetine is known to be a potent and selective inhibitor of the norepinephrine transporter (NET), which prevents cellular reuptake of norepinephrine throughout the brain, which is thought to improve the symptoms of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT), and blocks the N-methyl-d-aspartate (NMDA) receptor, indicating a role for the glutamatergic system in the pathophysiology of ADHD. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetic profile of atomoxetine is highly dependent on cytochrome P450 2D6 genetic polymorphisms of the individual. A large fraction of the population (up to 10% of Caucasians and 2% of people of African descent and 1% of Asians) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal CYP2D6 activity. Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs). Mean maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.h/ml. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The reported volume of distribution of oral atomoxetine was 1.6-2.6 L/kg. The steady-state volume of distribution of intravenous atomoxetine was approximately 0.85 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): At therapeutic concentrations, 98.7% of plasma atomoxetine is bound to protein, with 97.5% of that being bound to albumin, followed by alpha-1-acid glycoprotein and immunoglobulin G. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. People with reduced activity in the CYP2D6 pathway (also known as poor metabolizers or PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (also known as extensive metabolizers, or EMs). For PMs, the AUC of atomoxetine at steady-state is approximately 10-fold higher and Cmax is about 5-fold greater than for EMs. The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). In individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine is still the primary metabolite, but is formed by several other cytochrome P450 enzymes and at a slower rate. Another minor metabolite, N-Desmethyl-atomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine and lower plasma concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction (less than 3%) of the atomoxetine dose is excreted as unchanged atomoxetine, indicating extensive biotransformation. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The reported half-life depends on the CYP2D6 genetic polymorphisms of the individual and can range from 3 to 5.6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate of atomoxetine depends the CYP2D6 genetic polymorphisms of the individual and can range of 0.27-0.67 L.h/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine capsules and at least one other drug. There have been no reports of death involving overdose of atomoxetine capsules alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine capsules were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. If symptoms of overdose are suspected, a Certified Poison Control Center should be consulted for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Strattera •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atomoxetina Atomoxetine Tomoxetina Tomoxetine Tomoxetinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) used in the management of Attention Deficit Hyperactivity Disorder (ADHD).

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Atomoxetine interact? Information: •Drug A: Buserelin •Drug B: Atomoxetine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Atomoxetine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine has been shown to specifically increase norepinephrine and dopamine within the prefrontal cortex, which results in improved ADHD symptoms. Due to atomoxetine's noradrenergic activity, it also has effects on the cardiovascular system such as increased blood pressure and tachycardia. Sudden deaths, stroke, and myocardial infarction have been reported in patients taking atomoxetine at usual doses for ADHD. Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Although the role of atomoxetine in these cases is unknown, consideration should be given to not treating patients with clinically significant cardiac abnormalities. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. Atomoxetine capsules increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). All pediatric patients being treated with atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Postmarketing reports indicate that atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atomoxetine is known to be a potent and selective inhibitor of the norepinephrine transporter (NET), which prevents cellular reuptake of norepinephrine throughout the brain, which is thought to improve the symptoms of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT), and blocks the N-methyl-d-aspartate (NMDA) receptor, indicating a role for the glutamatergic system in the pathophysiology of ADHD. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The pharmacokinetic profile of atomoxetine is highly dependent on cytochrome P450 2D6 genetic polymorphisms of the individual. A large fraction of the population (up to 10% of Caucasians and 2% of people of African descent and 1% of Asians) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal CYP2D6 activity. Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs). Mean maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.h/ml. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The reported volume of distribution of oral atomoxetine was 1.6-2.6 L/kg. The steady-state volume of distribution of intravenous atomoxetine was approximately 0.85 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): At therapeutic concentrations, 98.7% of plasma atomoxetine is bound to protein, with 97.5% of that being bound to albumin, followed by alpha-1-acid glycoprotein and immunoglobulin G. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. People with reduced activity in the CYP2D6 pathway (also known as poor metabolizers or PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (also known as extensive metabolizers, or EMs). For PMs, the AUC of atomoxetine at steady-state is approximately 10-fold higher and Cmax is about 5-fold greater than for EMs. The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). In individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine is still the primary metabolite, but is formed by several other cytochrome P450 enzymes and at a slower rate. Another minor metabolite, N-Desmethyl-atomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine and lower plasma concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction (less than 3%) of the atomoxetine dose is excreted as unchanged atomoxetine, indicating extensive biotransformation. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The reported half-life depends on the CYP2D6 genetic polymorphisms of the individual and can range from 3 to 5.6 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance rate of atomoxetine depends the CYP2D6 genetic polymorphisms of the individual and can range of 0.27-0.67 L.h/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine capsules and at least one other drug. There have been no reports of death involving overdose of atomoxetine capsules alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine capsules were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. If symptoms of overdose are suspected, a Certified Poison Control Center should be consulted for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Strattera •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atomoxetina Atomoxetine Tomoxetina Tomoxetine Tomoxetinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) used in the management of Attention Deficit Hyperactivity Disorder (ADHD). Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Atropine interact?

•Drug A: Buserelin •Drug B: Atropine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Atropine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): The intravenous, intramuscular, subcutaneous, intraosseous and endotracheal use of atropine is indicated for the temporary blockade of severe or life-threatening muscarinic effects. The intramuscular use of atropine in the form of a pen injector is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides in adult and pediatric patients. The ophthalmic use of atropine is indicated for mydriasis, cycloplegia, and penalization of the healthy eye in the treatment of amblyopia. In combination with difenoxin or diphenoxylate (tablets for oral use), atropine is indicated as adjunctive therapy in the management of acute nonspecific diarrhea. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Atropine is an antimuscarinic agent that antagonizes the effects of acetylcholine. In small doses, atropine slows heart rate, and tachycardia develops due to paralysis of vagal control. Compared to scopolamine, atropine has a more potent and prolonged effect on the heart, intestine and bronchial muscle, but a weaker effect on the iris, ciliary body and certain secretory glands. Atropine leads to increased respiratory rate and depth of respiration, possibly due to the drug-induced bronchiolar dilatation rather than its mild effect on vagal excitation. At an adequate dose, atropine abolishes different types of reflex vagal cardiac slowing or asystole. Atropine can be used to prevent or abolish bradycardia or asystole induced by the injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. When vagal activity is an etiologic factor, atropine may also lessen the degree of partial heart block. In clinical doses, atropine counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure. The use of topical atropine in the eye induces mydriasis by inhibiting the contraction of the circular pupillary sphincter muscle normally stimulated by acetylcholine. This results in the contraction of the countering radial pupillary dilator muscle and pupil dilation. The use of atropine may precipitate acute glaucoma and convert partial organic pyloric stenosis into complete obstruction. Atropine may also lead to complete urinary retention in patients with prostatic hypertrophy and cause the thickening of bronchial secretions and formation of viscid plugs in patients with chronic lung disease. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atropine binds to and inhibits muscarinic acetylcholine receptors, competitively blocking the effects of acetylcholine and other choline esters. It acts as a reversible non-specific antagonist of muscarinic receptors, showing affinity for the M1, M2, M3, M4 and M5 receptor subtypes. Atropine antagonizes the effects of acetylcholine on tissues innervated by postganglionic cholinergic nerves, such as smooth muscle, cardiac tissue, exocrine glands and the central nervous system. Also, it acts in less innervated smooth muscle that responds to endogenous acetylcholine. The actions of atropine can be overcome by increasing the concentration of acetylcholine at receptor sites (for instance, the use of anticholinesterase agents that inhibit the hydrolysis of acetylcholine). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Intravenous atropine follows a non-linear pharmacokinetic model at doses between 0.5 and 4 mg. After intramuscular administration, atropine is rapidly absorbed. In adults given 1.67 mg of atropine intramuscularly, the C max was 9.6 ng/mL and the T max went from 3 to 60 minutes. In healthy subjects given 30 µL of atropine ophthalmic solution, the C max and T max were 288 pg/mL and 28 minutes, respectively. Atropine is well absorbed in the gastrointestinal tract and rapidly delivered to systemic circulation. When administered intramuscularly, atropine has a bioavailability of 50%. The AUC 0-INF and C max of atropine are higher in females than males (15%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Atropine is distributed throughout the body. Following intravenous administration, the total apparent volume of distribution of atropine ranged between 1.0 and 1.7 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of atropine ranges from 14% to 44%, and is saturable between 2 and 20 μg/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Atropine is mainly metabolized by enzymatic hydrolysis in the liver. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. The metabolism of atropine is inhibited by organophosphate pesticides. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 13 to 50% of atropine is excreted unchanged in the urine. In healthy volunteers given intravenous atropine, 29% of tropine was excreted in urine, along with 15% of an unidentified metabolite. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following intravenous and intramuscular doses of atropine, half-life values range from approximately 2 to 4 hours. In geriatric patients (65-75 years old), intravenous atropine has a longer half-life (10 hours). Also, the half-life of atropine is slightly shorter (approximately 20 minutes) in females than in males. In healthy volunteers given 30 µL of atropine sulfate by topical ocular administration, the half-life of atropine was approximately 2.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the total clearance of atropine ranged between 5.9 and 6.8 mL/min/kg. Exercise, before and after intramuscular administration, decreases the clearance of atropine. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): High doses of atropine may cause palpitation, dilated pupils, difficulty swallowing, hot dry skin, thirst, dizziness, restlessness, tremor, fatigue and ataxia. Toxic doses of atropine lead to restlessness and excitement, hallucinations, delirium and coma. In cases of severe intoxication, atropine can cause a circulatory collapse, leading to a decline in blood pressure and respiratory failure that may ensue in death following paralysis and coma. In case of atropine overdose, supportive treatment should be administered. Provide artificial respiration with oxygen if respiration is depressed, and follow cooling methods to reduce atropine-induced fever, especially in pediatric patients. In case of urinary retention, catheterization may be required. Atropine is mainly eliminated through the kidney; therefore, urinary output must be maintained and increased if possible. In case of atropine-induced photophobia, the room should be darkened. A short-acting barbiturate or diazepam may be given as needed to control marked excitement and convulsions; however, large doses should be avoided since central depressant action may coincide with the depression that occurs late in atropine poisoning. Central stimulants are not recommended. The acute oral toxicity (LD 50 ) of atropine in mice is 75 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Atnaa, Atropen, Busulfex, Donnatal, Duodote, Enlon-plus, Isopto Atropine, Lomotil, Minims Atropine Sulphate, Motofen, Phenohytro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atropin Atropina Atropine Atropinum dl-Hyoscyamine dl-tropyltropate Tropine tropate •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Atropine is a muscarinic antagonist used to treat poisoning by muscarinic agents, including organophosphates and other drugs.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Atropine interact? Information: •Drug A: Buserelin •Drug B: Atropine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Atropine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): The intravenous, intramuscular, subcutaneous, intraosseous and endotracheal use of atropine is indicated for the temporary blockade of severe or life-threatening muscarinic effects. The intramuscular use of atropine in the form of a pen injector is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides in adult and pediatric patients. The ophthalmic use of atropine is indicated for mydriasis, cycloplegia, and penalization of the healthy eye in the treatment of amblyopia. In combination with difenoxin or diphenoxylate (tablets for oral use), atropine is indicated as adjunctive therapy in the management of acute nonspecific diarrhea. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Atropine is an antimuscarinic agent that antagonizes the effects of acetylcholine. In small doses, atropine slows heart rate, and tachycardia develops due to paralysis of vagal control. Compared to scopolamine, atropine has a more potent and prolonged effect on the heart, intestine and bronchial muscle, but a weaker effect on the iris, ciliary body and certain secretory glands. Atropine leads to increased respiratory rate and depth of respiration, possibly due to the drug-induced bronchiolar dilatation rather than its mild effect on vagal excitation. At an adequate dose, atropine abolishes different types of reflex vagal cardiac slowing or asystole. Atropine can be used to prevent or abolish bradycardia or asystole induced by the injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. When vagal activity is an etiologic factor, atropine may also lessen the degree of partial heart block. In clinical doses, atropine counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure. The use of topical atropine in the eye induces mydriasis by inhibiting the contraction of the circular pupillary sphincter muscle normally stimulated by acetylcholine. This results in the contraction of the countering radial pupillary dilator muscle and pupil dilation. The use of atropine may precipitate acute glaucoma and convert partial organic pyloric stenosis into complete obstruction. Atropine may also lead to complete urinary retention in patients with prostatic hypertrophy and cause the thickening of bronchial secretions and formation of viscid plugs in patients with chronic lung disease. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Atropine binds to and inhibits muscarinic acetylcholine receptors, competitively blocking the effects of acetylcholine and other choline esters. It acts as a reversible non-specific antagonist of muscarinic receptors, showing affinity for the M1, M2, M3, M4 and M5 receptor subtypes. Atropine antagonizes the effects of acetylcholine on tissues innervated by postganglionic cholinergic nerves, such as smooth muscle, cardiac tissue, exocrine glands and the central nervous system. Also, it acts in less innervated smooth muscle that responds to endogenous acetylcholine. The actions of atropine can be overcome by increasing the concentration of acetylcholine at receptor sites (for instance, the use of anticholinesterase agents that inhibit the hydrolysis of acetylcholine). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Intravenous atropine follows a non-linear pharmacokinetic model at doses between 0.5 and 4 mg. After intramuscular administration, atropine is rapidly absorbed. In adults given 1.67 mg of atropine intramuscularly, the C max was 9.6 ng/mL and the T max went from 3 to 60 minutes. In healthy subjects given 30 µL of atropine ophthalmic solution, the C max and T max were 288 pg/mL and 28 minutes, respectively. Atropine is well absorbed in the gastrointestinal tract and rapidly delivered to systemic circulation. When administered intramuscularly, atropine has a bioavailability of 50%. The AUC 0-INF and C max of atropine are higher in females than males (15%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Atropine is distributed throughout the body. Following intravenous administration, the total apparent volume of distribution of atropine ranged between 1.0 and 1.7 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of atropine ranges from 14% to 44%, and is saturable between 2 and 20 μg/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Atropine is mainly metabolized by enzymatic hydrolysis in the liver. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. The metabolism of atropine is inhibited by organophosphate pesticides. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 13 to 50% of atropine is excreted unchanged in the urine. In healthy volunteers given intravenous atropine, 29% of tropine was excreted in urine, along with 15% of an unidentified metabolite. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following intravenous and intramuscular doses of atropine, half-life values range from approximately 2 to 4 hours. In geriatric patients (65-75 years old), intravenous atropine has a longer half-life (10 hours). Also, the half-life of atropine is slightly shorter (approximately 20 minutes) in females than in males. In healthy volunteers given 30 µL of atropine sulfate by topical ocular administration, the half-life of atropine was approximately 2.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, the total clearance of atropine ranged between 5.9 and 6.8 mL/min/kg. Exercise, before and after intramuscular administration, decreases the clearance of atropine. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): High doses of atropine may cause palpitation, dilated pupils, difficulty swallowing, hot dry skin, thirst, dizziness, restlessness, tremor, fatigue and ataxia. Toxic doses of atropine lead to restlessness and excitement, hallucinations, delirium and coma. In cases of severe intoxication, atropine can cause a circulatory collapse, leading to a decline in blood pressure and respiratory failure that may ensue in death following paralysis and coma. In case of atropine overdose, supportive treatment should be administered. Provide artificial respiration with oxygen if respiration is depressed, and follow cooling methods to reduce atropine-induced fever, especially in pediatric patients. In case of urinary retention, catheterization may be required. Atropine is mainly eliminated through the kidney; therefore, urinary output must be maintained and increased if possible. In case of atropine-induced photophobia, the room should be darkened. A short-acting barbiturate or diazepam may be given as needed to control marked excitement and convulsions; however, large doses should be avoided since central depressant action may coincide with the depression that occurs late in atropine poisoning. Central stimulants are not recommended. The acute oral toxicity (LD 50 ) of atropine in mice is 75 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Atnaa, Atropen, Busulfex, Donnatal, Duodote, Enlon-plus, Isopto Atropine, Lomotil, Minims Atropine Sulphate, Motofen, Phenohytro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atropin Atropina Atropine Atropinum dl-Hyoscyamine dl-tropyltropate Tropine tropate •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Atropine is a muscarinic antagonist used to treat poisoning by muscarinic agents, including organophosphates and other drugs. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Azatadine interact?

•Drug A: Buserelin •Drug B: Azatadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Azatadine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of the symptoms of upper respiratory mucosal congestion in perennial and allergic rhinitis, and for the relief of nasal congestion and eustachian t.b. congestion. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Azatadine is an antihistamine, related to cyproheptadine, with anti-serotonin, anticholinergic (drying), and sedative effects. Azatadine is in the same class of drugs as chlorpromazine (Thorazine) and trifluoperazine (Stelazine); however, unlike the other drugs in this class, azatadine is not used clinically as an anti-psychotic. Antihistamines antagonize the vasodilator effect of endogenously released histamine, especially in small vessels, and mitigate the effect of histamine which results in increased capillary permeability and edema formation. As consequences of these actions, antihistamines antagonize the physiological manifestations of histamine release in the nose following antigen-antibody interaction, such as congestion related to vascular engorgement, mucosal edema, and profuse, watery secretion, and irritation and sneezing resulting from histamine action on afferent nerve terminals. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Antihistamines such as azatadine appear to compete with histamine for histamine H1- receptor sites on effector cells. The antihistamines antagonize those pharmacological effects of histamine which are mediated through activation of H1- receptor sites and thereby reduce the intensity of allergic reactions and tissue injury response involving histamine release. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed after oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in mature rats and mice was greater than 1700 mg/kg and 600 mg/kg, respectively. Symptoms of overdose include clumsiness or unsteadiness, seizures, severe drowsiness, flushing or redness of face, hallucinations, muscle spasms (especially of neck and back), restlessness, shortness of breath, shuffling walk, tic-like (jerky) movements of head and face, trembling and shaking of hands, and insomnia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azatadin Azatadina Azatadine Azatadinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Azatadine is an H1 receptor antagonist used to treat perennial and allergic rhinitis as well as eustachian tube congestion.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Azatadine interact? Information: •Drug A: Buserelin •Drug B: Azatadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Azatadine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of the symptoms of upper respiratory mucosal congestion in perennial and allergic rhinitis, and for the relief of nasal congestion and eustachian t.b. congestion. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Azatadine is an antihistamine, related to cyproheptadine, with anti-serotonin, anticholinergic (drying), and sedative effects. Azatadine is in the same class of drugs as chlorpromazine (Thorazine) and trifluoperazine (Stelazine); however, unlike the other drugs in this class, azatadine is not used clinically as an anti-psychotic. Antihistamines antagonize the vasodilator effect of endogenously released histamine, especially in small vessels, and mitigate the effect of histamine which results in increased capillary permeability and edema formation. As consequences of these actions, antihistamines antagonize the physiological manifestations of histamine release in the nose following antigen-antibody interaction, such as congestion related to vascular engorgement, mucosal edema, and profuse, watery secretion, and irritation and sneezing resulting from histamine action on afferent nerve terminals. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Antihistamines such as azatadine appear to compete with histamine for histamine H1- receptor sites on effector cells. The antihistamines antagonize those pharmacological effects of histamine which are mediated through activation of H1- receptor sites and thereby reduce the intensity of allergic reactions and tissue injury response involving histamine release. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed after oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD 50 in mature rats and mice was greater than 1700 mg/kg and 600 mg/kg, respectively. Symptoms of overdose include clumsiness or unsteadiness, seizures, severe drowsiness, flushing or redness of face, hallucinations, muscle spasms (especially of neck and back), restlessness, shortness of breath, shuffling walk, tic-like (jerky) movements of head and face, trembling and shaking of hands, and insomnia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azatadin Azatadina Azatadine Azatadinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Azatadine is an H1 receptor antagonist used to treat perennial and allergic rhinitis as well as eustachian tube congestion. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Azithromycin interact?

•Drug A: Buserelin •Drug B: Azithromycin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Azithromycin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria in order to prevent the development antimicrobial resistance and maintain the efficacy of azithromycin. Azithromycin is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the microorganisms listed in the specific conditions below. Recommended dosages, duration of therapy and considerations for various patient populations may vary among these infections. Refer to the FDA label and "Indications" section of this drug entry for detailed information. Adults: Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage. Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae. Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established. Pediatric Patients Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit,. This results in the control of various bacterial infections,. The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad‐spectrum antibacterial activities. Azithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the ABCB1 gene. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): After oral administration, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg. Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum,. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake. This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues. •Protein binding (Drug A): 15% •Protein binding (Drug B): The serum protein binding of azithromycin varies in humans, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed, however, this drug is eliminated by the liver,. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Terminal elimination half-life: 68 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. dose) •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Rat Oral LD50: >2000 mk/kg Possible major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also an ongoing issue. Hepatotoxicity has been observed in rare cases. A note on the risk of liver toxicity: Due to the act that azithromycin is mainly eliminated by the liver, caution should be observed when azithromycin is given to patients with decreased hepatic function. A note on potential renal toxicity: Because limited data in patients with renal GFR <10 mL/min, caution should be exercised when prescribing azithromycin to these patients. Use in Pregnancy: This drug is categorized as a pregnancy category B drug. Reproduction studies have been done in rats and mice at doses up to moderately maternally toxic doses (for example, 200 mg/kg/day). These doses, based on a mg/m2 basis, are approximately 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no harmful effects to the fetus due to azithromycin were observed. There are, at this time, no conclusive and well-controlled studies that have been done in pregnant women. Because animal reproduction studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers: It is unknown at this time whether azithromycin is excreted in human milk. Because many other drugs are excreted in human milk, caution should be observed when azithromycin is given to a nursing woman. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to study carcinogenic potential. Azithromycin has demonstrated no potential to be mutagenic in standard laboratory tests. No evidence of negative effects on fertility due to azithromycin was found. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Azasite, Zithromax, Zmax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Azithromycin is a macrolide antibiotic used to treat a variety of bacterial infections.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Azithromycin interact? Information: •Drug A: Buserelin •Drug B: Azithromycin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Azithromycin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria in order to prevent the development antimicrobial resistance and maintain the efficacy of azithromycin. Azithromycin is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the microorganisms listed in the specific conditions below. Recommended dosages, duration of therapy and considerations for various patient populations may vary among these infections. Refer to the FDA label and "Indications" section of this drug entry for detailed information. Adults: Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage. Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae. Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established. Pediatric Patients Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit,. This results in the control of various bacterial infections,. The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad‐spectrum antibacterial activities. Azithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the ABCB1 gene. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): After oral administration, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg. Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum,. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake. This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues. •Protein binding (Drug A): 15% •Protein binding (Drug B): The serum protein binding of azithromycin varies in humans, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed, however, this drug is eliminated by the liver,. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Terminal elimination half-life: 68 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. dose) •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Rat Oral LD50: >2000 mk/kg Possible major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also an ongoing issue. Hepatotoxicity has been observed in rare cases. A note on the risk of liver toxicity: Due to the act that azithromycin is mainly eliminated by the liver, caution should be observed when azithromycin is given to patients with decreased hepatic function. A note on potential renal toxicity: Because limited data in patients with renal GFR <10 mL/min, caution should be exercised when prescribing azithromycin to these patients. Use in Pregnancy: This drug is categorized as a pregnancy category B drug. Reproduction studies have been done in rats and mice at doses up to moderately maternally toxic doses (for example, 200 mg/kg/day). These doses, based on a mg/m2 basis, are approximately 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no harmful effects to the fetus due to azithromycin were observed. There are, at this time, no conclusive and well-controlled studies that have been done in pregnant women. Because animal reproduction studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers: It is unknown at this time whether azithromycin is excreted in human milk. Because many other drugs are excreted in human milk, caution should be observed when azithromycin is given to a nursing woman. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to study carcinogenic potential. Azithromycin has demonstrated no potential to be mutagenic in standard laboratory tests. No evidence of negative effects on fertility due to azithromycin was found. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Azasite, Zithromax, Zmax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Azithromycin is a macrolide antibiotic used to treat a variety of bacterial infections. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Bedaquiline interact?

•Drug A: Buserelin •Drug B: Bedaquiline •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Bedaquiline. •Extended Description: In a drug interaction study of bedaquiline and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Bedaquiline is indicated as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. This indication is approved under FDA accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) than the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation. Bedaquiline inhibits mycobacterial TB at a minimal inhibitory concentration (MIC) from 0.002-0.06 μg/ml and with a MIC 50 of 0.03 μg/ml. The proportion of naturally resistant bacteria is low, estimated to be in one strain over 10 /10 bacteria. Bacteria that have smaller ATP stores (such as dormant, nonreplicating bacilli) are more susceptible to bedaquiline. Additionally, bedaquiline is also effective against nontuberculous mycobacteria, with MICs ranging from 0.06 to 0.5 μg/ml. A potential for the development of resistance to bedaquiline in M. tuberculosis exists. Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump (Rv0678 mutations) have been associated with increased bedaquiline MIC values in isolates of M. tuberculosis. Target-based mutations generated in preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4 micrograms per mL. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases in bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.5 micrograms per mL. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in M. tuberculosis.. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After the recommended dosing regimen of bedaquiline (400 mg for 2 weeks followed by 200 mg three times per week for 22 weeks), the C max and AUC 24h were calculated to be 1.659 μg/ml and 25.863 μg.h/ml respectively. After a single oral dose administration of bedaquiline, maximum plasma concentrations (C max ) are typically achieved at approximately 5 hours post-dose. C max and the area under the plasma concentration-time curve (AUC) increased proportionally up to 700 mg (1.75 times the 400 mg loading dose). Administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by approximately 2-fold compared to administration under fasted conditions. Bedaquiline should be taken with food to enhance its oral bioavailability. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution in the central compartment is estimated to be approximately 164 Liters. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of bedaquiline is greater than 99.9%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 was the major CYP isoenzyme involved in the in vitro metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After reaching C max, bedaquiline concentrations decline tri-exponentially. Based on preclinical studies, bedaquiline is mainly excreted in feces. The urinary excretion of unchanged bedaquiline was less than or equal to 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects the slow release of bedaquiline and M2 from peripheral tissues. •Clearance (Drug A): No clearance available •Clearance (Drug B): Bedaquiline has a low apparent clearance of approximately 2.78 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma. Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1-fold to 2-fold of those observed in adult patients in the clinical trials. No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay, and an in vivo mouse bone marrow micronucleus assay. SIRTURO did not affect fertility when evaluated in male and female rats at approximately twice the clinical exposure based on AUC comparisons. There was no effect of maternal treatment on sexual maturation, mating performance, or fertility in the F1 generation exposed to bedaquiline in utero at approximately twice the human exposure. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sirturo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bedaquilina Bedaquiline Bédaquiline Bedaquilinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bedaquiline is a diarylquinoline antimycobacterial used in combination with other antibacterials to treat pulmonary multidrug resistant tuberculosis (MDR-TB).

In a drug interaction study of bedaquiline and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval. The severity of the interaction is moderate.

Question: Does Buserelin and Bedaquiline interact? Information: •Drug A: Buserelin •Drug B: Bedaquiline •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Bedaquiline. •Extended Description: In a drug interaction study of bedaquiline and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Bedaquiline is indicated as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). Reserve SIRTURO for use when an effective treatment regimen cannot otherwise be provided. This indication is approved under FDA accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4-fold to 6-fold lower) than the parent compound. However, M2 plasma concentrations appeared to correlate with QT prolongation. Bedaquiline inhibits mycobacterial TB at a minimal inhibitory concentration (MIC) from 0.002-0.06 μg/ml and with a MIC 50 of 0.03 μg/ml. The proportion of naturally resistant bacteria is low, estimated to be in one strain over 10 /10 bacteria. Bacteria that have smaller ATP stores (such as dormant, nonreplicating bacilli) are more susceptible to bedaquiline. Additionally, bedaquiline is also effective against nontuberculous mycobacteria, with MICs ranging from 0.06 to 0.5 μg/ml. A potential for the development of resistance to bedaquiline in M. tuberculosis exists. Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump (Rv0678 mutations) have been associated with increased bedaquiline MIC values in isolates of M. tuberculosis. Target-based mutations generated in preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4 micrograms per mL. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases in bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.5 micrograms per mL. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, by binding to subunit c of the enzyme that is essential for the generation of energy in M. tuberculosis.. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After the recommended dosing regimen of bedaquiline (400 mg for 2 weeks followed by 200 mg three times per week for 22 weeks), the C max and AUC 24h were calculated to be 1.659 μg/ml and 25.863 μg.h/ml respectively. After a single oral dose administration of bedaquiline, maximum plasma concentrations (C max ) are typically achieved at approximately 5 hours post-dose. C max and the area under the plasma concentration-time curve (AUC) increased proportionally up to 700 mg (1.75 times the 400 mg loading dose). Administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by approximately 2-fold compared to administration under fasted conditions. Bedaquiline should be taken with food to enhance its oral bioavailability. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution in the central compartment is estimated to be approximately 164 Liters. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of bedaquiline is greater than 99.9%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): CYP3A4 was the major CYP isoenzyme involved in the in vitro metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After reaching C max, bedaquiline concentrations decline tri-exponentially. Based on preclinical studies, bedaquiline is mainly excreted in feces. The urinary excretion of unchanged bedaquiline was less than or equal to 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects the slow release of bedaquiline and M2 from peripheral tissues. •Clearance (Drug A): No clearance available •Clearance (Drug B): Bedaquiline has a low apparent clearance of approximately 2.78 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is no experience with the treatment of acute overdose with SIRTURO. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma. Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. Exposures at this dose in rats (AUCs) were within 1-fold to 2-fold of those observed in adult patients in the clinical trials. No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay, and an in vivo mouse bone marrow micronucleus assay. SIRTURO did not affect fertility when evaluated in male and female rats at approximately twice the clinical exposure based on AUC comparisons. There was no effect of maternal treatment on sexual maturation, mating performance, or fertility in the F1 generation exposed to bedaquiline in utero at approximately twice the human exposure. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sirturo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bedaquilina Bedaquiline Bédaquiline Bedaquilinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bedaquiline is a diarylquinoline antimycobacterial used in combination with other antibacterials to treat pulmonary multidrug resistant tuberculosis (MDR-TB). Output: In a drug interaction study of bedaquiline and ketoconazole in adults, a greater effect on QTc was observed after repeated dosing with bedaquiline and ketoconazole in combination than after repeated dosing with the individual drugs. Additive or synergistic QT prolongation was observed when bedaquiline was co-administered with other drugs that prolong the QT interval. The severity of the interaction is moderate.

Does Buserelin and Benzatropine interact?

•Drug A: Buserelin •Drug B: Benzatropine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Benzatropine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in pyrilamine and the anticholinergic activity was found to be equal to atropine ex vivo and of about 50% activity in vivo. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Benztropine is expected to present a large volume of distribution between 12-30 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): About 95% of the administered dose of benztropine is found bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Benztropine is mainly excreted in the urine but it is also found in the feces unchanged. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of benztropine is very variable and it is reported to be of around 36 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Extensive pharmacodynamic or pharmacokinetic studies have not been performed. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 of benztropine is reported to be of 940 mg/kg in rats. In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cogentin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benzatropina Benzatropine Benzatropinum Benztropine Tropine benzohydryl ether •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Benzatropine is an anticholinergic drug used to treat Parkinson's disease (PD) and extrapyramidal symptoms, except tardive dyskinesia.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Benzatropine interact? Information: •Drug A: Buserelin •Drug B: Benzatropine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Benzatropine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in pyrilamine and the anticholinergic activity was found to be equal to atropine ex vivo and of about 50% activity in vivo. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Benztropine is expected to present a large volume of distribution between 12-30 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): About 95% of the administered dose of benztropine is found bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Benztropine is mainly excreted in the urine but it is also found in the feces unchanged. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life of benztropine is very variable and it is reported to be of around 36 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Extensive pharmacodynamic or pharmacokinetic studies have not been performed. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The oral LD50 of benztropine is reported to be of 940 mg/kg in rats. In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cogentin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benzatropina Benzatropine Benzatropinum Benztropine Tropine benzohydryl ether •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Benzatropine is an anticholinergic drug used to treat Parkinson's disease (PD) and extrapyramidal symptoms, except tardive dyskinesia. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Benzocaine interact?

•Drug A: Buserelin •Drug B: Benzocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Benzocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Benzocaine is indicated for local anesthesia in dentistry, minor trauma, and as preparation for infiltrative anesthesia. Benzocaine products are indicated for topical anesthesia in a wide variety of conditions including skin irritation, oral pain, and hemorrhoids. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Benzocaine is indicated for use as a topical anesthetic. It has a duration of action of approximately 10 minutes and a wide therapeutic window. Patients should be counselled regarding the risks of methemoglobinemia. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Benzocaine diffuses into nerve cells where it binds to sodium channels, preventing the channels from opening, and blocking the influx of sodium ions. Nerve cells unable to allow sodium into cells cannot depolarize and conduct nerve impulses. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Benzocaine binds to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Benzocaine undergoes ester hydrolysis to form 4-aminobenzoic acid, acetylation to form acetylbenzocaine, or N-hydroxylation to form benzocaine hydroxide. 4-aminobenzoic acid can be acetylated or acetylbenzocaine can undergo ester hydrolysis to form 4-acetaminobenzoic acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with local anesthetic systemic toxicity syndrome, decreased cardiovascular function, decreased central nervous system function, cardiac arrest, bradycardia, hypotension, cardiac arrhythmias, syncope, and seizures. Patients should be treated with symptomatic and supportive measures which include airway maintenance, controlling seizures, and hemodynamic stabilization. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anbesol Cold Sore Therapy, Cepacol Sore Throat Plus Cough, Cetacaine, Chloraseptic Sore Throat, Chloraseptic Sore Throat + Cough, Diphen, Docusol Plus, Enemeez Plus, Medicaine Sting and Bite, One Touch Reformulated Apr 2009, Orasep Reformulated Dec 2013, Rectogel, Salinocaine, Topex, Vagisil Original Formula, Zap, Zilactin-B •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amben ethyl ester Benzocaina Benzocaine Benzocainum Ethyl aminobenzoate Ethyl p-aminobenzoate Ethyl p-aminophenylcarboxylate p-(Ethoxycarbonyl)aniline p-Carbethoxyaniline p-Ethoxycarboxylic aniline •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Benzocaine is a topical local anesthetic used for the temporary relief of pain and itching associated with minor burns, sunburn, scrapes and insect bites or minor skin irritations.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Benzocaine interact? Information: •Drug A: Buserelin •Drug B: Benzocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Benzocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Benzocaine is indicated for local anesthesia in dentistry, minor trauma, and as preparation for infiltrative anesthesia. Benzocaine products are indicated for topical anesthesia in a wide variety of conditions including skin irritation, oral pain, and hemorrhoids. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Benzocaine is indicated for use as a topical anesthetic. It has a duration of action of approximately 10 minutes and a wide therapeutic window. Patients should be counselled regarding the risks of methemoglobinemia. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Benzocaine diffuses into nerve cells where it binds to sodium channels, preventing the channels from opening, and blocking the influx of sodium ions. Nerve cells unable to allow sodium into cells cannot depolarize and conduct nerve impulses. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Benzocaine binds to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Benzocaine undergoes ester hydrolysis to form 4-aminobenzoic acid, acetylation to form acetylbenzocaine, or N-hydroxylation to form benzocaine hydroxide. 4-aminobenzoic acid can be acetylated or acetylbenzocaine can undergo ester hydrolysis to form 4-acetaminobenzoic acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with local anesthetic systemic toxicity syndrome, decreased cardiovascular function, decreased central nervous system function, cardiac arrest, bradycardia, hypotension, cardiac arrhythmias, syncope, and seizures. Patients should be treated with symptomatic and supportive measures which include airway maintenance, controlling seizures, and hemodynamic stabilization. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anbesol Cold Sore Therapy, Cepacol Sore Throat Plus Cough, Cetacaine, Chloraseptic Sore Throat, Chloraseptic Sore Throat + Cough, Diphen, Docusol Plus, Enemeez Plus, Medicaine Sting and Bite, One Touch Reformulated Apr 2009, Orasep Reformulated Dec 2013, Rectogel, Salinocaine, Topex, Vagisil Original Formula, Zap, Zilactin-B •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amben ethyl ester Benzocaina Benzocaine Benzocainum Ethyl aminobenzoate Ethyl p-aminobenzoate Ethyl p-aminophenylcarboxylate p-(Ethoxycarbonyl)aniline p-Carbethoxyaniline p-Ethoxycarboxylic aniline •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Benzocaine is a topical local anesthetic used for the temporary relief of pain and itching associated with minor burns, sunburn, scrapes and insect bites or minor skin irritations. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Benzyl alcohol interact?

•Drug A: Buserelin •Drug B: Benzyl alcohol •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Benzyl alcohol. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): 1250 mg/kg (rat, oral) LD50 400 mg/kg IPR-RAT LD50 2000 mg/kg SKN-RBT LD50 53 mg/kg IVN-RAT LD50 2500 mg/kg ORL-GPG LD50 •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cipro, Cipro HC, Itch-X, Ivy-dry Cream, Ulesfia, Zilactin Cold Sore •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (hydroxymethyl)benzene Alcoholum benzylicum Alcool benzylique Alcoolbenzylique alpha-Hydroxytoluene Aromatic alcohol Bentalol Benzalalcohol Benzalcohol Benzenecarbinol Benzenemethanol Benzoyl alcohol Benzyl alcohol Benzylalkohol Benzylic alcohol Hydroxymethylbenzene Phenylcarbinol Phenylmethanol Phenylmethyl alcohol •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Benzyl alcohol is an antiparasitic agent used for the topical treatment of head lice infestation in patients 6 months of age and older.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Benzyl alcohol interact? Information: •Drug A: Buserelin •Drug B: Benzyl alcohol •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Benzyl alcohol. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): 1250 mg/kg (rat, oral) LD50 400 mg/kg IPR-RAT LD50 2000 mg/kg SKN-RBT LD50 53 mg/kg IVN-RAT LD50 2500 mg/kg ORL-GPG LD50 •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cipro, Cipro HC, Itch-X, Ivy-dry Cream, Ulesfia, Zilactin Cold Sore •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (hydroxymethyl)benzene Alcoholum benzylicum Alcool benzylique Alcoolbenzylique alpha-Hydroxytoluene Aromatic alcohol Bentalol Benzalalcohol Benzalcohol Benzenecarbinol Benzenemethanol Benzoyl alcohol Benzyl alcohol Benzylalkohol Benzylic alcohol Hydroxymethylbenzene Phenylcarbinol Phenylmethanol Phenylmethyl alcohol •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Benzyl alcohol is an antiparasitic agent used for the topical treatment of head lice infestation in patients 6 months of age and older. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Berotralstat interact?

•Drug A: Buserelin •Drug B: Berotralstat •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Berotralstat. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema (HAE). It had a fast onset of action, long duration of action, and acceptable tolerance in clinical trials. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE. Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks. Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 ng hr/mL (range: 1880 to 3790 ng hr/mL) and 1600 ng hr/mL (range: 950 to 4170 ng hr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding is approximately 99%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): There is no information on the clearance rate. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is no information on the LD 50 or overdose of berotralstat. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Orladeyo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Berotralstat is an inhibitor of plasma kallikrein used for prophylaxis of angioedema attacks in patients with hereditary angioedema.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Berotralstat interact? Information: •Drug A: Buserelin •Drug B: Berotralstat •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Berotralstat. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema (HAE). It had a fast onset of action, long duration of action, and acceptable tolerance in clinical trials. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, berotralstat reduced HAE attack rates at 24 weeks, and its effects sustained through 48 weeks. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE. Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks. Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 ng hr/mL (range: 1880 to 3790 ng hr/mL) and 1600 ng hr/mL (range: 950 to 4170 ng hr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding is approximately 99%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): There is no information on the clearance rate. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is no information on the LD 50 or overdose of berotralstat. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Orladeyo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Berotralstat is an inhibitor of plasma kallikrein used for prophylaxis of angioedema attacks in patients with hereditary angioedema. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Bexagliflozin interact?

•Drug A: Buserelin •Drug B: Bexagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Bexagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Healthy subjects and adults with type 2 diabetes mellitus given single or multiple doses of bexagliflozin had dose-dependent increases in urinary glucose excretion (UGE) accompanied by increases in urine volume. A 20 mg bexagliflozin dose can provide near-maximal UGE, and elevated UGE values are maintained with multiple-dose administration. Bexagliflozin does not cause clinically significant QTc interval prolongation at 5 times the recommended dose. The use of bexagliflozin may cause ketoacidosis, volume depletion, urosepsis, pyelonephritis, necrotizing fasciitis of the perineum and genital mycotic infections. There is also an increased incidence of lower limb amputation in patients treated with bexagliflozin compared to those receiving a placebo. In addition, the use of bexagliflozin in patients treated with insulin and insulin secretagogues may increase the risk of hypoglycemia. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bexagliflozin is a highly selective sodium–glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is located in the proximal renal tubule, a part of the kidney where most reabsorption takes place, and they transport glucose and sodium from the tubular lumen to the epithelium. By inhibiting SGLT2, bexagliflozin reduces glucose reabsorption in the kidney and promotes its excretion in urine. Therefore, in patients with type 2 diabetes mellitus (T2DM), bexagliflozin reduces blood glucose levels independently of insulin sensitivity. Aside from improving glycemic control, bexagliflozin may also reduce body weight, systolic blood pressure, and albuminuria. The mechanism of action for these other effects have not been fully elucidated, but it is possible that they depend on the initial natriuresis caused by bexagliflozin, followed by a change in tissue sodium handling. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Healthy subjects and adult patients with type 2 diabetes mellitus given bexagliflozin have similar pharmacokinetic profiles. In a fasted state, the mean C max and AUC 0-∞ of bexagliflozin were 134 ng/mL and 1,162 ng·h/mL, respectively. Bexagliflozin does not follow a time-dependent pharmacokinetic profile, and after multiple doses, approximately up to 20% is accumulated in plasma. The peak plasma concentration of bexagliflozin is reached between 2 and 4 hours after oral administration. This timing can be delayed if bexagliflozin is taken after a meal or with medications that slow gastric emptying. Between single doses of 3 mg and 90 mg (0.15 to 4.5 times the recommended dose), the plasma C max and AUC of bexagliflozin increase in a dose-proportional manner. Compared to dosing in the fasted state, consuming a standard high-fat, high-caloric meal leads to a 31% and 10% higher C max and AUC, respectively. Under these conditions, the median T max was increased to 5 hours. The effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Bexagliflozin has an apparent volume of distribution of 262 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 93% of bexagliflozin is bound to plasma protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Bexagliflozin is metabolized in the liver mainly by UGT1A9 and, to a lesser extent, CYP3A. In healthy volunteers given an oral [14C]-bexagliflozin solution, the 3'-O-glucuronide, a pharmacologically inactive metabolite, constituted 32.2% of the parent compound AUC. The rest of the bexagliflozin metabolites contributed less than 10% of the parent AUC. None of the metabolites are expected to have clinically relevant pharmacological effects. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Bexagliflozin is mainly eliminated through feces and urine. In healthy subjects given an oral [14C]-bexagliflozin solution, 91.6% of input radioactivity was recovered. Of this amount, 51.1% was recovered in feces, mainly as the parent compound, while 40.5% was recovered in urine, mostly as the 3'-O-glucuronide. The proportions of input radioactivity recovered as bexagliflozin in urine and feces were 1.5% and 28.7%, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Bexagliflozin has an apparent terminal elimination half-life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Population pharmacokinetic modeling has shown that the apparent oral clearance of bexagliflozin is 19.1 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In case of a bexagliflozin overdose, the FDA product label recommends contacting the Poison Help line or a medical toxicologist for additional overdosage management recommendations. Usual supportive measures based on the patient’s clinical status should be employed. The removal of bexagliflozin by hemodialysis has not been evaluated. Carcinogenicity was evaluated in mice and rats, and no drug-related neoplastic findings were reported at up to the highest doses, which corresponded to 156 times (mice) and 68 times (rats) the clinical dose of bexagliflozin (20 mg) based on AUC. In vitro and in vivo studies found that bexagliflozin was not mutagenic or clastogenic. Fertility studies done in male and female rats showed that bexagliflozin had no effects on mating, fertility or early embryonic development at up to 200 mg/kg/day, which corresponded to 280 and 439 times the clinical dose of bexagliflozin in males and females, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Brenzavvy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bexagliflozin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bexagliflozin is a sodium-glucose co-transporter 2 inhibitor used to improve glycemic control in patients with type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Bexagliflozin interact? Information: •Drug A: Buserelin •Drug B: Bexagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Bexagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Healthy subjects and adults with type 2 diabetes mellitus given single or multiple doses of bexagliflozin had dose-dependent increases in urinary glucose excretion (UGE) accompanied by increases in urine volume. A 20 mg bexagliflozin dose can provide near-maximal UGE, and elevated UGE values are maintained with multiple-dose administration. Bexagliflozin does not cause clinically significant QTc interval prolongation at 5 times the recommended dose. The use of bexagliflozin may cause ketoacidosis, volume depletion, urosepsis, pyelonephritis, necrotizing fasciitis of the perineum and genital mycotic infections. There is also an increased incidence of lower limb amputation in patients treated with bexagliflozin compared to those receiving a placebo. In addition, the use of bexagliflozin in patients treated with insulin and insulin secretagogues may increase the risk of hypoglycemia. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bexagliflozin is a highly selective sodium–glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is located in the proximal renal tubule, a part of the kidney where most reabsorption takes place, and they transport glucose and sodium from the tubular lumen to the epithelium. By inhibiting SGLT2, bexagliflozin reduces glucose reabsorption in the kidney and promotes its excretion in urine. Therefore, in patients with type 2 diabetes mellitus (T2DM), bexagliflozin reduces blood glucose levels independently of insulin sensitivity. Aside from improving glycemic control, bexagliflozin may also reduce body weight, systolic blood pressure, and albuminuria. The mechanism of action for these other effects have not been fully elucidated, but it is possible that they depend on the initial natriuresis caused by bexagliflozin, followed by a change in tissue sodium handling. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Healthy subjects and adult patients with type 2 diabetes mellitus given bexagliflozin have similar pharmacokinetic profiles. In a fasted state, the mean C max and AUC 0-∞ of bexagliflozin were 134 ng/mL and 1,162 ng·h/mL, respectively. Bexagliflozin does not follow a time-dependent pharmacokinetic profile, and after multiple doses, approximately up to 20% is accumulated in plasma. The peak plasma concentration of bexagliflozin is reached between 2 and 4 hours after oral administration. This timing can be delayed if bexagliflozin is taken after a meal or with medications that slow gastric emptying. Between single doses of 3 mg and 90 mg (0.15 to 4.5 times the recommended dose), the plasma C max and AUC of bexagliflozin increase in a dose-proportional manner. Compared to dosing in the fasted state, consuming a standard high-fat, high-caloric meal leads to a 31% and 10% higher C max and AUC, respectively. Under these conditions, the median T max was increased to 5 hours. The effects of food on bexagliflozin pharmacokinetics are not considered clinically relevant. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Bexagliflozin has an apparent volume of distribution of 262 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 93% of bexagliflozin is bound to plasma protein. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Bexagliflozin is metabolized in the liver mainly by UGT1A9 and, to a lesser extent, CYP3A. In healthy volunteers given an oral [14C]-bexagliflozin solution, the 3'-O-glucuronide, a pharmacologically inactive metabolite, constituted 32.2% of the parent compound AUC. The rest of the bexagliflozin metabolites contributed less than 10% of the parent AUC. None of the metabolites are expected to have clinically relevant pharmacological effects. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Bexagliflozin is mainly eliminated through feces and urine. In healthy subjects given an oral [14C]-bexagliflozin solution, 91.6% of input radioactivity was recovered. Of this amount, 51.1% was recovered in feces, mainly as the parent compound, while 40.5% was recovered in urine, mostly as the 3'-O-glucuronide. The proportions of input radioactivity recovered as bexagliflozin in urine and feces were 1.5% and 28.7%, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Bexagliflozin has an apparent terminal elimination half-life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Population pharmacokinetic modeling has shown that the apparent oral clearance of bexagliflozin is 19.1 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): In case of a bexagliflozin overdose, the FDA product label recommends contacting the Poison Help line or a medical toxicologist for additional overdosage management recommendations. Usual supportive measures based on the patient’s clinical status should be employed. The removal of bexagliflozin by hemodialysis has not been evaluated. Carcinogenicity was evaluated in mice and rats, and no drug-related neoplastic findings were reported at up to the highest doses, which corresponded to 156 times (mice) and 68 times (rats) the clinical dose of bexagliflozin (20 mg) based on AUC. In vitro and in vivo studies found that bexagliflozin was not mutagenic or clastogenic. Fertility studies done in male and female rats showed that bexagliflozin had no effects on mating, fertility or early embryonic development at up to 200 mg/kg/day, which corresponded to 280 and 439 times the clinical dose of bexagliflozin in males and females, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Brenzavvy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bexagliflozin •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bexagliflozin is a sodium-glucose co-transporter 2 inhibitor used to improve glycemic control in patients with type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Bilastine interact?

•Drug A: Buserelin •Drug B: Bilastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Bilastine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For symptomatic relief of nasal and non-nasal symptoms of seasonal rhinitis in patients 12 years of age and older and for symptomatic relief in chronic spontaneous urticaria in patients 18 years of age and older. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bilastine is an antiallergenic and acts to reduce allergic symptoms such as nasal congestion and urticaria. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bilastine is a selective histamine H1 receptor antagonist (Ki = 64nM). During allergic response mast cells undergo degranulation which releases histamine and other subastances. By binding to and preventing activation of the H1 receptor, bilastine reduces the development of allergic symptoms due to the release of histamine from mast cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bilastine has a Tmax of 1.13 h. The absolute bioavailability is 61%. No accumulation observed with daily dosing of 20-100 mg after 14 days. Cmax decreased by 25 % and 33% when taken with a low fat and high fat meal compared to fasted state. Administration with grapefruit juice decreased Cmax by 30%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Bilastine is 84-90% bound to human plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Bilastine does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Bilastine is mainly excreted in the feces (66.5%) with some excreted in the urine (28.3%). Nearly all is excreted as the parent compound. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean half life of elimination is 14.5h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Bilastine has a total clearance is 9.20 L/h and a renal clearance of 8.7 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common adverse effects experienced during clinical trials were abdominal pain, dizziness, headache, and somnolence. Bilastine is associated with Q/T prolongation. The no observed adverse effect level of bilastine is 1200 mg/kg/day in rats and 125 mg/kg/day in dogs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Blexten •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bilastine is a peripheral histamine H1-antagonist used to treat seasonal allergic rhinitis and chronic spontaneous urticaria.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Bilastine interact? Information: •Drug A: Buserelin •Drug B: Bilastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Bilastine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For symptomatic relief of nasal and non-nasal symptoms of seasonal rhinitis in patients 12 years of age and older and for symptomatic relief in chronic spontaneous urticaria in patients 18 years of age and older. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bilastine is an antiallergenic and acts to reduce allergic symptoms such as nasal congestion and urticaria. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bilastine is a selective histamine H1 receptor antagonist (Ki = 64nM). During allergic response mast cells undergo degranulation which releases histamine and other subastances. By binding to and preventing activation of the H1 receptor, bilastine reduces the development of allergic symptoms due to the release of histamine from mast cells. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bilastine has a Tmax of 1.13 h. The absolute bioavailability is 61%. No accumulation observed with daily dosing of 20-100 mg after 14 days. Cmax decreased by 25 % and 33% when taken with a low fat and high fat meal compared to fasted state. Administration with grapefruit juice decreased Cmax by 30%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Bilastine is 84-90% bound to human plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Bilastine does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Bilastine is mainly excreted in the feces (66.5%) with some excreted in the urine (28.3%). Nearly all is excreted as the parent compound. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean half life of elimination is 14.5h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Bilastine has a total clearance is 9.20 L/h and a renal clearance of 8.7 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common adverse effects experienced during clinical trials were abdominal pain, dizziness, headache, and somnolence. Bilastine is associated with Q/T prolongation. The no observed adverse effect level of bilastine is 1200 mg/kg/day in rats and 125 mg/kg/day in dogs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Blexten •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bilastine is a peripheral histamine H1-antagonist used to treat seasonal allergic rhinitis and chronic spontaneous urticaria. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Bortezomib interact?

•Drug A: Buserelin •Drug B: Bortezomib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Bortezomib is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell lymphoma. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread. Bortezomib is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following intravenous administration of 1 mg/m and 1.3 mg/m doses, the mean C max of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the C max ranged from 67 to 106 ng/mL at the dose of 1 mg/m and 89 to 120 ng/mL for the 1.3 mg/m dose. In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m or 1.3 mg/m. Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue. •Protein binding (Drug A): 15% •Protein binding (Drug B): Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Bortezomib is eliminated by both renal and hepatic routes. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m bortezomib. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following the administration of a first dose of 1 mg/m and 1.3 mg/m, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The Lowest published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose. The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Velcade •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bortezomib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bortezomib is a proteasome inhibitor used to treat multiple myeloma in patients who have not been successfully treated with at least two previous therapies.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Bortezomib interact? Information: •Drug A: Buserelin •Drug B: Bortezomib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Bortezomib is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell lymphoma. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread. Bortezomib is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following intravenous administration of 1 mg/m and 1.3 mg/m doses, the mean C max of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the C max ranged from 67 to 106 ng/mL at the dose of 1 mg/m and 89 to 120 ng/mL for the 1.3 mg/m dose. In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m or 1.3 mg/m. Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue. •Protein binding (Drug A): 15% •Protein binding (Drug B): Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Bortezomib is eliminated by both renal and hepatic routes. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m bortezomib. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following the administration of a first dose of 1 mg/m and 1.3 mg/m, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The Lowest published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose. The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Velcade •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bortezomib •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bortezomib is a proteasome inhibitor used to treat multiple myeloma in patients who have not been successfully treated with at least two previous therapies. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Bretylium interact?

•Drug A: Buserelin •Drug B: Bretylium •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Bretylium is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use in the prophylaxis and therapy of ventricular fibrillation. Also used in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bretylium is a bromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium also suppresses ventricular fibrillation and ventricular arrhythmias. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium have been demonstrated in animal experiments: increase in ventricular fibrillation threshold, increase in action potential duration and effective refractory period without changes in heart rate, little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium, decrease in the disparity in action potential duration between normal and infarcted regions, and increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolites have been identified following administration in man and laboratory animals. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). During hemodialysis, this patient's arterial and venous bretylium concentrations declined rapidly, resulting in a half-life of 13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral, mouse: LD 50 = 400 mg/kg. In the presence of life-threatening arrhythmias, underdosing with bretylium probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium serum levels were 8000 ng/mL. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bretylium •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bretylium is a norepinephrine release inhibitor used for the prophylaxis and therapy of ventricular fibrillation, as well as the treatment of life-threatening ventricular arrhythmias.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Bretylium interact? Information: •Drug A: Buserelin •Drug B: Bretylium •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Bretylium is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For use in the prophylaxis and therapy of ventricular fibrillation. Also used in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bretylium is a bromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium also suppresses ventricular fibrillation and ventricular arrhythmias. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Bretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium have been demonstrated in animal experiments: increase in ventricular fibrillation threshold, increase in action potential duration and effective refractory period without changes in heart rate, little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium, decrease in the disparity in action potential duration between normal and infarcted regions, and increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolites have been identified following administration in man and laboratory animals. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). During hemodialysis, this patient's arterial and venous bretylium concentrations declined rapidly, resulting in a half-life of 13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral, mouse: LD 50 = 400 mg/kg. In the presence of life-threatening arrhythmias, underdosing with bretylium probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium serum levels were 8000 ng/mL. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bretylium •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bretylium is a norepinephrine release inhibitor used for the prophylaxis and therapy of ventricular fibrillation, as well as the treatment of life-threatening ventricular arrhythmias. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Bromocriptine interact?

•Drug A: Buserelin •Drug B: Bromocriptine •Severity: MODERATE •Description: The therapeutic efficacy of Bromocriptine can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 90-96% bound to serum albumin •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2-8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cycloset, Parlodel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromocriptina Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Bromocriptine interact? Information: •Drug A: Buserelin •Drug B: Bromocriptine •Severity: MODERATE •Description: The therapeutic efficacy of Bromocriptine can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 90-96% bound to serum albumin •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2-8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cycloset, Parlodel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromocriptina Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Brompheniramine interact?

•Drug A: Buserelin •Drug B: Brompheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Brompheniramine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Antihistamines are well absorbed from the gastrointestinal tract after oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic (cytochrome P-450 system), some renal. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bromfed DM, Lodrane D, M-end PE, Mar-cof BP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromfeniramina Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Brompheniramine interact? Information: •Drug A: Buserelin •Drug B: Brompheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Brompheniramine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Antihistamines are well absorbed from the gastrointestinal tract after oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic (cytochrome P-450 system), some renal. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bromfed DM, Lodrane D, M-end PE, Mar-cof BP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromfeniramina Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Buclizine interact?

•Drug A: Buserelin •Drug B: Buclizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buclizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness and vertigo (dizziness caused by other medical problems). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Buclizine is a piperazine-derivative antihistamine used as an antivertigo/antiemetic agent. Buclizine is used in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used in the management of vertigo in diseases affecting the vestibular apparatus. Although the mechanism by which buclizine exerts its antiemetic and antivertigo effects has not been fully elucidated, its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistaminic, central nervous system depressant, and local anesthetic effects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Vomiting (emesis) is essentially a protective mechanism for removing irritant or otherwise harmful substances from the upper GI tract. Emesis or vomiting is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). The vomiting centre possesses neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness principally involves overstimulation of these pathways due to various sensory stimuli. Hence the action of buclizine which acts to block the histamine receptors in the vomiting centre and thus reduce activity along these pathways. Furthermore since buclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buclizina Buclizine Buclizinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Buclizine is an antihistamine and antiemetic drug for the treatment of allergy symptoms and prevention of nausea and vomiting.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Buclizine interact? Information: •Drug A: Buserelin •Drug B: Buclizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buclizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness and vertigo (dizziness caused by other medical problems). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Buclizine is a piperazine-derivative antihistamine used as an antivertigo/antiemetic agent. Buclizine is used in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used in the management of vertigo in diseases affecting the vestibular apparatus. Although the mechanism by which buclizine exerts its antiemetic and antivertigo effects has not been fully elucidated, its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistaminic, central nervous system depressant, and local anesthetic effects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Vomiting (emesis) is essentially a protective mechanism for removing irritant or otherwise harmful substances from the upper GI tract. Emesis or vomiting is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). The vomiting centre possesses neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness principally involves overstimulation of these pathways due to various sensory stimuli. Hence the action of buclizine which acts to block the histamine receptors in the vomiting centre and thus reduce activity along these pathways. Furthermore since buclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buclizina Buclizine Buclizinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Buclizine is an antihistamine and antiemetic drug for the treatment of allergy symptoms and prevention of nausea and vomiting. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Bupivacaine interact?

•Drug A: Buserelin •Drug B: Bupivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Bupivacaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Only 6% of bupivacaine is excreted unchanged in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Bupivacaine interact? Information: •Drug A: Buserelin •Drug B: Bupivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Bupivacaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Only 6% of bupivacaine is excreted unchanged in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Canagliflozin interact?

•Drug A: Buserelin •Drug B: Canagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Canagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. A note on type 2 diabetes and cardiovascular disease The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bioavailability and steady-state The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. Effect of food on absorption Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: Feces 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite Urine About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose information If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canagliflozin has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis. Pregnancy and lactation Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans. There are known risks, however, of uncontrolled diabetes in pregnancy. Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing. Mutagenesis and carcinogenicity Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin was not found to be mutagenic in several in vivo assays performed on rats. The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canagliflozin was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Invokamet, Invokana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Canagliflozin Canagliflozina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to manage hyperglycemia in type 2 diabetes mellitus (DM). Also used to reduce the risk of major cardiovascular events in patients with established cardiovascular disease and type 2 DM.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Canagliflozin interact? Information: •Drug A: Buserelin •Drug B: Canagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Canagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. A note on type 2 diabetes and cardiovascular disease The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Bioavailability and steady-state The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. Effect of food on absorption Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: Feces 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite Urine About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose. •Clearance (Drug A): No clearance available •Clearance (Drug B): In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose information If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canagliflozin has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis. Pregnancy and lactation Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans. There are known risks, however, of uncontrolled diabetes in pregnancy. Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing. Mutagenesis and carcinogenicity Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin was not found to be mutagenic in several in vivo assays performed on rats. The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canagliflozin was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Invokamet, Invokana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Canagliflozin Canagliflozina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to manage hyperglycemia in type 2 diabetes mellitus (DM). Also used to reduce the risk of major cardiovascular events in patients with established cardiovascular disease and type 2 DM. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Capsaicin interact?

•Drug A: Buserelin •Drug B: Capsaicin •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Capsaicin. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal. The peak blood concentration can be reached within 1 hour following administration. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26.6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2.47 ± 0.13 ng/ml was reached at 47.1 ± 2.0 minutes. Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood. Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL but the maximum value observed in any patient was 17.8 ng/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral ingestion of equipotent dose of 26.6 mg of pure capsaicin, the half life was approximately 24.9 ± 5.0 min. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h. The mean population elimination half-life was 1.64 h following application of a topical patch containing 179 mg of capsaicin. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute oral LD50 and dermal LD50 in mouse are 47.2 mg/kg and >512 mg/kg, respectively. Capsaicin is shown to be mutagenic for bacteria and yeast. Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Capzasin Quick Relief, Capzasin-HP, Castiva Warming, Dendracin Neurodendraxcin, Lidopro, Medi-derm, Medi-derm With Lidocaine, Medrox, Qutenza, Rematex, Xoten-C, Zostrix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capsaicin Capsaicina Isodecenoic acid vanillylamide •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Capsaicin is a topical analgesic agent used for the symptomatic relief of neuropathic pain associated with post-herpetic neuralgia, as well as other muscle and joint pain.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Capsaicin interact? Information: •Drug A: Buserelin •Drug B: Capsaicin •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Capsaicin. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal. The peak blood concentration can be reached within 1 hour following administration. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26.6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2.47 ± 0.13 ng/ml was reached at 47.1 ± 2.0 minutes. Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood. Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL but the maximum value observed in any patient was 17.8 ng/mL. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral ingestion of equipotent dose of 26.6 mg of pure capsaicin, the half life was approximately 24.9 ± 5.0 min. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h. The mean population elimination half-life was 1.64 h following application of a topical patch containing 179 mg of capsaicin. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Acute oral LD50 and dermal LD50 in mouse are 47.2 mg/kg and >512 mg/kg, respectively. Capsaicin is shown to be mutagenic for bacteria and yeast. Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Capzasin Quick Relief, Capzasin-HP, Castiva Warming, Dendracin Neurodendraxcin, Lidopro, Medi-derm, Medi-derm With Lidocaine, Medrox, Qutenza, Rematex, Xoten-C, Zostrix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capsaicin Capsaicina Isodecenoic acid vanillylamide •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Capsaicin is a topical analgesic agent used for the symptomatic relief of neuropathic pain associated with post-herpetic neuralgia, as well as other muscle and joint pain. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Carbinoxamine interact?

•Drug A: Buserelin •Drug B: Carbinoxamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Carbinoxamine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For symptomatic relief of seasonal and perennial allergic rhinitis and vasomotor rhinitis, as well as allergic conjunctivitis caused by foods and inhaled allergens. Also for the relief of allergic reactions to blood or plasma, and the symptomatic management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Carbinoxamine is a first generation antihistamine of the ethanolamine class. Ethanolamine antihistamines have significant antimuscarinic activity and produce marked sedation in most patients. In addition to the usual allergic symptoms, the drug also treats irritant cough and nausea, vomiting, and vertigo associated with motion sickness. It also is used commonly to treat drug-induced extrapyramidal symptoms as well as to treat mild cases of Parkinson's disease. Rather than preventing the release of histamine, as do cromolyn and nedocromil, carbinoxamine competes with free histamine for binding at HA-receptor sites. Carbinoxamine competitively antagonizes the effects of histamine on HA-receptors in the GI tract, uterus, large blood vessels, and bronchial muscle. Ethanolamine derivatives have greater anticholinergic activity than do other antihistamines, which probably accounts for the antidyskinetic action of carbinoxamine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Carbinoxamine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding. Carbinoxamine's anticholinergic action appears to be due to a central antimuscarinic effect, which also may be responsible for its antiemetic effects, although the exact mechanism is unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10 to 20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Karbinal, Ryvent •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carbinoxamin Carbinoxamina Carbinoxamine Carbinoxamine base Carbinoxaminum Paracarbinoxamine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Carbinoxamine is a first generation antihistamine used to treat allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, allergic reactions, and mild allergic reactions.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Carbinoxamine interact? Information: •Drug A: Buserelin •Drug B: Carbinoxamine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Carbinoxamine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For symptomatic relief of seasonal and perennial allergic rhinitis and vasomotor rhinitis, as well as allergic conjunctivitis caused by foods and inhaled allergens. Also for the relief of allergic reactions to blood or plasma, and the symptomatic management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Carbinoxamine is a first generation antihistamine of the ethanolamine class. Ethanolamine antihistamines have significant antimuscarinic activity and produce marked sedation in most patients. In addition to the usual allergic symptoms, the drug also treats irritant cough and nausea, vomiting, and vertigo associated with motion sickness. It also is used commonly to treat drug-induced extrapyramidal symptoms as well as to treat mild cases of Parkinson's disease. Rather than preventing the release of histamine, as do cromolyn and nedocromil, carbinoxamine competes with free histamine for binding at HA-receptor sites. Carbinoxamine competitively antagonizes the effects of histamine on HA-receptors in the GI tract, uterus, large blood vessels, and bronchial muscle. Ethanolamine derivatives have greater anticholinergic activity than do other antihistamines, which probably accounts for the antidyskinetic action of carbinoxamine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Carbinoxamine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding. Carbinoxamine's anticholinergic action appears to be due to a central antimuscarinic effect, which also may be responsible for its antiemetic effects, although the exact mechanism is unknown. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 10 to 20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Karbinal, Ryvent •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carbinoxamin Carbinoxamina Carbinoxamine Carbinoxamine base Carbinoxaminum Paracarbinoxamine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Carbinoxamine is a first generation antihistamine used to treat allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, allergic reactions, and mild allergic reactions. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Celiprolol interact?

•Drug A: Buserelin •Drug B: Celiprolol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Celiprolol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%. •Protein binding (Drug A): 15% •Protein binding (Drug B): 25-30%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celiprolol Celiprololum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Celiprolol is a beta-blocker for the management of hypertension and angina pectoris.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Celiprolol interact? Information: •Drug A: Buserelin •Drug B: Celiprolol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Celiprolol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%. •Protein binding (Drug A): 15% •Protein binding (Drug B): 25-30%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celiprolol Celiprololum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Celiprolol is a beta-blocker for the management of hypertension and angina pectoris. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ceritinib interact?

•Drug A: Buserelin •Drug B: Ceritinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ceritinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half life is 41 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zykadia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Céritinib Ceritinib Ceritinibum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ceritinib is an antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients with inadequate clinical response or intolerance to crizotinib.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ceritinib interact? Information: •Drug A: Buserelin •Drug B: Ceritinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ceritinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half life is 41 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zykadia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Céritinib Ceritinib Ceritinibum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ceritinib is an antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients with inadequate clinical response or intolerance to crizotinib. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Cetirizine interact?

•Drug A: Buserelin •Drug B: Cetirizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cetirizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Seasonal Allergic Rhinitis: Indicated for the relief of symptoms associated with seasonal allergic rhinitis caused by allergens such as ragweed, grass and tree pollens in adults and children 2 years of age and above. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes. Perennial allergic rhinitis: This drug is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens including dust mites, animal dander, and molds in adults and children 6 months of age and older. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing. Chronic urticaria: Cetirizine is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older. It markedly reduces the occurrence, severity, and duration of hives and significantly reduces pruritus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): General effects and respiratory effects Cetirizine, the active metabolite of the piperazine H 1 -receptor antagonist hydroxyzine, minimizes or eliminates the symptoms of chronic idiopathic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, allergic asthma, physical urticaria, and atopic dermatitis. The clinical efficacy of cetirizine for allergic respiratory diseases has been well established in numerous trials. Effects on urticaria/anti-inflammatory effects It has anti-inflammatory properties that may play a role in asthma management. There is evidence that cetirizine improves symptoms of urticaria. Marked clinical inhibition of a wheal and flare response occurs in infants, children as well as adults within 20 minutes of one oral dose and lasts for 24 h. Concomitant use of cetirizine reduces the duration and dose of topical anti-inflammatory formulas used for the treatment of atopic dermatitis. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cetirizine, a metabolite of hydroxyzine, is an antihistamine drug. Its main effects are achieved through selective inhibition of peripheral H1 receptors. The antihistamine activity of cetirizine has been shown in a variety of animal and human models. In vivo and ex vivo animal models have shown insignificant anticholinergic and antiserotonergic effects. In clinical studies, however, dry mouth was found to be more frequent with cetirizine than with a placebo. In vitro receptor binding studies have demonstrated no detectable affinity of cetirizine for histamine receptors other than the H1 receptors. Studies with radiolabeled cetirizine administration in the rat have demonstrated insignificant penetration into the brain. Ex vivo studies in the mouse have shown that systemically administered cetirizine does not occupy cerebral H1 receptors significantly. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of about 1 hour after oral administration of tablets or syrup formulation in adult volunteers. Bioavailability was found to be similar between the tablet and syrup dosage forms. When healthy study volunteers were given several doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/mL was measured. Effect of food on absorption Food had no effect on cetirizine exposure (AUC), however, Tmax was delayed by 1.7 hours and Cmax was decreased by 23% in the fed state. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Apparent volume of distribution: 0.44 +/- 0.19 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The mean plasma protein binding of cetirizine is 93%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): A mass balance clinical trial comprised of 6 healthy male study volunteers showed that 70% of the administered radioactivity was measured in the urine and 10% in the feces after cetirizine administration. About 50% of the radioactivity was measured in the urine as unchanged cetirizine. Most of the rapid increase in peak plasma radioactivity was related to the parent drug, implying a low level of first pass metabolism. This prevents potential interactions of cetirizine with drugs interacting with hepatic cytochrome enzymes. Cetirizine is metabolized partially by oxidative O-dealkylation to a metabolite with insignificant antihistaminic activity. The enzyme or enzymes responsible for this step in cetirizine metabolism have not yet been identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Mainly eliminated in the urine,. Between 70 – 85% of an orally administered dose can be found in the urine and 10 – 13% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Plasma elimination half-life is 8.3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent total body clearance: approximately 53 mL/min. Cetirizine is mainly eliminated by the kidneys,. Dose adjustment is required for patients with moderate to severe renal impairment and in patients on hemodialysis. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD50 (rat): 365 mg/kg; Intraperitoneal LDLO (mouse): 138 mg/kg; Oral TDLO (rat): 50 mg/kg; Oral TDLO (mouse): 0.1 mg/kg. Carcinogenesis and mutagenesis: In a 2-year carcinogenicity study in rats, cetirizine was not shown to be carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults). In a 2-year carcinogenicity study in mice, cetirizine administration lead to an incidence of benign liver tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults). The clinical significance of these findings during long-term use of cetirizine is unknown at this time. Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in rats. Impairment of fertility In a fertility and reproduction study in mice, cetirizine did not negatively impact fertility at an oral dose of 64 mg/kg (approximately 25 times the maximum recommended daily oral dose in adults). Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum recommended daily oral dose in adults). There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, cetirizine should be used in pregnancy only if clearly needed. Use in breastfeeding/nursing Cetirizine has been reported to be excreted in human breast milk. The use of cetirizine in nursing mothers is not recommended. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aller-tec, Aller-tec D, Quzyttir, Reactine, Wal Zyr 24 Hour Allergy, Wal Zyr D, Wal-zyr, Zerviate, Zyrtec, Zyrtec-D •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cetirizine is a selective Histamine-1 antagonist drug used in allergic rhinitis and chronic urticaria.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Cetirizine interact? Information: •Drug A: Buserelin •Drug B: Cetirizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cetirizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Seasonal Allergic Rhinitis: Indicated for the relief of symptoms associated with seasonal allergic rhinitis caused by allergens such as ragweed, grass and tree pollens in adults and children 2 years of age and above. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes. Perennial allergic rhinitis: This drug is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens including dust mites, animal dander, and molds in adults and children 6 months of age and older. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing. Chronic urticaria: Cetirizine is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older. It markedly reduces the occurrence, severity, and duration of hives and significantly reduces pruritus. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): General effects and respiratory effects Cetirizine, the active metabolite of the piperazine H 1 -receptor antagonist hydroxyzine, minimizes or eliminates the symptoms of chronic idiopathic urticaria, perennial allergic rhinitis, seasonal allergic rhinitis, allergic asthma, physical urticaria, and atopic dermatitis. The clinical efficacy of cetirizine for allergic respiratory diseases has been well established in numerous trials. Effects on urticaria/anti-inflammatory effects It has anti-inflammatory properties that may play a role in asthma management. There is evidence that cetirizine improves symptoms of urticaria. Marked clinical inhibition of a wheal and flare response occurs in infants, children as well as adults within 20 minutes of one oral dose and lasts for 24 h. Concomitant use of cetirizine reduces the duration and dose of topical anti-inflammatory formulas used for the treatment of atopic dermatitis. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cetirizine, a metabolite of hydroxyzine, is an antihistamine drug. Its main effects are achieved through selective inhibition of peripheral H1 receptors. The antihistamine activity of cetirizine has been shown in a variety of animal and human models. In vivo and ex vivo animal models have shown insignificant anticholinergic and antiserotonergic effects. In clinical studies, however, dry mouth was found to be more frequent with cetirizine than with a placebo. In vitro receptor binding studies have demonstrated no detectable affinity of cetirizine for histamine receptors other than the H1 receptors. Studies with radiolabeled cetirizine administration in the rat have demonstrated insignificant penetration into the brain. Ex vivo studies in the mouse have shown that systemically administered cetirizine does not occupy cerebral H1 receptors significantly. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of about 1 hour after oral administration of tablets or syrup formulation in adult volunteers. Bioavailability was found to be similar between the tablet and syrup dosage forms. When healthy study volunteers were given several doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/mL was measured. Effect of food on absorption Food had no effect on cetirizine exposure (AUC), however, Tmax was delayed by 1.7 hours and Cmax was decreased by 23% in the fed state. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Apparent volume of distribution: 0.44 +/- 0.19 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The mean plasma protein binding of cetirizine is 93%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): A mass balance clinical trial comprised of 6 healthy male study volunteers showed that 70% of the administered radioactivity was measured in the urine and 10% in the feces after cetirizine administration. About 50% of the radioactivity was measured in the urine as unchanged cetirizine. Most of the rapid increase in peak plasma radioactivity was related to the parent drug, implying a low level of first pass metabolism. This prevents potential interactions of cetirizine with drugs interacting with hepatic cytochrome enzymes. Cetirizine is metabolized partially by oxidative O-dealkylation to a metabolite with insignificant antihistaminic activity. The enzyme or enzymes responsible for this step in cetirizine metabolism have not yet been identified. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Mainly eliminated in the urine,. Between 70 – 85% of an orally administered dose can be found in the urine and 10 – 13% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Plasma elimination half-life is 8.3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Apparent total body clearance: approximately 53 mL/min. Cetirizine is mainly eliminated by the kidneys,. Dose adjustment is required for patients with moderate to severe renal impairment and in patients on hemodialysis. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD50 (rat): 365 mg/kg; Intraperitoneal LDLO (mouse): 138 mg/kg; Oral TDLO (rat): 50 mg/kg; Oral TDLO (mouse): 0.1 mg/kg. Carcinogenesis and mutagenesis: In a 2-year carcinogenicity study in rats, cetirizine was not shown to be carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults). In a 2-year carcinogenicity study in mice, cetirizine administration lead to an incidence of benign liver tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults). The clinical significance of these findings during long-term use of cetirizine is unknown at this time. Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in rats. Impairment of fertility In a fertility and reproduction study in mice, cetirizine did not negatively impact fertility at an oral dose of 64 mg/kg (approximately 25 times the maximum recommended daily oral dose in adults). Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum recommended daily oral dose in adults). There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, cetirizine should be used in pregnancy only if clearly needed. Use in breastfeeding/nursing Cetirizine has been reported to be excreted in human breast milk. The use of cetirizine in nursing mothers is not recommended. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aller-tec, Aller-tec D, Quzyttir, Reactine, Wal Zyr 24 Hour Allergy, Wal Zyr D, Wal-zyr, Zerviate, Zyrtec, Zyrtec-D •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cetirizine is a selective Histamine-1 antagonist drug used in allergic rhinitis and chronic urticaria. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Chlorcyclizine interact?

•Drug A: Buserelin •Drug B: Chlorcyclizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chlorcyclizine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed after oral administration and widely distributed throughout the body. Metabolised by N-demethylation to form norchlorcyclizine and by N-oxidation. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): After a single oral dose of 2 mg/kg to 4 subjects, average peak plasma concentrations of about 0.05 mg/L and 0.03 mg/L were attained in 5 h for unchanged drug and norchlorcyclizine, respectively. After oral administration of 50 mg 3 times a day for 6 days, plasma concentrations of norchlorcyclizine of 0.05 to 0.11 mg/L were reported on the first day after the cessation of treatment and plasma concentrations of 0.02 to 0.04 mg/L were found on the 10th day after cessation of treatment [Kuntzman et al. 1973]. •Protein binding (Drug A): 15% •Protein binding (Drug B): about 85 to 90%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): High concentrations of the N-desmethyl metabolite are found in the liver, lungs, kidney, and spleen. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Slowly excreted in the urine; measurable amounts of norchlorcyclizine have been detected in the urine for up to 3 weeks after the cessation of chronic oral administration. About 0.5% of a single dose is excreted in the urine as the N-oxide. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): about 12 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ahist Antihistamine, Biclora, Bonine for Kids, Stahist Ad Liquid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): No summary available

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Chlorcyclizine interact? Information: •Drug A: Buserelin •Drug B: Chlorcyclizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chlorcyclizine. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed after oral administration and widely distributed throughout the body. Metabolised by N-demethylation to form norchlorcyclizine and by N-oxidation. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): After a single oral dose of 2 mg/kg to 4 subjects, average peak plasma concentrations of about 0.05 mg/L and 0.03 mg/L were attained in 5 h for unchanged drug and norchlorcyclizine, respectively. After oral administration of 50 mg 3 times a day for 6 days, plasma concentrations of norchlorcyclizine of 0.05 to 0.11 mg/L were reported on the first day after the cessation of treatment and plasma concentrations of 0.02 to 0.04 mg/L were found on the 10th day after cessation of treatment [Kuntzman et al. 1973]. •Protein binding (Drug A): 15% •Protein binding (Drug B): about 85 to 90%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): High concentrations of the N-desmethyl metabolite are found in the liver, lungs, kidney, and spleen. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Slowly excreted in the urine; measurable amounts of norchlorcyclizine have been detected in the urine for up to 3 weeks after the cessation of chronic oral administration. About 0.5% of a single dose is excreted in the urine as the N-oxide. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): about 12 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ahist Antihistamine, Biclora, Bonine for Kids, Stahist Ad Liquid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): No summary available Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Chloroprocaine interact?

•Drug A: Buserelin •Drug B: Chloroprocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Chloroprocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Chloroprocaine for intrathecal injection is indicated for the production of subarachnoid block (spinal anesthesia) in adults. It is also indicated for the production of local anesthesia by infiltration, peripheral and central nerve block, and a preservative-free form can also be used for lumbar and caudal epidural blocks. Topical chloroprocaine for ophthalmic use is indicated for ocular surface anesthesia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chloroprocaine is an ester local anesthetic agent indicated for the production of local or regional anesthesia with effects on the cardiovascular and central nervous systems. Compared with lidocaine and bupivacaine, chloroprocaine has shorter ambulation and discharge times. Chloroprocaine has minimal effects on cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance at therapeutic doses. However, at toxic blood concentrations, chloroprocaine may cause atrioventricular block and cardiac arrest, as well as decreased cardiac output and arterial blood pressure. A high concentration of chloroprocaine in plasma can also lead to central nervous system stimulation, depression, or both. Some signs of central stimulation include restlessness, tremors and shivering, which may progress to convulsions. Depression, coma and respiratory arrest may also occur. As with other local anesthetics, patients may experience depression of the central nervous system without a prior stage of stimulation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chloroprocaine acts mainly by binding to the alpha subunit on the cytoplasmic region of voltage-gated sodium channels and inhibiting sodium influx in neuronal cell membranes. This lowers the nerve membrane permeability to sodium and decreases the rate of rise of the action potential. Therefore, chloroprocaine inhibits signal conduction and leads to a reversible nerve conduction blockade. The progression of anesthesia depends on the diameter, myelination and conduction velocity of nerve fibers, and the order of loss of nerve function is the following: 1) pain, 2) temperature, 3) touch, 4) proprioception, and 5) skeletal muscle tone. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Thanks to its low risk for systemic toxicity, chloroprocaine has a rapid onset of action that usually ranges between 6 to 12 minutes. The duration of chloroprocaine-induced anesthesia may be up to 60 minutes. The absorption rate of local anesthetics depends on the total dose and concentration of chloroprocaine, as well as the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic injection. The presence of epinephrine reduces the rate of absorption and plasma concentration of local anesthetics. The systemic exposure to chloroprocaine following its topical ocular administration has not been evaluated. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Compared to the other clinically used local anesthetics, chloroprocaine has one of the lowest protein binding percentages. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In plasma, chloroprocaine is quickly metabolized by pseudocholinesterases, a group of enzymes that perform the hydrolysis of the ester linkage. In ocular tissues, chloroprocaine is metabolized by nonspecific esterases. The hydrolysis of chloroprocaine leads to the production of ß-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Like most local anesthetics and their metabolites, chloroprocaine is mainly excreted by the kidneys. The urinary excretion of chloroprocaine may be affected by urinary perfusion and factors that have an effect on urinary pH. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In adults, the average in vitro plasma half-life of chloroprocaine is 21 seconds for males and 25 seconds for females. In neonates, the average in vitro plasma half-life is 43 seconds. Following intrapartum epidural anesthesia, the apparent in vivo half-life of chloroprocaine detected in maternal plasma was 3.1 minutes (range from 1.5 to 6.4 minutes). •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Most chloroprocaine overdose cases are related to high plasma levels during its therapeutic use or to the unintended administration of a subarachnoid injection. In mice, the intravenous LD 50 of chloroprocaine HCl is 97 mg/kg and the subcutaneous LD 50 of chloroprocaine HCl is 950 mg/kg. The first consideration in the management of local anesthetic emergencies is prevention, which can be achieved by carefully monitoring patients’ cardiovascular and respiratory vital signs, as well as their state of consciousness. If there are any changes, oxygen should be administered. In patients with chloroprocaine overdose with convulsions, underventilation or apnea, the drug label recommends giving immediate attention to maintaining a patent airway, assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. If convulsions persist, provide small increments of an ultra-short acting barbiturate or a benzodiazepine intravenously. Refer to the chloroprocaine drug label for a complete description of the procedures recommended in case of overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Clorotekal, Iheezo, Nesacaine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-(Diethylamino)ethyl 4-amino-2-chlorobenzoate Chloroprocain Chloroprocaine Chloroprocainum Chlorprocaine Cloroprocaina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chloroprocaine is a local anesthetic agent indicated for intrathecal injection in adults for the production of subarachnoid block, spinal anesthesia, or ocular surface anesthesia.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Chloroprocaine interact? Information: •Drug A: Buserelin •Drug B: Chloroprocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Chloroprocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Chloroprocaine for intrathecal injection is indicated for the production of subarachnoid block (spinal anesthesia) in adults. It is also indicated for the production of local anesthesia by infiltration, peripheral and central nerve block, and a preservative-free form can also be used for lumbar and caudal epidural blocks. Topical chloroprocaine for ophthalmic use is indicated for ocular surface anesthesia. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chloroprocaine is an ester local anesthetic agent indicated for the production of local or regional anesthesia with effects on the cardiovascular and central nervous systems. Compared with lidocaine and bupivacaine, chloroprocaine has shorter ambulation and discharge times. Chloroprocaine has minimal effects on cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance at therapeutic doses. However, at toxic blood concentrations, chloroprocaine may cause atrioventricular block and cardiac arrest, as well as decreased cardiac output and arterial blood pressure. A high concentration of chloroprocaine in plasma can also lead to central nervous system stimulation, depression, or both. Some signs of central stimulation include restlessness, tremors and shivering, which may progress to convulsions. Depression, coma and respiratory arrest may also occur. As with other local anesthetics, patients may experience depression of the central nervous system without a prior stage of stimulation. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chloroprocaine acts mainly by binding to the alpha subunit on the cytoplasmic region of voltage-gated sodium channels and inhibiting sodium influx in neuronal cell membranes. This lowers the nerve membrane permeability to sodium and decreases the rate of rise of the action potential. Therefore, chloroprocaine inhibits signal conduction and leads to a reversible nerve conduction blockade. The progression of anesthesia depends on the diameter, myelination and conduction velocity of nerve fibers, and the order of loss of nerve function is the following: 1) pain, 2) temperature, 3) touch, 4) proprioception, and 5) skeletal muscle tone. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Thanks to its low risk for systemic toxicity, chloroprocaine has a rapid onset of action that usually ranges between 6 to 12 minutes. The duration of chloroprocaine-induced anesthesia may be up to 60 minutes. The absorption rate of local anesthetics depends on the total dose and concentration of chloroprocaine, as well as the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic injection. The presence of epinephrine reduces the rate of absorption and plasma concentration of local anesthetics. The systemic exposure to chloroprocaine following its topical ocular administration has not been evaluated. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Compared to the other clinically used local anesthetics, chloroprocaine has one of the lowest protein binding percentages. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In plasma, chloroprocaine is quickly metabolized by pseudocholinesterases, a group of enzymes that perform the hydrolysis of the ester linkage. In ocular tissues, chloroprocaine is metabolized by nonspecific esterases. The hydrolysis of chloroprocaine leads to the production of ß-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Like most local anesthetics and their metabolites, chloroprocaine is mainly excreted by the kidneys. The urinary excretion of chloroprocaine may be affected by urinary perfusion and factors that have an effect on urinary pH. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): In adults, the average in vitro plasma half-life of chloroprocaine is 21 seconds for males and 25 seconds for females. In neonates, the average in vitro plasma half-life is 43 seconds. Following intrapartum epidural anesthesia, the apparent in vivo half-life of chloroprocaine detected in maternal plasma was 3.1 minutes (range from 1.5 to 6.4 minutes). •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Most chloroprocaine overdose cases are related to high plasma levels during its therapeutic use or to the unintended administration of a subarachnoid injection. In mice, the intravenous LD 50 of chloroprocaine HCl is 97 mg/kg and the subcutaneous LD 50 of chloroprocaine HCl is 950 mg/kg. The first consideration in the management of local anesthetic emergencies is prevention, which can be achieved by carefully monitoring patients’ cardiovascular and respiratory vital signs, as well as their state of consciousness. If there are any changes, oxygen should be administered. In patients with chloroprocaine overdose with convulsions, underventilation or apnea, the drug label recommends giving immediate attention to maintaining a patent airway, assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. If convulsions persist, provide small increments of an ultra-short acting barbiturate or a benzodiazepine intravenously. Refer to the chloroprocaine drug label for a complete description of the procedures recommended in case of overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Clorotekal, Iheezo, Nesacaine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-(Diethylamino)ethyl 4-amino-2-chlorobenzoate Chloroprocain Chloroprocaine Chloroprocainum Chlorprocaine Cloroprocaina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chloroprocaine is a local anesthetic agent indicated for intrathecal injection in adults for the production of subarachnoid block, spinal anesthesia, or ocular surface anesthesia. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Chloroquine interact?

•Drug A: Buserelin •Drug B: Chloroquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chloroquine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Chloroquine is indicated to treat infections of P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used to treat extraintestinal amebiasis. Chloroquine is also used off label for the treatment of rheumatic diseases, as well as treatment and prophylaxis of Zika virus. Chloroquine is currently undergoing clinical trials for the treatment of COVID-19. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin. Plasmodium species continue to accumulate toxic heme, killing the parasite. Chloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH. The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell. Chloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%. Intravenous chloroquine reaches a C max of 650-1300µg/L and oral chloroquine reaches a C max of 65-128µg/L with a T max of 0.5h. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of chloroquine is 200-800L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Chloroquine is 46-74% bound to plasma proteins. (-)-chloroquine binds more strongly to alpha-1-acid glycoprotein and (+)-chloroquine binds more strongly to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine. It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1. N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Chloroquine is predominantly eliminated in the urine. 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of chloroquine is 20-60 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Chloroquine has a total plasma clearance of 0.35-1L/h/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, convulsions, respiratory arrest, cardiac arrest, and hypokalemia. Overdose should be managed with symptomatic and supportive treatment which may include prompt emesis, gastric lavage, and activated charcoal. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chloraquine Chlorochin Chloroquina Chloroquine Chloroquinium Chloroquinum Cloroquina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chloroquine is an antimalarial drug used to treat susceptible infections with P. vivax, P. malariae, P. ovale, and P. falciparum. It is also used for second line treatment for rheumatoid arthritis.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Chloroquine interact? Information: •Drug A: Buserelin •Drug B: Chloroquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chloroquine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Chloroquine is indicated to treat infections of P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used to treat extraintestinal amebiasis. Chloroquine is also used off label for the treatment of rheumatic diseases, as well as treatment and prophylaxis of Zika virus. Chloroquine is currently undergoing clinical trials for the treatment of COVID-19. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin. Plasmodium species continue to accumulate toxic heme, killing the parasite. Chloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH. The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell. Chloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%. Intravenous chloroquine reaches a C max of 650-1300µg/L and oral chloroquine reaches a C max of 65-128µg/L with a T max of 0.5h. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of chloroquine is 200-800L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Chloroquine is 46-74% bound to plasma proteins. (-)-chloroquine binds more strongly to alpha-1-acid glycoprotein and (+)-chloroquine binds more strongly to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine. It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1. N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Chloroquine is predominantly eliminated in the urine. 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life of chloroquine is 20-60 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Chloroquine has a total plasma clearance of 0.35-1L/h/kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, convulsions, respiratory arrest, cardiac arrest, and hypokalemia. Overdose should be managed with symptomatic and supportive treatment which may include prompt emesis, gastric lavage, and activated charcoal. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chloraquine Chlorochin Chloroquina Chloroquine Chloroquinium Chloroquinum Cloroquina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chloroquine is an antimalarial drug used to treat susceptible infections with P. vivax, P. malariae, P. ovale, and P. falciparum. It is also used for second line treatment for rheumatoid arthritis. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Chlorpheniramine interact?

•Drug A: Buserelin •Drug B: Chlorpheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chlorpheniramine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed in the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 72% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic via Cytochrome P450 (CYP450) enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 21-27 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD50 (rat): 306 mg/kg; Oral LD50 (mice): 130 mg/kg; Oral LD50 (guinea pig): 198 mg/kg [Registry of Toxic Effects of Chemical Substances. Ed. D. Sweet, US Dept. of Health & Human Services: Cincinatti, 2010.] Also a mild reproductive toxin to women of childbearing age. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aller-chlor, Allerest PE, Children's Nyquil Cold and Cough, Codar Ar, Coricidin Hbp Cold & Flu, Coricidin Hbp Cough and Cold, Dimetapp Long Acting Cough Plus Cold, Robitussin Pediatric Cough & Cold LA, Scot-tussin Sugar Free DM, Sudogest, Tussicaps, Tussionex, Tuxarin, Tuzistra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorophenylpyridamine Chlorphenamin Chlorphenamine Chlorphenaminum Chlorpheniramine Chlorpheniramine polistirex Chlorpheniraminum Clorfenamina Clorfeniramina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorpheniramine is a histamine-H1 receptor antagonist indicated for the management of symptoms associated with upper respiratory allergies.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Chlorpheniramine interact? Information: •Drug A: Buserelin •Drug B: Chlorpheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chlorpheniramine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed in the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 72% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic via Cytochrome P450 (CYP450) enzymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 21-27 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD50 (rat): 306 mg/kg; Oral LD50 (mice): 130 mg/kg; Oral LD50 (guinea pig): 198 mg/kg [Registry of Toxic Effects of Chemical Substances. Ed. D. Sweet, US Dept. of Health & Human Services: Cincinatti, 2010.] Also a mild reproductive toxin to women of childbearing age. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aller-chlor, Allerest PE, Children's Nyquil Cold and Cough, Codar Ar, Coricidin Hbp Cold & Flu, Coricidin Hbp Cough and Cold, Dimetapp Long Acting Cough Plus Cold, Robitussin Pediatric Cough & Cold LA, Scot-tussin Sugar Free DM, Sudogest, Tussicaps, Tussionex, Tuxarin, Tuzistra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorophenylpyridamine Chlorphenamin Chlorphenamine Chlorphenaminum Chlorpheniramine Chlorpheniramine polistirex Chlorpheniraminum Clorfenamina Clorfeniramina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorpheniramine is a histamine-H1 receptor antagonist indicated for the management of symptoms associated with upper respiratory allergies. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Chlorpromazine interact?

•Drug A: Buserelin •Drug B: Chlorpromazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chlorpromazine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of schizophrenia; to control nausea and vomiting; for relief of restlessness and apprehension before surgery; for acute intermittent porphyria; as an adjunct in the treatment of tetanus; to control the manifestations of the manic type of manic-depressive illness; for relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 20 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): > 90% to plasma proteins, primarily albumin •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Kidneys, ~ 37% excreted in urine •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): ~ 30 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, restlessness •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpromazine Chlorpromazinum Clorpromazina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorpromazine is a phenothiazine antipsychotic used to treat nausea, vomiting, preoperative anxiety, schizophrenia, bipolar disorder, and severe behavioral problems in children.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Chlorpromazine interact? Information: •Drug A: Buserelin •Drug B: Chlorpromazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Chlorpromazine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of schizophrenia; to control nausea and vomiting; for relief of restlessness and apprehension before surgery; for acute intermittent porphyria; as an adjunct in the treatment of tetanus; to control the manifestations of the manic type of manic-depressive illness; for relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 20 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): > 90% to plasma proteins, primarily albumin •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Kidneys, ~ 37% excreted in urine •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): ~ 30 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, restlessness •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpromazine Chlorpromazinum Clorpromazina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorpromazine is a phenothiazine antipsychotic used to treat nausea, vomiting, preoperative anxiety, schizophrenia, bipolar disorder, and severe behavioral problems in children. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Chlorpropamide interact?

•Drug A: Buserelin •Drug B: Chlorpropamide •Severity: MODERATE •Description: The therapeutic efficacy of Chlorpropamide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chlorpropamide, a second-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Chlorpropamide is twice as potent as the related second-generation agent glipizide. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Sulfonylureas such as chlorpropamide bind to ATP-sensitive potassium channels on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed from the GI tract. Peak plasma concentrations occur within 2-4 hours and the onset of action occurs within one hour. The maximal effect of chlorpropamide is seen 3-6 hours following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Highly bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Up to 80% of dose is metabolized likely through the liver to to 2-hydroxylchlorpropamide (2-OH CPA), p-chlorobenzenesulfonylurea (CBSU), 3-hydroxylchlorpropamide (3-OH CPA), and p-chlorobenzenesulfonamide (CBSA); CBSA may be produced by decomposition in urine. It is unknown whether chlorpropamide metabolites exert hypoglycemic effects. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 80-90% of a single oral dose is excreted in the urine as unchaged drug and metabolites within 96 hours. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Approximately 36 hours with interindividual variation ranging from 25-60 hours. Duration of effect persists for at least 24 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): IPN-RAT LD 50 580 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpropamid Chlorpropamide Chlorpropamidum Clorpropamida •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorpropamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Chlorpropamide interact? Information: •Drug A: Buserelin •Drug B: Chlorpropamide •Severity: MODERATE •Description: The therapeutic efficacy of Chlorpropamide can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chlorpropamide, a second-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Chlorpropamide is twice as potent as the related second-generation agent glipizide. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Sulfonylureas such as chlorpropamide bind to ATP-sensitive potassium channels on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Readily absorbed from the GI tract. Peak plasma concentrations occur within 2-4 hours and the onset of action occurs within one hour. The maximal effect of chlorpropamide is seen 3-6 hours following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Highly bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Up to 80% of dose is metabolized likely through the liver to to 2-hydroxylchlorpropamide (2-OH CPA), p-chlorobenzenesulfonylurea (CBSU), 3-hydroxylchlorpropamide (3-OH CPA), and p-chlorobenzenesulfonamide (CBSA); CBSA may be produced by decomposition in urine. It is unknown whether chlorpropamide metabolites exert hypoglycemic effects. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 80-90% of a single oral dose is excreted in the urine as unchaged drug and metabolites within 96 hours. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Approximately 36 hours with interindividual variation ranging from 25-60 hours. Duration of effect persists for at least 24 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): IPN-RAT LD 50 580 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpropamid Chlorpropamide Chlorpropamidum Clorpropamida •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorpropamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Chlorprothixene interact?

•Drug A: Buserelin •Drug B: Chlorprothixene •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Chlorprothixene is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occuring as part of bipolar disorders. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chlorprothixene is a typical antipsychotic drug of the thioxanthine class. It has a low antipsychotic potency (half to 2/3 of chlorpromazine). Chlorprothixene has not thoroughly demonstrated an antidepressant or analgesic effect but it has demonstrated antiemetic effects. It is used in the treatment of nervous, mental, and emotional conditions. Improvement in such conditions is thought to result from the effect of the medicine on nerve pathways in specific areas of the brain. Chlorprothixene has a similar side effect profile to chlorpromazine, though allergic side effects and liver damage are less frequent. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chlorprothixene blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Incomplete bioavailability. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8 to 12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include difficulty in breathing (severe), dizziness (severe), drowsiness (severe), muscle trembling, jerking, stiffness, or uncontrolled movements (severe), small pupils, unusual excitement, and unusual tiredness or weakness (severe). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorprothixen Chlorprothixene Chlorprothixine Chlorprotixen Chlorprotixene Chlorprotixine Chlothixen •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorprothixene is a thioxanthene antipsychotic.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Chlorprothixene interact? Information: •Drug A: Buserelin •Drug B: Chlorprothixene •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Chlorprothixene is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occuring as part of bipolar disorders. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Chlorprothixene is a typical antipsychotic drug of the thioxanthine class. It has a low antipsychotic potency (half to 2/3 of chlorpromazine). Chlorprothixene has not thoroughly demonstrated an antidepressant or analgesic effect but it has demonstrated antiemetic effects. It is used in the treatment of nervous, mental, and emotional conditions. Improvement in such conditions is thought to result from the effect of the medicine on nerve pathways in specific areas of the brain. Chlorprothixene has a similar side effect profile to chlorpromazine, though allergic side effects and liver damage are less frequent. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Chlorprothixene blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Incomplete bioavailability. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 8 to 12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of overdose include difficulty in breathing (severe), dizziness (severe), drowsiness (severe), muscle trembling, jerking, stiffness, or uncontrolled movements (severe), small pupils, unusual excitement, and unusual tiredness or weakness (severe). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorprothixen Chlorprothixene Chlorprothixine Chlorprotixen Chlorprotixene Chlorprotixine Chlothixen •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Chlorprothixene is a thioxanthene antipsychotic. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Cilostazol interact?

•Drug A: Buserelin •Drug B: Cilostazol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cilostazol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for the alleviation of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cilostazol reduces the symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C max and a 25% increase in AUC. Absolute bioavailability is not known. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 95-98% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-trans-hydroxy-cilostazol. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 11-13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Information on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD 50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cilostazol Cilostazole Cilostazolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cilostazol is an antiplatelet agent and vasodilator used for the symptomatic relief of intermittent claudication.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Cilostazol interact? Information: •Drug A: Buserelin •Drug B: Cilostazol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cilostazol is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for the alleviation of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cilostazol reduces the symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C max and a 25% increase in AUC. Absolute bioavailability is not known. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 95-98% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-trans-hydroxy-cilostazol. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 11-13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Information on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD 50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cilostazol Cilostazole Cilostazolum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cilostazol is an antiplatelet agent and vasodilator used for the symptomatic relief of intermittent claudication. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Cinchocaine interact?

•Drug A: Buserelin •Drug B: Cinchocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Cinchocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dibucaine is an amide-type local anesthetic, similar to lidocaine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Local anesthetics block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions through sodium channel inhibition. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In general, ionized forms (salts) of local anesthetics are not readily absorbed through intact skin. However, both nonionized (bases) and ionized forms of local anesthetics are readily absorbed through traumatized or abraded skin into the systemic circulation. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Subcutaneous LD 50 in rat is 27 mg/kg. Symptoms of overdose include convulsions, hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nupercainal, Proctol, Proctosedyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinchocaine Cinchocainum Cincocainio Dibucaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cinchocaine is an anesthetic used for local or regional anesthesia.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Cinchocaine interact? Information: •Drug A: Buserelin •Drug B: Cinchocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Cinchocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dibucaine is an amide-type local anesthetic, similar to lidocaine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Local anesthetics block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions through sodium channel inhibition. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In general, ionized forms (salts) of local anesthetics are not readily absorbed through intact skin. However, both nonionized (bases) and ionized forms of local anesthetics are readily absorbed through traumatized or abraded skin into the systemic circulation. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Primarily hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Subcutaneous LD 50 in rat is 27 mg/kg. Symptoms of overdose include convulsions, hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nupercainal, Proctol, Proctosedyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinchocaine Cinchocainum Cincocainio Dibucaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cinchocaine is an anesthetic used for local or regional anesthesia. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Cinnarizine interact?

•Drug A: Buserelin •Drug B: Cinnarizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Cinnarizine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of vertigo/meniere's disease, nausea and vomiting, motion sickness and also useful for vestibular symptoms of other origins. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinarizina Cinnarizine Cinnarizinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cinnarizine is a drug used for the management of labyrinthine disorder symptoms, including vertigo, tinnitus, nystagmus, nausea, and vomiting.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Cinnarizine interact? Information: •Drug A: Buserelin •Drug B: Cinnarizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Cinnarizine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of vertigo/meniere's disease, nausea and vomiting, motion sickness and also useful for vestibular symptoms of other origins. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinarizina Cinnarizine Cinnarizinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cinnarizine is a drug used for the management of labyrinthine disorder symptoms, including vertigo, tinnitus, nystagmus, nausea, and vomiting. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Ciprofloxacin interact?

•Drug A: Buserelin •Drug B: Ciprofloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ciprofloxacin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ciprofloxacin is only indicated in infections caused by susceptible bacteria. Ciprofloxacin immediate release tablets, oral suspensions, and intravenous injections are indicated for the treatment of skin and skin structure infections, bone and joint infections, complicated intra-abdominal infections, nosocomial pneumonia, febrile neutropenia, adults who have inhaled anthrax, plague, chronic bacterial prostatitis, lower respiratory tract infections including acute exacerbations of chronic bronchitis, urinary tract infections, complicated urinary tract infections in pediatrics, complicated pyelonephritis in pediatrics, and acute sinusitis. A ciprofloxacin otic solution and otic suspension with hydrocortisone are indicated for acute otitis externa. Ciprofloxacin suspension with dexamethasone is indicated for acute otitis media in pediatric patients with tympanostomy tubes or acute otitis externa. A ciprofloxacin intratympanic injection is indicated for pediatric patients with bilateral otitis media with effusion who are having tympanostomy tubes placed or pediatric patients 6 months or older with acute otitis externa. A ciprofloxacin eye drop is indicated for bacterial corneal ulcers and conjunctivitis. A ciprofloxacin eye ointment is indicated for bacterial conjunctivitis. A ciprofloxacin extended release tablet is indicated for uncomplicated urinary tract infections, complicated urinary tract infections, and acute uncomplicated pyelonephritis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ciprofloxacin is a second generation fluoroquinolone that is active against many Gram negative and Gram positive bacteria. It produces its action through inhibition of bacterial DNA gyrase and topoisomerase IV. Ciprofloxacin binds to bacterial DNA gyrase with 100 times the affinity of mammalian DNA gyrase. There is no cross resistance between fluoroquinolones and other classes of antibiotics, so it may be of clinical value when other antibiotics are no longer effective. Ciprofloxain and its derivatives are also being investigated for its action against malaria, cancers, and AIDS. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ciprofloxacin acts on bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Ciprofloxacin's targeting of the alpha subunits of DNA gyrase prevents it from supercoiling the bacterial DNA which prevents DNA replication. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0.94mg/L in 0.81 hours with an average area under the curve of 1.013L/h*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0.161L/kg and a total volume of distribution of 2.00-3.04L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): 20-40%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ciprofloxacin is primarily metabolized by CYP1A2. The primary metabolites oxociprofloxacin and sulociprofloxacin make up 3-8% of the total dose each. Ciprofloxacin is also converted to the minor metabolites desethylene ciprofloxacin and formylciprofloxacin. These 4 metabolites account for 15% of a total oral dose. There is a lack of available data on the enzymes and types of reactions involved in forming these metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average half life following a 250mg oral dose was 4.71 hours and 3.65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average renal clearance after a 250mg oral dose is 5.08mL/min*kg. Following a 100mg intravenous dose, the average total clearance is 9.62mL/min*kg, average renal clearance is 4.42mL/min*kg, and average non renal clearance is 5.21mL/min*kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with nausea, vomiting, abdominal pain, crystalluria, nephrotoxicity, and oliguria. Ciprofloxacin overdose typically leads to acute renal failure. An overdose may progress over the next 6 days with rising serum creatinine and BUN, as well as anuria. Patients may require prednisone therapy, urgent hemodialysis, or supportive therapy. Depending on the degree of overdose, patients may recover normal kidney function or progress to chronic kidney failure. The oral LD50 in rats is >2000mg/kg. Ciprofloxacin for intratympanic injection or otic use has low systemic absorption and so it unlikely to be a risk in pregnancy or lactation. There is generally no harm to the fetus in animal studies, however high doses may lead to gastrointestinal disturbances in the mother which may increase the incidence of abortion. In human studies there was no increase in fetal malformations above background rates. The risk and benefit of ciprofloxacin should be weighed in pregnancy and breast feeding. 2/8 in vitro tests and 0/3 in vivo tests of mutagenicity of ciprofloxacin have yielded a positive result. Oral doses of 200 and 300 times the maximum recommended clinical dose in rats and mice have shown no carcinogenicity or tumorigenicity. Oral doses above the maximum recommended clinical dose have shown no effects on fertility in rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cetraxal, Ciloxan, Cipro, Cipro HC, Ciprodex, Ciprofloxacin, Otiprio, Otixal, Otovel, Proquin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciprofloxacin Ciprofloxacine Ciprofloxacino Ciprofloxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ciprofloxacin is a second generation fluoroquinolone used to treat various susceptible bacterial infections.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Ciprofloxacin interact? Information: •Drug A: Buserelin •Drug B: Ciprofloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ciprofloxacin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Ciprofloxacin is only indicated in infections caused by susceptible bacteria. Ciprofloxacin immediate release tablets, oral suspensions, and intravenous injections are indicated for the treatment of skin and skin structure infections, bone and joint infections, complicated intra-abdominal infections, nosocomial pneumonia, febrile neutropenia, adults who have inhaled anthrax, plague, chronic bacterial prostatitis, lower respiratory tract infections including acute exacerbations of chronic bronchitis, urinary tract infections, complicated urinary tract infections in pediatrics, complicated pyelonephritis in pediatrics, and acute sinusitis. A ciprofloxacin otic solution and otic suspension with hydrocortisone are indicated for acute otitis externa. Ciprofloxacin suspension with dexamethasone is indicated for acute otitis media in pediatric patients with tympanostomy tubes or acute otitis externa. A ciprofloxacin intratympanic injection is indicated for pediatric patients with bilateral otitis media with effusion who are having tympanostomy tubes placed or pediatric patients 6 months or older with acute otitis externa. A ciprofloxacin eye drop is indicated for bacterial corneal ulcers and conjunctivitis. A ciprofloxacin eye ointment is indicated for bacterial conjunctivitis. A ciprofloxacin extended release tablet is indicated for uncomplicated urinary tract infections, complicated urinary tract infections, and acute uncomplicated pyelonephritis. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Ciprofloxacin is a second generation fluoroquinolone that is active against many Gram negative and Gram positive bacteria. It produces its action through inhibition of bacterial DNA gyrase and topoisomerase IV. Ciprofloxacin binds to bacterial DNA gyrase with 100 times the affinity of mammalian DNA gyrase. There is no cross resistance between fluoroquinolones and other classes of antibiotics, so it may be of clinical value when other antibiotics are no longer effective. Ciprofloxain and its derivatives are also being investigated for its action against malaria, cancers, and AIDS. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Ciprofloxacin acts on bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Ciprofloxacin's targeting of the alpha subunits of DNA gyrase prevents it from supercoiling the bacterial DNA which prevents DNA replication. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0.94mg/L in 0.81 hours with an average area under the curve of 1.013L/h*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0.161L/kg and a total volume of distribution of 2.00-3.04L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): 20-40%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Ciprofloxacin is primarily metabolized by CYP1A2. The primary metabolites oxociprofloxacin and sulociprofloxacin make up 3-8% of the total dose each. Ciprofloxacin is also converted to the minor metabolites desethylene ciprofloxacin and formylciprofloxacin. These 4 metabolites account for 15% of a total oral dose. There is a lack of available data on the enzymes and types of reactions involved in forming these metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): 27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The average half life following a 250mg oral dose was 4.71 hours and 3.65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average renal clearance after a 250mg oral dose is 5.08mL/min*kg. Following a 100mg intravenous dose, the average total clearance is 9.62mL/min*kg, average renal clearance is 4.42mL/min*kg, and average non renal clearance is 5.21mL/min*kg. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing an overdose may present with nausea, vomiting, abdominal pain, crystalluria, nephrotoxicity, and oliguria. Ciprofloxacin overdose typically leads to acute renal failure. An overdose may progress over the next 6 days with rising serum creatinine and BUN, as well as anuria. Patients may require prednisone therapy, urgent hemodialysis, or supportive therapy. Depending on the degree of overdose, patients may recover normal kidney function or progress to chronic kidney failure. The oral LD50 in rats is >2000mg/kg. Ciprofloxacin for intratympanic injection or otic use has low systemic absorption and so it unlikely to be a risk in pregnancy or lactation. There is generally no harm to the fetus in animal studies, however high doses may lead to gastrointestinal disturbances in the mother which may increase the incidence of abortion. In human studies there was no increase in fetal malformations above background rates. The risk and benefit of ciprofloxacin should be weighed in pregnancy and breast feeding. 2/8 in vitro tests and 0/3 in vivo tests of mutagenicity of ciprofloxacin have yielded a positive result. Oral doses of 200 and 300 times the maximum recommended clinical dose in rats and mice have shown no carcinogenicity or tumorigenicity. Oral doses above the maximum recommended clinical dose have shown no effects on fertility in rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cetraxal, Ciloxan, Cipro, Cipro HC, Ciprodex, Ciprofloxacin, Otiprio, Otixal, Otovel, Proquin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciprofloxacin Ciprofloxacine Ciprofloxacino Ciprofloxacinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Ciprofloxacin is a second generation fluoroquinolone used to treat various susceptible bacterial infections. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Cisapride interact?

•Drug A: Buserelin •Drug B: Cisapride •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Cisapride. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cisapride is a parasympathomimetic which acts as a serotonin 5-HT 4 agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cisapride acts through the stimulation of the serotonin 5-HT 4 receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 97.5% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 6-12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cisapride is a medication used to treat heartburn associated with GERD.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Cisapride interact? Information: •Drug A: Buserelin •Drug B: Cisapride •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Cisapride. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cisapride is a parasympathomimetic which acts as a serotonin 5-HT 4 agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cisapride acts through the stimulation of the serotonin 5-HT 4 receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 97.5% •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 6-12 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cisapride is a medication used to treat heartburn associated with GERD. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Citalopram interact?

•Drug A: Buserelin •Drug B: Citalopram •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Citalopram. •Extended Description: As an SSRI, citalopram can cause a dose-dependent QT prolongation due to the inhibition of the IKr channel.1 Therefore, the concomitant use of citalopram with another QT-prolonging agent can cause additional QT prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Citalopram is approved by the FDA for treating adults with major depressive disorder. It has also been used off-label to treat various diseases, including but not limited to sexual dysfunction, ethanol abuse, psychiatric conditions such as obsessive-compulsive disorder (OCD), social anxiety disorder, panic disorder, and diabetic neuropathy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Citalopram belongs to a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). It has been found to relieve or manage symptoms of depression, anxiety, eating disorders and obsessive-compulsive disorder among other mood disorders. The antidepressant, anti-anxiety, and other actions of citalopram are linked to its inhibition of CNS central uptake of serotonin. Serotonergic abnormalities have been reported in patients with mood disorders. Behavioral and neuropsychological effects of serotonin include the regulation of mood, perception, reward, anger, aggression, appetite, memory, sexuality, and attention, as examples. The onset of action for depression is approximately 1 to 4 weeks. The complete response may take 8-12 weeks after initiation of citalopram. In vitro studies demonstrate that citalopram is a strong and selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine central reuptake. The chronic administration of citalopram has been shown to downregulate central norepinephrine receptors, similar to other drugs effective in the treatment of major depressive disorder. Citalopram does not inhibit monoamine oxidase. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of citalopram is unclear but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT), potentially through the inhibition of the serotonin transporter (solute carrier family 6 member 4, SLC6A4 ). Citalopram binds with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs. Particularly, citalopram has no or very low affinity for 5-HT 1A, 5-HT 2A, dopamine D 1 and D 2, α 1 -, α 2 -, and β-adrenergic, histamine H 1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of citalopram is about 12 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Citalopram is metabolized mainly in the liver via N -demethylation to its main metabolite, demethylcitalopram by CYP2C19 and CYP3A4. Other metabolites include didemethylcitalopram via CYP2D6 metabolism, citalopram N -oxide and propionic acid derivative via monoamine oxidase enzymes A and B and aldehyde oxidase. Citalopram metabolites exert little pharmacologic activity in comparison to the parent drug and are not likely to contribute to the clinical effect of citalopram. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 12 to 23% of an oral dose of citalopram is found unchanged in the urine, while 10% is found in feces. Following intravenous administrations of citalopram, the fraction of the drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life of citalopram is about 35 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including citalopram, during pregnancy. There also are risks associated with untreated depression in pregnancy. Citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the Maximum Recommended Human Dose (MRHD) of 40 mg, based on mg/m2 body surface area. Citalopram caused maternal toxicity of CNS clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the MRHD. At this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). The no observed adverse effect level (NOAEL) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the MRHD. Citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the MRHD of 40 mg, based on mg/m2 body surface area. No maternal or embryofetal toxicity was observed. The NOAEL for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the MRHD. Citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 40 mg, based on mg/m2 body surface area. Citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the MRHD. The NOAEL for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the MRHD. In a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the MRHD. A NOAEL was not determined in that study. SSRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction. The following have been reported with citalopram tablet overdosage: • Seizures, which may be delayed, and altered mental status including coma. • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension is most commonly seen, but hypotension can rarely be seen alone or with co‐ingestants including alcohol. • Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk). Prolonged cardiac monitoring is recommended in citalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a citalopram overdose. Consider contacting a Poison Center (1‐800‐221‐2222) or a medical toxicologist for additional overdosage management recommendations. Citalopram increased the incidence of small intestine carcinoma in rats treated for 24 months at doses of 8 and 24 mg/kg/day in the diet, which are approximately 2 and 6 times the Maximum Recommended Human Dose (MRHD) of 40 mg, respectively, based on mg/m2 body surface area. A no-effect level (NOEL) for this finding was not established. Citalopram did not increase the incidence of tumors in mice treated for 18 months at doses up to 240 mg/kg/day in the diet, which is approximately 30 times the MRDH of 40 mg based on mg/m2 body surface area. Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays. Citalopram was administered orally to female and male rats at doses of 32, 48, and 72 mg/kg/day prior to and throughout mating and continuing to gestation. These doses are approximately 8, 12, and 17 times the MRHD of 40 mg based on mg/m2 body surface area. Mating and fertility were decreased at doses ≥ 32 mg/kg/day, which is approximately 8 times the MRHD. Gestation duration was increased to 48 mg/kg/day, which is approximately 12 times the MRHD. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Celexa, Ctp •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Citalopram is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression.

As an SSRI, citalopram can cause a dose-dependent QT prolongation due to the inhibition of the IKr channel.1 Therefore, the concomitant use of citalopram with another QT-prolonging agent can cause additional QT prolongation. The severity of the interaction is moderate.

Question: Does Buserelin and Citalopram interact? Information: •Drug A: Buserelin •Drug B: Citalopram •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Citalopram. •Extended Description: As an SSRI, citalopram can cause a dose-dependent QT prolongation due to the inhibition of the IKr channel.1 Therefore, the concomitant use of citalopram with another QT-prolonging agent can cause additional QT prolongation. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Citalopram is approved by the FDA for treating adults with major depressive disorder. It has also been used off-label to treat various diseases, including but not limited to sexual dysfunction, ethanol abuse, psychiatric conditions such as obsessive-compulsive disorder (OCD), social anxiety disorder, panic disorder, and diabetic neuropathy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Citalopram belongs to a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). It has been found to relieve or manage symptoms of depression, anxiety, eating disorders and obsessive-compulsive disorder among other mood disorders. The antidepressant, anti-anxiety, and other actions of citalopram are linked to its inhibition of CNS central uptake of serotonin. Serotonergic abnormalities have been reported in patients with mood disorders. Behavioral and neuropsychological effects of serotonin include the regulation of mood, perception, reward, anger, aggression, appetite, memory, sexuality, and attention, as examples. The onset of action for depression is approximately 1 to 4 weeks. The complete response may take 8-12 weeks after initiation of citalopram. In vitro studies demonstrate that citalopram is a strong and selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine central reuptake. The chronic administration of citalopram has been shown to downregulate central norepinephrine receptors, similar to other drugs effective in the treatment of major depressive disorder. Citalopram does not inhibit monoamine oxidase. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of citalopram is unclear but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT), potentially through the inhibition of the serotonin transporter (solute carrier family 6 member 4, SLC6A4 ). Citalopram binds with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs. Particularly, citalopram has no or very low affinity for 5-HT 1A, 5-HT 2A, dopamine D 1 and D 2, α 1 -, α 2 -, and β-adrenergic, histamine H 1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of citalopram is about 12 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Citalopram is metabolized mainly in the liver via N -demethylation to its main metabolite, demethylcitalopram by CYP2C19 and CYP3A4. Other metabolites include didemethylcitalopram via CYP2D6 metabolism, citalopram N -oxide and propionic acid derivative via monoamine oxidase enzymes A and B and aldehyde oxidase. Citalopram metabolites exert little pharmacologic activity in comparison to the parent drug and are not likely to contribute to the clinical effect of citalopram. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 12 to 23% of an oral dose of citalopram is found unchanged in the urine, while 10% is found in feces. Following intravenous administrations of citalopram, the fraction of the drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life of citalopram is about 35 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including citalopram, during pregnancy. There also are risks associated with untreated depression in pregnancy. Citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the Maximum Recommended Human Dose (MRHD) of 40 mg, based on mg/m2 body surface area. Citalopram caused maternal toxicity of CNS clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the MRHD. At this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). The no observed adverse effect level (NOAEL) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the MRHD. Citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the MRHD of 40 mg, based on mg/m2 body surface area. No maternal or embryofetal toxicity was observed. The NOAEL for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the MRHD. Citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 40 mg, based on mg/m2 body surface area. Citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the MRHD. The NOAEL for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the MRHD. In a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the MRHD. A NOAEL was not determined in that study. SSRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction. The following have been reported with citalopram tablet overdosage: • Seizures, which may be delayed, and altered mental status including coma. • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension is most commonly seen, but hypotension can rarely be seen alone or with co‐ingestants including alcohol. • Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk). Prolonged cardiac monitoring is recommended in citalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a citalopram overdose. Consider contacting a Poison Center (1‐800‐221‐2222) or a medical toxicologist for additional overdosage management recommendations. Citalopram increased the incidence of small intestine carcinoma in rats treated for 24 months at doses of 8 and 24 mg/kg/day in the diet, which are approximately 2 and 6 times the Maximum Recommended Human Dose (MRHD) of 40 mg, respectively, based on mg/m2 body surface area. A no-effect level (NOEL) for this finding was not established. Citalopram did not increase the incidence of tumors in mice treated for 18 months at doses up to 240 mg/kg/day in the diet, which is approximately 30 times the MRDH of 40 mg based on mg/m2 body surface area. Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays. Citalopram was administered orally to female and male rats at doses of 32, 48, and 72 mg/kg/day prior to and throughout mating and continuing to gestation. These doses are approximately 8, 12, and 17 times the MRHD of 40 mg based on mg/m2 body surface area. Mating and fertility were decreased at doses ≥ 32 mg/kg/day, which is approximately 8 times the MRHD. Gestation duration was increased to 48 mg/kg/day, which is approximately 12 times the MRHD. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Celexa, Ctp •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Citalopram is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression. Output: As an SSRI, citalopram can cause a dose-dependent QT prolongation due to the inhibition of the IKr channel.1 Therefore, the concomitant use of citalopram with another QT-prolonging agent can cause additional QT prolongation. The severity of the interaction is moderate.

Does Buserelin and Clarithromycin interact?

•Drug A: Buserelin •Drug B: Clarithromycin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clarithromycin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): An alternative medication for the treatment of acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae in patients with a history of type I penicillin hypersensitivity. Also for the treatment of pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes, as well as respiratory tract infections including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, mild to moderate community-acquired pneuomia, Legionnaires' disease, and pertussis. Other indications include treatment of uncomplicated skin or skin structure infections, helicobacter pylori infection, duodenal ulcer disease, bartonella infections, early Lyme disease, and encephalitis caused by Toxoplasma gondii (in HIV infected patients in conjunction with pyrimethamine). Clarithromycin may also decrease the incidence of cryptosporidiosis, prevent the occurence of α-hemolytic (viridans group) streptococcal endocarditis, as well as serve as a primary prevention for Mycobacterium avium complex (MAC) bacteremia or disseminated infections (in adults, adolescents, and children with advanced HIV infection). Clarithromycin is indicated in combination with vonoprazan and amoxicillin as co-packaged triple therapy to treat Helicobacter pylori ( H. pylori ) infection in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clarithromycin is a macrolide antibiotic whose spectrum of activity includes many gram-positive ( Staphylococcus aureus, S. pneumoniae, and S. pyogenes ) and gram-negative aerobic bacteria ( Haemophilus influenzae, H. parainfluenzae, and Moraxella catarrhalis ), many anaerobic bacteria, some mycobacteria, and some other organisms including Mycoplasma, Ureaplasma, Chlamydia, Toxoplasma, and Borrelia. Other aerobic bacteria that clarithromycin has activity against include C. pneumoniae and M. pneumoniae. Clarithromycin has an in-vitro activity that is similar or greater than that of erythromycin against erythromycin-susceptible organisms. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and the drug concentration. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Clarithromycin is well-absorbed, acid stable and may be taken with food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): ~ 70% protein bound •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic - predominantly metabolized by CYP3A4 resulting in numerous drug interactions. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 3-4 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of toxicity include diarrhea, nausea, abnormal taste, dyspepsia, and abdominal discomfort. Transient hearing loss with high doses has been observed. Pseudomembraneous colitis has been reported with clarithromycin use. Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have also occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic failure is usually reversible, but fatalities have been reported. Clarithromycin may also cause tooth decolouration which may be removed by dental cleaning. Fetal abnormalities, such as cardiovascular defects, cleft palate and fetal growth retardation, have been observed in animals. Clarithromycin may cause QT prolongation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Biaxin, Biaxin Bid, Omeclamox, Prevpac, Voquezna 14 Day Triplepak 20;500;500 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-O-methyl erythromycin 6-O-methylerythromycin 6-O-methylerythromycin A Clarithromycin Clarithromycina Clarithromycine Clarithromycinum Claritromicina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clarithromycin is a macrolide antibiotic used for the treatment of a wide variety of bacterial infections such as acute otitis, pharyngitis, tonsillitis, respiratory tract infections, uncomplicated skin infections, and helicobacter pylori infection.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Clarithromycin interact? Information: •Drug A: Buserelin •Drug B: Clarithromycin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clarithromycin. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): An alternative medication for the treatment of acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae in patients with a history of type I penicillin hypersensitivity. Also for the treatment of pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes, as well as respiratory tract infections including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, mild to moderate community-acquired pneuomia, Legionnaires' disease, and pertussis. Other indications include treatment of uncomplicated skin or skin structure infections, helicobacter pylori infection, duodenal ulcer disease, bartonella infections, early Lyme disease, and encephalitis caused by Toxoplasma gondii (in HIV infected patients in conjunction with pyrimethamine). Clarithromycin may also decrease the incidence of cryptosporidiosis, prevent the occurence of α-hemolytic (viridans group) streptococcal endocarditis, as well as serve as a primary prevention for Mycobacterium avium complex (MAC) bacteremia or disseminated infections (in adults, adolescents, and children with advanced HIV infection). Clarithromycin is indicated in combination with vonoprazan and amoxicillin as co-packaged triple therapy to treat Helicobacter pylori ( H. pylori ) infection in adults. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clarithromycin is a macrolide antibiotic whose spectrum of activity includes many gram-positive ( Staphylococcus aureus, S. pneumoniae, and S. pyogenes ) and gram-negative aerobic bacteria ( Haemophilus influenzae, H. parainfluenzae, and Moraxella catarrhalis ), many anaerobic bacteria, some mycobacteria, and some other organisms including Mycoplasma, Ureaplasma, Chlamydia, Toxoplasma, and Borrelia. Other aerobic bacteria that clarithromycin has activity against include C. pneumoniae and M. pneumoniae. Clarithromycin has an in-vitro activity that is similar or greater than that of erythromycin against erythromycin-susceptible organisms. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and the drug concentration. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Clarithromycin is well-absorbed, acid stable and may be taken with food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): ~ 70% protein bound •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic - predominantly metabolized by CYP3A4 resulting in numerous drug interactions. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 3-4 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Symptoms of toxicity include diarrhea, nausea, abnormal taste, dyspepsia, and abdominal discomfort. Transient hearing loss with high doses has been observed. Pseudomembraneous colitis has been reported with clarithromycin use. Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have also occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic failure is usually reversible, but fatalities have been reported. Clarithromycin may also cause tooth decolouration which may be removed by dental cleaning. Fetal abnormalities, such as cardiovascular defects, cleft palate and fetal growth retardation, have been observed in animals. Clarithromycin may cause QT prolongation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Biaxin, Biaxin Bid, Omeclamox, Prevpac, Voquezna 14 Day Triplepak 20;500;500 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-O-methyl erythromycin 6-O-methylerythromycin 6-O-methylerythromycin A Clarithromycin Clarithromycina Clarithromycine Clarithromycinum Claritromicina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clarithromycin is a macrolide antibiotic used for the treatment of a wide variety of bacterial infections such as acute otitis, pharyngitis, tonsillitis, respiratory tract infections, uncomplicated skin infections, and helicobacter pylori infection. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Clemastine interact?

•Drug A: Buserelin •Drug B: Clemastine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clemastine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and acrimation. Also for the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Used as self-medication for temporary relief of symptoms associated with the common cold. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clemastine is an antihistamine that also induces anticholinergic and sedative effects. Antihistamines competitively antagonize various physiological effects of histamine including increased capillary permeability and dilatation, the formation of edema, the "flare" and "itch" response, and gastrointestinal and respiratory smooth muscle constriction. Within the vascular tree, H1- receptor antagonists inhibit both the vasoconstrictor and vasodilator effects of histamine. Depending on the dose, H1- receptor antagonists can produce CNS stimulation or depression. Most antihistamines exhibit central and/or peripheral anticholinergic activity. Antihistamines act by competitively blocking H1- receptor sites. Antihistamines do not pharmacologically antagonize or chemically inactivate histamine, nor do they prevent the release of histamine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Clemastine is a selective histamine H1 antagonist and binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Antihistamines appear to be metabolized in the liver chiefly via mono- and didemethylation and glucuronide conjugation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urinary excretion is the major mode of elimination. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD 50 in rat and mouse is 3550 mg/kg and 730 mg/kg, respectively. Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. In children, stimulation predominates initially in a syndrome which may include excitement, hallucinations, ataxia, incoordination, muscle twitching, athetosis, hyperthermia, cyanosis convulsions, tremors, and hyperreflexia followed by postictal depression and cardio-respiratory arrest. Convulsions in children may be preceded by mild depression. Dry mouth, fixed dilated pupils, flushing of the face, and fever are common. In adults, CNS depression, ranging from drowsiness to coma, is more common. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Wal-hist 12 Hr Relief •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Clemastina Clemastine Clemastinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clemastine is an antihistamine with sedative and anticholinergic effects used to treat the symptoms of allergic rhinitis.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Clemastine interact? Information: •Drug A: Buserelin •Drug B: Clemastine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clemastine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and acrimation. Also for the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Used as self-medication for temporary relief of symptoms associated with the common cold. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clemastine is an antihistamine that also induces anticholinergic and sedative effects. Antihistamines competitively antagonize various physiological effects of histamine including increased capillary permeability and dilatation, the formation of edema, the "flare" and "itch" response, and gastrointestinal and respiratory smooth muscle constriction. Within the vascular tree, H1- receptor antagonists inhibit both the vasoconstrictor and vasodilator effects of histamine. Depending on the dose, H1- receptor antagonists can produce CNS stimulation or depression. Most antihistamines exhibit central and/or peripheral anticholinergic activity. Antihistamines act by competitively blocking H1- receptor sites. Antihistamines do not pharmacologically antagonize or chemically inactivate histamine, nor do they prevent the release of histamine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Clemastine is a selective histamine H1 antagonist and binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Antihistamines appear to be metabolized in the liver chiefly via mono- and didemethylation and glucuronide conjugation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urinary excretion is the major mode of elimination. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral LD 50 in rat and mouse is 3550 mg/kg and 730 mg/kg, respectively. Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. In children, stimulation predominates initially in a syndrome which may include excitement, hallucinations, ataxia, incoordination, muscle twitching, athetosis, hyperthermia, cyanosis convulsions, tremors, and hyperreflexia followed by postictal depression and cardio-respiratory arrest. Convulsions in children may be preceded by mild depression. Dry mouth, fixed dilated pupils, flushing of the face, and fever are common. In adults, CNS depression, ranging from drowsiness to coma, is more common. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Wal-hist 12 Hr Relief •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Clemastina Clemastine Clemastinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clemastine is an antihistamine with sedative and anticholinergic effects used to treat the symptoms of allergic rhinitis. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Clofazimine interact?

•Drug A: Buserelin •Drug B: Clofazimine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Clofazimine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Clofazimine is indicated for the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. To prevent the development of drug resistance, it should be used only in combination with other antimycobacterial leprosy treatments. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) due primarily to its action on the bacterial outer membrane, though there is some evidence that activity on the bacterial respiratory chain and ion transporters may play a role. It also exerts anti-inflammatory properties due to the suppression of T-lymphocyte activity. Clofazimine has a relatively long duration of action owing to its long residence time in the body, but is still administered daily. Approximately 75-100% of patients receiving clofazimine will experience an orange-pink to brownish-black discoloration of the skin, conjunctivae, and bodily fluids. Skin discoloration may take several months or years to reverse following the cessation of therapy. Clofazimine has also been implicated in abdominal obstruction, in some cases fatal, due to the deposition of drug and formation of crystals in the intestinal mucosa - complaints of abdominal pain and nausea/vomiting should be investigated promptly, and the doses of clofazimine should be lowered or discontinued if it is found to be the culprit. Its use should be avoided in patients with hepatic dysfunction. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Although the precise mechanism(s) of action of clofazimine have not been elucidated, its antimicrobial activity appears to be membrane-directed. It was previously thought that, due to its lipophilicity, clofazimine participated in the generation of intracellular reactive oxygen species (ROS) via redox cycling, specifically H 2 O 2 and superoxide, which then exerted an antimicrobial effect. A more recent and compelling theory involves clofazimine interacting with bacterial membrane phospholipids to generate antimicrobial lysophospholipids - bactericidal efficacy may, then, arise from the combined membrane-destabilizing effects of both clofazimine and lysophospholipids, which interfere with K+ uptake and, ultimately, ATP production. The anti-inflammatory activity of clofazimine is the result of its inhibition of T-lymphocyte activation and proliferation. Several mechanisms have been proposed, including direct antagonism of T-cell Kv 1.3 potassium channels and indirect action by promoting the release of E-series prostaglandins and reactive oxygen species from bystander neutrophils and monocytes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption varies from 45 to 62% following oral administration in leprosy patients. Co-administration of a 200mg dose of clofazimine with food resulted in a C max of 0.41 mg/L with a T max of 8 h; administered in a fasting state, the corresponding C max was 30% lower while the time to Cmax was 12 h. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Clofazimine is highly lipophilic and therefore deposits primarily in fatty tissues and cells of the reticuloendothelial system, where it is taken up by macrophages and further distributed throughout the body. Crystalized deposits have been found in the mesenteric lymph nodes, adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin. •Protein binding (Drug A): 15% •Protein binding (Drug B): Clofazimine is bound primarily to beta-lipoproteins (and, to a lesser extent, alpha-lipoproteins) in the serum. This binding was saturable at concentrations of ~10 µg/mL. Binding to gamma-globulin and albumin is negligible. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Three metabolites have been identified in the urine following repeated oral doses of clofazimine. It is unclear whether these metabolites are pharmacologically active. Metabolite I may be the result of the hydrolytic dehalogenation of clofazimine and metabolite II presumably is formed by a hydrolytic deamination reaction followed by glucuronidation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Part of an ingested dose of clofazimine is found in the feces, which may represent excretion in the bile, and a small amount is also eliminated in the sputum, sebum, and sweat. Excretion of unchanged drug and metabolites in a 24-hour urine collection was negligible. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life is approximately 25 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The reported oral LD 50 of clofazimine in rats and mice is 8400 mg/kg and >5000 mg/kg, respectively. No specific data are available regarding the treatment of clofazimine overdosage. In cases of overdose consider gastrointestinal decontamination via gastric lavage or induced vomiting. Employ symptomatic and supportive measures as clinically indicated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clofazimine is a riminophenazine antimycobacterial used to treat leprosy.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Clofazimine interact? Information: •Drug A: Buserelin •Drug B: Clofazimine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Clofazimine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Clofazimine is indicated for the treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. To prevent the development of drug resistance, it should be used only in combination with other antimycobacterial leprosy treatments. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) due primarily to its action on the bacterial outer membrane, though there is some evidence that activity on the bacterial respiratory chain and ion transporters may play a role. It also exerts anti-inflammatory properties due to the suppression of T-lymphocyte activity. Clofazimine has a relatively long duration of action owing to its long residence time in the body, but is still administered daily. Approximately 75-100% of patients receiving clofazimine will experience an orange-pink to brownish-black discoloration of the skin, conjunctivae, and bodily fluids. Skin discoloration may take several months or years to reverse following the cessation of therapy. Clofazimine has also been implicated in abdominal obstruction, in some cases fatal, due to the deposition of drug and formation of crystals in the intestinal mucosa - complaints of abdominal pain and nausea/vomiting should be investigated promptly, and the doses of clofazimine should be lowered or discontinued if it is found to be the culprit. Its use should be avoided in patients with hepatic dysfunction. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Although the precise mechanism(s) of action of clofazimine have not been elucidated, its antimicrobial activity appears to be membrane-directed. It was previously thought that, due to its lipophilicity, clofazimine participated in the generation of intracellular reactive oxygen species (ROS) via redox cycling, specifically H 2 O 2 and superoxide, which then exerted an antimicrobial effect. A more recent and compelling theory involves clofazimine interacting with bacterial membrane phospholipids to generate antimicrobial lysophospholipids - bactericidal efficacy may, then, arise from the combined membrane-destabilizing effects of both clofazimine and lysophospholipids, which interfere with K+ uptake and, ultimately, ATP production. The anti-inflammatory activity of clofazimine is the result of its inhibition of T-lymphocyte activation and proliferation. Several mechanisms have been proposed, including direct antagonism of T-cell Kv 1.3 potassium channels and indirect action by promoting the release of E-series prostaglandins and reactive oxygen species from bystander neutrophils and monocytes. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Absorption varies from 45 to 62% following oral administration in leprosy patients. Co-administration of a 200mg dose of clofazimine with food resulted in a C max of 0.41 mg/L with a T max of 8 h; administered in a fasting state, the corresponding C max was 30% lower while the time to Cmax was 12 h. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Clofazimine is highly lipophilic and therefore deposits primarily in fatty tissues and cells of the reticuloendothelial system, where it is taken up by macrophages and further distributed throughout the body. Crystalized deposits have been found in the mesenteric lymph nodes, adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin. •Protein binding (Drug A): 15% •Protein binding (Drug B): Clofazimine is bound primarily to beta-lipoproteins (and, to a lesser extent, alpha-lipoproteins) in the serum. This binding was saturable at concentrations of ~10 µg/mL. Binding to gamma-globulin and albumin is negligible. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Three metabolites have been identified in the urine following repeated oral doses of clofazimine. It is unclear whether these metabolites are pharmacologically active. Metabolite I may be the result of the hydrolytic dehalogenation of clofazimine and metabolite II presumably is formed by a hydrolytic deamination reaction followed by glucuronidation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Part of an ingested dose of clofazimine is found in the feces, which may represent excretion in the bile, and a small amount is also eliminated in the sputum, sebum, and sweat. Excretion of unchanged drug and metabolites in a 24-hour urine collection was negligible. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life is approximately 25 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The reported oral LD 50 of clofazimine in rats and mice is 8400 mg/kg and >5000 mg/kg, respectively. No specific data are available regarding the treatment of clofazimine overdosage. In cases of overdose consider gastrointestinal decontamination via gastric lavage or induced vomiting. Employ symptomatic and supportive measures as clinically indicated. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clofazimine is a riminophenazine antimycobacterial used to treat leprosy. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Clomipramine interact?

•Drug A: Buserelin •Drug B: Clomipramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clomipramine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. •Protein binding (Drug A): 15% •Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anafranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Clomipramine interact? Information: •Drug A: Buserelin •Drug B: Clomipramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clomipramine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. •Protein binding (Drug A): 15% •Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anafranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Clozapine interact?

•Drug A: Buserelin •Drug B: Clozapine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clozapine. •Extended Description: Clozapine has been observed to cause various cardiac side effects, including QTc prolongation in a dose-dependent manner.2,1 This is likely due to clozapine's affinity to various muscarinic receptors and adrenoceptors.. Therefore, the co-administration of clozapine with another drug known to cause QTc prolongation can have an additive effect in increasing the risk of this side effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM). Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). •Protein binding (Drug A): 15% •Protein binding (Drug B): Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. •Clearance (Drug A): No clearance available •Clearance (Drug B): The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Clozaril, Fazaclo, Versacloz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients.

Clozapine has been observed to cause various cardiac side effects, including QTc prolongation in a dose-dependent manner.2,1 This is likely due to clozapine's affinity to various muscarinic receptors and adrenoceptors.. Therefore, the co-administration of clozapine with another drug known to cause QTc prolongation can have an additive effect in increasing the risk of this side effect. The severity of the interaction is moderate.

Question: Does Buserelin and Clozapine interact? Information: •Drug A: Buserelin •Drug B: Clozapine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Clozapine. •Extended Description: Clozapine has been observed to cause various cardiac side effects, including QTc prolongation in a dose-dependent manner.2,1 This is likely due to clozapine's affinity to various muscarinic receptors and adrenoceptors.. Therefore, the co-administration of clozapine with another drug known to cause QTc prolongation can have an additive effect in increasing the risk of this side effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM). Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). •Protein binding (Drug A): 15% •Protein binding (Drug B): Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. •Clearance (Drug A): No clearance available •Clearance (Drug B): The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Clozaril, Fazaclo, Versacloz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients. Output: Clozapine has been observed to cause various cardiac side effects, including QTc prolongation in a dose-dependent manner.2,1 This is likely due to clozapine's affinity to various muscarinic receptors and adrenoceptors.. Therefore, the co-administration of clozapine with another drug known to cause QTc prolongation can have an additive effect in increasing the risk of this side effect. The severity of the interaction is moderate.

Does Buserelin and Cocaine interact?

•Drug A: Buserelin •Drug B: Cocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Cocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the introduction of local (topical) anesthesia of accessible mucous membranes of the oral, laryngeal and nasal cavities. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cocaine is a local anesthetic indicated for the introduction of local (topical) anesthesia of accessible mucous membranes of the oral, laryngeal and nasal cavities. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cocaine produces anesthesia by inhibiting excitation of nerve endings or by blocking conduction in peripheral nerves. This is achieved by reversibly binding to and inactivating sodium channels. Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve. Cocaine is the only local anesthetic with vasoconstrictive properties. This is a result of its blockade of norepinephrine reuptake in the autonomic nervous system. Cocaine binds differentially to the dopamine, serotonin, and norepinephrine transport proteins and directly prevents the re-uptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons. Its effect on dopamine levels is most responsible for the addictive property of cocaine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cocaine is absorbed from all sites of application, including mucous membranes and gastrointestinal mucosa. By oral or intra-nasal route, 60 to 80% of cocaine is absorbed. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Cocaine is metabolized to benzoylecgonine and ecgonine methyl ester, which are both excreted in the urine. In the presence of alcohol, a further active metabolite, cocaethylene is formed, and is more toxic then cocaine itself. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 1 hour •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Intense agitation, convulsions, hypertension, rhythm disturbance, coronary insufficiency, hyperthermia, rhabdomyolysis, and renal impairment. Oral mouse LD 50 = 96 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Goprelto, Numbrino •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benzoylmethylecgonine beta-Cocain Cocain Cocaina Cocaine Cocainum Kokain L-Cocain L-Cocaine Methyl benzoylecgonine Neurocaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cocaine is an ester local anesthetic used during diagnostic procedures and surgeries in or through the nasal cavities.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Cocaine interact? Information: •Drug A: Buserelin •Drug B: Cocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Cocaine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the introduction of local (topical) anesthesia of accessible mucous membranes of the oral, laryngeal and nasal cavities. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cocaine is a local anesthetic indicated for the introduction of local (topical) anesthesia of accessible mucous membranes of the oral, laryngeal and nasal cavities. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cocaine produces anesthesia by inhibiting excitation of nerve endings or by blocking conduction in peripheral nerves. This is achieved by reversibly binding to and inactivating sodium channels. Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve. Cocaine is the only local anesthetic with vasoconstrictive properties. This is a result of its blockade of norepinephrine reuptake in the autonomic nervous system. Cocaine binds differentially to the dopamine, serotonin, and norepinephrine transport proteins and directly prevents the re-uptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons. Its effect on dopamine levels is most responsible for the addictive property of cocaine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Cocaine is absorbed from all sites of application, including mucous membranes and gastrointestinal mucosa. By oral or intra-nasal route, 60 to 80% of cocaine is absorbed. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. Cocaine is metabolized to benzoylecgonine and ecgonine methyl ester, which are both excreted in the urine. In the presence of alcohol, a further active metabolite, cocaethylene is formed, and is more toxic then cocaine itself. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 1 hour •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Intense agitation, convulsions, hypertension, rhythm disturbance, coronary insufficiency, hyperthermia, rhabdomyolysis, and renal impairment. Oral mouse LD 50 = 96 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Goprelto, Numbrino •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benzoylmethylecgonine beta-Cocain Cocain Cocaina Cocaine Cocainum Kokain L-Cocain L-Cocaine Methyl benzoylecgonine Neurocaine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cocaine is an ester local anesthetic used during diagnostic procedures and surgeries in or through the nasal cavities. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Does Buserelin and Corifollitropin alfa interact?

•Drug A: Buserelin •Drug B: Corifollitropin alfa •Severity: MAJOR •Description: The therapeutic efficacy of Corifollitropin alfa can be increased when used in combination with Buserelin. •Extended Description: One study suggests that corlifollitropin alfa with gonadotropin-releasing hormone agonists indicate a higher ovarian response, although supporting data are limited in the literature. The purpose of corlifollitropin therapy is controlled ovarian stimulation, which may be unregulated by the administration of GnRH agonists, promoting uncontrolled proliferation. This can lead to neoplasms, both malignant and benign, as well as ovarian hyper stimulation syndrome (OHSS). Multiple gestation, low birth weight, and venous thromboembolism may result. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Controlled ovarian stimulation in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): A single dose of corifollitropin alfa could initiate and sustain multi-follicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. This drug is structurally similar to follicle stimulating hormone (FSH), a hormone naturally present in females. FSH stimulates the production of eggs (ova) in the ovaries. In corifollitropin alfa, a peptide is attached to the FSH to prolong its activity. As a result, one single dose of the medicine can be administered to stimulate egg production for seven days, replacing daily injections that are normally needed with other FSH medicines. In phase III clinical trials, the number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Corifollitropin alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit). Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG). This unit interacts with the FSH receptor to stimulate the release of oocytes. Corifollitropin alfa does not demonstrate any intrinsic LH/hCG activity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After one single subcutaneous injection of this drug, the maximal serum concentration is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady-state volume of distribution is 9.2 L. Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms. •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolic fate of corifollitropin alfa highly resembles that of endogenous glycoprotein hormones, which predominantly is comprised of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part). Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.13 L/h (0.10-0.18 L/h1) •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea. More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome, which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg. In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur. About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Elonva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Corifollitropin alfa is a FSH analogue indicated for Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program.

One study suggests that corlifollitropin alfa with gonadotropin-releasing hormone agonists indicate a higher ovarian response, although supporting data are limited in the literature. The purpose of corlifollitropin therapy is controlled ovarian stimulation, which may be unregulated by the administration of GnRH agonists, promoting uncontrolled proliferation. This can lead to neoplasms, both malignant and benign, as well as ovarian hyper stimulation syndrome (OHSS). Multiple gestation, low birth weight, and venous thromboembolism may result. The severity of the interaction is major.

Question: Does Buserelin and Corifollitropin alfa interact? Information: •Drug A: Buserelin •Drug B: Corifollitropin alfa •Severity: MAJOR •Description: The therapeutic efficacy of Corifollitropin alfa can be increased when used in combination with Buserelin. •Extended Description: One study suggests that corlifollitropin alfa with gonadotropin-releasing hormone agonists indicate a higher ovarian response, although supporting data are limited in the literature. The purpose of corlifollitropin therapy is controlled ovarian stimulation, which may be unregulated by the administration of GnRH agonists, promoting uncontrolled proliferation. This can lead to neoplasms, both malignant and benign, as well as ovarian hyper stimulation syndrome (OHSS). Multiple gestation, low birth weight, and venous thromboembolism may result. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Controlled ovarian stimulation in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): A single dose of corifollitropin alfa could initiate and sustain multi-follicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. This drug is structurally similar to follicle stimulating hormone (FSH), a hormone naturally present in females. FSH stimulates the production of eggs (ova) in the ovaries. In corifollitropin alfa, a peptide is attached to the FSH to prolong its activity. As a result, one single dose of the medicine can be administered to stimulate egg production for seven days, replacing daily injections that are normally needed with other FSH medicines. In phase III clinical trials, the number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Corifollitropin alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit). Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG). This unit interacts with the FSH receptor to stimulate the release of oocytes. Corifollitropin alfa does not demonstrate any intrinsic LH/hCG activity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After one single subcutaneous injection of this drug, the maximal serum concentration is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%). •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady-state volume of distribution is 9.2 L. Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms. •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolic fate of corifollitropin alfa highly resembles that of endogenous glycoprotein hormones, which predominantly is comprised of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part). Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.13 L/h (0.10-0.18 L/h1) •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea. More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome, which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg. In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur. About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Elonva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Corifollitropin alfa is a FSH analogue indicated for Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program. Output: One study suggests that corlifollitropin alfa with gonadotropin-releasing hormone agonists indicate a higher ovarian response, although supporting data are limited in the literature. The purpose of corlifollitropin therapy is controlled ovarian stimulation, which may be unregulated by the administration of GnRH agonists, promoting uncontrolled proliferation. This can lead to neoplasms, both malignant and benign, as well as ovarian hyper stimulation syndrome (OHSS). Multiple gestation, low birth weight, and venous thromboembolism may result. The severity of the interaction is major.

Does Buserelin and Crizotinib interact?

•Drug A: Buserelin •Drug B: Crizotinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Crizotinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Crizotinib is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. Additionally, crizotinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In a phase I study, 37 patients with a variety of solid-tumor cancers refractory to therapy received 50 to 300 mg of crizotinib daily or twice daily. In this group, two patients with non-small cell lung cancer (NSCLC) exhibiting echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations responded to therapy; therefore, following studies focused on patients with advanced ALK-positive disease. In this group of patients, the 6-month progression-free survival among crizotinib users was approximately 72%. When compared to ALK mutation-positive patients that did not receive crizotinib, ALK mutation-positive patients treated with crizotinib had a higher two-year overall survival rate (54% vs 36%). The use of crizotinib may lead to hepatotoxicity, interstitial lung disease (ILD), pneumonitis, QT interval prolongation, bradycardia, severe visual loss, ​​embryo-fetal toxicity and gastrointestinal toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Crizotinib is a tyrosine kinase receptor inhibitor that targets anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). When activated, ALK inhibits apoptosis and promotes cell proliferation, and ALK-gene translocations can lead to the expression of oncogenic fusion proteins. A small portion of non-small cell lung cancer (NSCLC) patients have ALK-positive tumors. Most of these cases are characterized by the fusion of ALK with the chimeric protein echinoderm microtubule-associated protein-like 4 (EML4), resulting in increased kinase activity. Crizotinib inhibits ALK by inhibiting its phosphorylation and creating an inactive protein conformation. This ultimately lowers the proliferation of cells carrying this genetic mutation and tumour survivability. In vitro assays on tumor cell lines demonstrated that crizotinib inhibits ALK, ROS1, and c-Met phosphorylation in a concentration-dependent manner. In vivo studies in mice with tumor xenografts that expressed EML4- or nucleophosmin (NPM)-ALK fusion proteins or c-Met showed that crizotinib has antitumor activity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and C max increased in a dose-proportional manner. A single crizotinib dose of crizotinib is absorbed with a median t max 4 to 6 hours. In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng⋅hr/mL, the mean C max was 99.60 ng/mL, and the median t max was 5.0 hours. The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. High-fat meals reduce the AUC 0-INF and C max of crizotinib by approximately 14%. Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics. In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Crizotinib is 91% bound to plasma protein. In vitro studies suggest that this is not affected by drug concentration. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation. Non-metabolic elimination, such as biliary excretion, can not be excluded. PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified. In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3- to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5- to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following single doses of crizotinib, the plasma terminal half-life was 42 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr),, possibly due to CYP3A auto-inhibition. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily). This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors. The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures. There is no antidote for crizotinib. In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic. Carcinogenicity studies with crizotinib have not been performed. In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles. In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xalkori •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Crizotinib is a receptor tyrosine kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) where the tumors have been confirmed to be anaplastic lymphoma kinase (ALK), or ROS1-positive.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Crizotinib interact? Information: •Drug A: Buserelin •Drug B: Crizotinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Crizotinib. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Crizotinib is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. Additionally, crizotinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In a phase I study, 37 patients with a variety of solid-tumor cancers refractory to therapy received 50 to 300 mg of crizotinib daily or twice daily. In this group, two patients with non-small cell lung cancer (NSCLC) exhibiting echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations responded to therapy; therefore, following studies focused on patients with advanced ALK-positive disease. In this group of patients, the 6-month progression-free survival among crizotinib users was approximately 72%. When compared to ALK mutation-positive patients that did not receive crizotinib, ALK mutation-positive patients treated with crizotinib had a higher two-year overall survival rate (54% vs 36%). The use of crizotinib may lead to hepatotoxicity, interstitial lung disease (ILD), pneumonitis, QT interval prolongation, bradycardia, severe visual loss, ​​embryo-fetal toxicity and gastrointestinal toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Crizotinib is a tyrosine kinase receptor inhibitor that targets anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). When activated, ALK inhibits apoptosis and promotes cell proliferation, and ALK-gene translocations can lead to the expression of oncogenic fusion proteins. A small portion of non-small cell lung cancer (NSCLC) patients have ALK-positive tumors. Most of these cases are characterized by the fusion of ALK with the chimeric protein echinoderm microtubule-associated protein-like 4 (EML4), resulting in increased kinase activity. Crizotinib inhibits ALK by inhibiting its phosphorylation and creating an inactive protein conformation. This ultimately lowers the proliferation of cells carrying this genetic mutation and tumour survivability. In vitro assays on tumor cell lines demonstrated that crizotinib inhibits ALK, ROS1, and c-Met phosphorylation in a concentration-dependent manner. In vivo studies in mice with tumor xenografts that expressed EML4- or nucleophosmin (NPM)-ALK fusion proteins or c-Met showed that crizotinib has antitumor activity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and C max increased in a dose-proportional manner. A single crizotinib dose of crizotinib is absorbed with a median t max 4 to 6 hours. In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng⋅hr/mL, the mean C max was 99.60 ng/mL, and the median t max was 5.0 hours. The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. High-fat meals reduce the AUC 0-INF and C max of crizotinib by approximately 14%. Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics. In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Crizotinib is 91% bound to plasma protein. In vitro studies suggest that this is not affected by drug concentration. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation. Non-metabolic elimination, such as biliary excretion, can not be excluded. PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified. In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3- to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5- to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Following single doses of crizotinib, the plasma terminal half-life was 42 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr),, possibly due to CYP3A auto-inhibition. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily). This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors. The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures. There is no antidote for crizotinib. In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic. Carcinogenicity studies with crizotinib have not been performed. In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles. In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Xalkori •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Crizotinib is a receptor tyrosine kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) where the tumors have been confirmed to be anaplastic lymphoma kinase (ALK), or ROS1-positive. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Cyclizine interact?

•Drug A: Buserelin •Drug B: Cyclizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cyclizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness, and vertigo (dizziness caused by other medical problems). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cyclizine is a piperazine-derivative antihistamine used as an antivertigo/antiemetic agent. Cyclizine is used in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used in the management of vertigo in diseases affecting the vestibular apparatus. Although the mechanism by which cyclizine exerts its antiemetic and antivertigo effects has not been fully elucidated, its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistaminic, central nervous system depressant, and local anesthetic effects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Vomiting (emesis) is essentially a protective mechanism for removing irritant or otherwise harmful substances from the upper GI tract. Emesis or vomiting is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). The vomiting centre possesses neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness principally involves overstimulation of these pathways due to various sensory stimuli. Hence the action of cyclizine which acts to block the histamine receptors in the vomiting centre and thus reduce activity along these pathways. Furthermore since cyclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Cyclizine is metabolised to its N-demethylated derivative, norcyclizine, which has little antihistaminic (H1) activity compared to Cyclizine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciclizina Cyclizine Cyclizinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cyclizine is an antihistamine and antiemetic drug used for the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness, and vertigo.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Cyclizine interact? Information: •Drug A: Buserelin •Drug B: Cyclizine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cyclizine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness, and vertigo (dizziness caused by other medical problems). •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cyclizine is a piperazine-derivative antihistamine used as an antivertigo/antiemetic agent. Cyclizine is used in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used in the management of vertigo in diseases affecting the vestibular apparatus. Although the mechanism by which cyclizine exerts its antiemetic and antivertigo effects has not been fully elucidated, its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistaminic, central nervous system depressant, and local anesthetic effects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Vomiting (emesis) is essentially a protective mechanism for removing irritant or otherwise harmful substances from the upper GI tract. Emesis or vomiting is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). The vomiting centre possesses neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness principally involves overstimulation of these pathways due to various sensory stimuli. Hence the action of cyclizine which acts to block the histamine receptors in the vomiting centre and thus reduce activity along these pathways. Furthermore since cyclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Cyclizine is metabolised to its N-demethylated derivative, norcyclizine, which has little antihistaminic (H1) activity compared to Cyclizine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 20 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciclizina Cyclizine Cyclizinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cyclizine is an antihistamine and antiemetic drug used for the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness, and vertigo. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Cyproheptadine interact?

•Drug A: Buserelin •Drug B: Cyproheptadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cyproheptadine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In the US, prescription cyproheptadine is indicated for the treatment of various allergic symptomatologies - including dermatographia, rhinitis, conjunctivitis, and urticaria - as well as adjunctive therapy in the management of anaphylaxis following treatment with epinephrine. In Canada, cyproheptadine is available over-the-counter and is indicated for the treatment of pruritus and for appetite stimulation. In Australia, cyproheptadine is additionally indicated for the treatment vascular headaches. Cyproheptadine is also used off-label for the treatment of serotonin syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cyproheptadine has been observed to antagonize several pharmacodynamic effects of serotonin in laboratory animals, including bronchoconstriction and vasodepression, and has demonstrated similar efficacy in antagonizing histamine-mediated effects. The reason for its efficacy in preventing anaphylactic shock has not been elucidated, but appears to be related to its anti-serotonergic effects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cyproheptadine appears to exert its antihistamine and antiserotonin effects by competing with free histamine and serotonin for binding at their respective receptors. Antagonism of serotonin on the appetite center of the hypothalamus may account for cyproheptadine's ability to stimulate the appetite. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): A single study examining the difference in absorption of orally administered versus sublingually administered cyproheptadine in five healthy males demonstrated a mean C max of 30.0 mcg/L and 4.0 mcg/L, respectively, and a mean AUC of 209 mcg.h/L and 25 mcg.h/L, respectively. The T max of orally and sublingually administered cyproheptadine was 4 hours and 9.6 hours, respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The principal metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 2-20% of the radioactivity from an orally administered radio-labeled dose of cyproheptadine is excreted in the feces, of which approximately 34% is unchanged parent drug (less than 5.7% of the total dose). At least 40% of radioactivity is recovered in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdosage with cyproheptadine is likely to result in significant sedation - although paradoxical stimulation has been noted in pediatric patients - and anticholinergic adverse effects such as dry mouth and flushing. Most patients appear to recover without incident, as a review of cyproheptadine overdose cases in Hong Kong found the majority of patients had no or mild symptoms following intentional overdose. In the event of overdosage with cyproheptadine, prescribing information recommends the induction of vomiting (if it has not occurred spontaneously) using syrup of ipecac. Gastric lavage and activated charcoal may also be considered. Vasopressors may be used to treat hypotension and intravenous physostigmine salicylate may be considered for the treatment of significant CNS symptoms depending on the clinical picture. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciproheptadina Cyproheptadin Cyproheptadine Cyproheptadinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cyproheptadine is a combined serotonin and histamine antagonist used in the treatment of allergic symptoms, for appetite stimulation, and off-label in the treatment of serotonin syndrome.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Cyproheptadine interact? Information: •Drug A: Buserelin •Drug B: Cyproheptadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Cyproheptadine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In the US, prescription cyproheptadine is indicated for the treatment of various allergic symptomatologies - including dermatographia, rhinitis, conjunctivitis, and urticaria - as well as adjunctive therapy in the management of anaphylaxis following treatment with epinephrine. In Canada, cyproheptadine is available over-the-counter and is indicated for the treatment of pruritus and for appetite stimulation. In Australia, cyproheptadine is additionally indicated for the treatment vascular headaches. Cyproheptadine is also used off-label for the treatment of serotonin syndrome. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Cyproheptadine has been observed to antagonize several pharmacodynamic effects of serotonin in laboratory animals, including bronchoconstriction and vasodepression, and has demonstrated similar efficacy in antagonizing histamine-mediated effects. The reason for its efficacy in preventing anaphylactic shock has not been elucidated, but appears to be related to its anti-serotonergic effects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Cyproheptadine appears to exert its antihistamine and antiserotonin effects by competing with free histamine and serotonin for binding at their respective receptors. Antagonism of serotonin on the appetite center of the hypothalamus may account for cyproheptadine's ability to stimulate the appetite. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): A single study examining the difference in absorption of orally administered versus sublingually administered cyproheptadine in five healthy males demonstrated a mean C max of 30.0 mcg/L and 4.0 mcg/L, respectively, and a mean AUC of 209 mcg.h/L and 25 mcg.h/L, respectively. The T max of orally and sublingually administered cyproheptadine was 4 hours and 9.6 hours, respectively. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The principal metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 2-20% of the radioactivity from an orally administered radio-labeled dose of cyproheptadine is excreted in the feces, of which approximately 34% is unchanged parent drug (less than 5.7% of the total dose). At least 40% of radioactivity is recovered in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdosage with cyproheptadine is likely to result in significant sedation - although paradoxical stimulation has been noted in pediatric patients - and anticholinergic adverse effects such as dry mouth and flushing. Most patients appear to recover without incident, as a review of cyproheptadine overdose cases in Hong Kong found the majority of patients had no or mild symptoms following intentional overdose. In the event of overdosage with cyproheptadine, prescribing information recommends the induction of vomiting (if it has not occurred spontaneously) using syrup of ipecac. Gastric lavage and activated charcoal may also be considered. Vasopressors may be used to treat hypotension and intravenous physostigmine salicylate may be considered for the treatment of significant CNS symptoms depending on the clinical picture. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciproheptadina Cyproheptadin Cyproheptadine Cyproheptadinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Cyproheptadine is a combined serotonin and histamine antagonist used in the treatment of allergic symptoms, for appetite stimulation, and off-label in the treatment of serotonin syndrome. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dabrafenib interact?

•Drug A: Buserelin •Drug B: Dabrafenib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dabrafenib. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As monotherapy, dabrafenib is indicated to treat unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In combination with trametinib, dabrafenib is indicated to treat for: the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. Dabrafenib has limitations of use: it is neither indicated for treating patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition nor wild-type BRAF solid tumours. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and trametinib both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity. The melanoma approval for use with trametinib is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket. Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D. BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis. Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vc/F) is 70.3 L. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein. •Protein binding (Drug A): 15% •Protein binding (Drug B): Dabrafenib is 99.7% bound to human plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials. Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test. In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC). Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tafinlar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dabrafenib interact? Information: •Drug A: Buserelin •Drug B: Dabrafenib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dabrafenib. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): As monotherapy, dabrafenib is indicated to treat unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In combination with trametinib, dabrafenib is indicated to treat for: the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. Dabrafenib has limitations of use: it is neither indicated for treating patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition nor wild-type BRAF solid tumours. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and trametinib both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity. The melanoma approval for use with trametinib is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket. Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D. BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis. Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vc/F) is 70.3 L. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein. •Protein binding (Drug A): 15% •Protein binding (Drug B): Dabrafenib is 99.7% bound to human plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials. Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test. In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC). Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Tafinlar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dapagliflozin interact?

•Drug A: Buserelin •Drug B: Dapagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Dapagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dapagliflozin is indicated as an adjunct treatment to improve glycemic control in adult patients with type 2 diabetes mellitus along with diet and exercise. For patients with chronic kidney disease at risk of progression, dapagliflozin in used to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure. Dapagliflozin is also indicated to either reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure or reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. Combination products with dapagliflozin also exist, either as a dapagliflozin-saxagliptin or dapagliflozin-metformin hydrochloride formulation. Both are used as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near-maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dapagliflozin inhibits the sodium-glucose cotransporter 2(SGLT2) which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose reabsorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral dapagliflozin reaches a maximum concentration within 1 hour of administration when patients have been fasting. Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with an increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution was estimated to be 118L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dapagliflozin is primarily glucuronidated to become the inactive 3-O-glucuronide metabolite(60.7%). Dapagliflozin also produces another minor glucuronidated metabolite(5.4%), a de-ethylated metabolite(<5%), and a hydroxylated metabolite(<5%). Metabolism of dapagliflozin is mediated by cytochrome p-450(CYP)1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP3A4, uridine diphosphate glucuronyltransferase(UGT)1A9, UGT2B4, and UGT2B7. Glucuronidation to the major metabolite is mediated by UGT1A9. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ C]-dapagliflozin, 75% and 21% of total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as the parent drug. In feces, approximately 15% of the dose is excreted as the parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of 10 mg. In healthy subjects given a single oral dose of 50 mg of dapagliflozin, the mean terminal half-life was 13.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral plasma clearance was 4.9 mL/min/kg, and renal clearance was 5.6 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Age, gender, race, and body weight do not affect dapagliflozin dosing requirements. Although age does not affect dosing requirements, safety has not been established in pediatric populations and patients at an especially advanced age may be more susceptible to adverse effects. Animal studies in pregnancy showed no fetal toxicity in the first trimester but exposure later in pregnancy was associated with renal pelvic dilatation and maternal toxicity at much higher doses than the maximum recommended human dose. Due to this data, dapagliflozin is not recommended in the second and third trimester of pregnancy. Dapagliflozin is excreted in milk from rats, though this may not necessarily be the case in humans. Children under 2 years old who are exposed to dapagliflozin may be at risk of improper kidney development. Dapagliflozin is not recommended in patients with a creatinine clearance below 45mL/min and is contraindicated in patients with creatinine clearance below 30mL/min. Dose adjustments are not necessary in patients with hepatic impairment at any stage, although the risk and benefit to the patient must be assessed as there is limited data on dapagliflozin use in this population. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Edistride, Farxiga, Forxiga, Qtern, Qternmet, Xigduo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dapagliflozin Dapagliflozina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor used in the management of type 2 diabetes mellitus.

Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Question: Does Buserelin and Dapagliflozin interact? Information: •Drug A: Buserelin •Drug B: Dapagliflozin •Severity: MODERATE •Description: The therapeutic efficacy of Dapagliflozin can be decreased when used in combination with Buserelin. •Extended Description: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dapagliflozin is indicated as an adjunct treatment to improve glycemic control in adult patients with type 2 diabetes mellitus along with diet and exercise. For patients with chronic kidney disease at risk of progression, dapagliflozin in used to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure. Dapagliflozin is also indicated to either reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure or reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. Combination products with dapagliflozin also exist, either as a dapagliflozin-saxagliptin or dapagliflozin-metformin hydrochloride formulation. Both are used as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near-maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dapagliflozin inhibits the sodium-glucose cotransporter 2(SGLT2) which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose reabsorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral dapagliflozin reaches a maximum concentration within 1 hour of administration when patients have been fasting. Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with an increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution was estimated to be 118L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dapagliflozin is primarily glucuronidated to become the inactive 3-O-glucuronide metabolite(60.7%). Dapagliflozin also produces another minor glucuronidated metabolite(5.4%), a de-ethylated metabolite(<5%), and a hydroxylated metabolite(<5%). Metabolism of dapagliflozin is mediated by cytochrome p-450(CYP)1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP3A4, uridine diphosphate glucuronyltransferase(UGT)1A9, UGT2B4, and UGT2B7. Glucuronidation to the major metabolite is mediated by UGT1A9. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ C]-dapagliflozin, 75% and 21% of total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as the parent drug. In feces, approximately 15% of the dose is excreted as the parent drug. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of 10 mg. In healthy subjects given a single oral dose of 50 mg of dapagliflozin, the mean terminal half-life was 13.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral plasma clearance was 4.9 mL/min/kg, and renal clearance was 5.6 mL/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Age, gender, race, and body weight do not affect dapagliflozin dosing requirements. Although age does not affect dosing requirements, safety has not been established in pediatric populations and patients at an especially advanced age may be more susceptible to adverse effects. Animal studies in pregnancy showed no fetal toxicity in the first trimester but exposure later in pregnancy was associated with renal pelvic dilatation and maternal toxicity at much higher doses than the maximum recommended human dose. Due to this data, dapagliflozin is not recommended in the second and third trimester of pregnancy. Dapagliflozin is excreted in milk from rats, though this may not necessarily be the case in humans. Children under 2 years old who are exposed to dapagliflozin may be at risk of improper kidney development. Dapagliflozin is not recommended in patients with a creatinine clearance below 45mL/min and is contraindicated in patients with creatinine clearance below 30mL/min. Dose adjustments are not necessary in patients with hepatic impairment at any stage, although the risk and benefit to the patient must be assessed as there is limited data on dapagliflozin use in this population. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Edistride, Farxiga, Forxiga, Qtern, Qternmet, Xigduo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dapagliflozin Dapagliflozina •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor used in the management of type 2 diabetes mellitus. Output: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. The severity of the interaction is moderate.

Does Buserelin and Darbepoetin alfa interact?

•Drug A: Buserelin •Drug B: Darbepoetin alfa •Severity: MODERATE •Description: The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Buserelin. •Extended Description: Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of anemia (from renal transplants or certain HIV treatment) •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Darbepoetin alfa is used in the treatment of anemia. It is involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Erythropoietin interacts with progenitor stem cells to increase red cell production. Binding of erythropoietin to the erythropoietin receptor leads to receptor dimerization, which facilitates activation of JAK-STAT signaling pathways within the cytosol. Activated STAT (signal transducers and activators of transcription) proteins are then translocated to the nucleus where they serve as transcription factors which regulate the activation of specific genes involved in cell division or differentiation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aranesp •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Darbepoetin alfa is a recombinant form of human erythropoietin used to increase differentiation of progenitor cells to red blood cells in the treatment of anemia.

Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. The severity of the interaction is moderate.

Question: Does Buserelin and Darbepoetin alfa interact? Information: •Drug A: Buserelin •Drug B: Darbepoetin alfa •Severity: MODERATE •Description: The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Buserelin. •Extended Description: Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment of anemia (from renal transplants or certain HIV treatment) •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Darbepoetin alfa is used in the treatment of anemia. It is involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Erythropoietin interacts with progenitor stem cells to increase red cell production. Binding of erythropoietin to the erythropoietin receptor leads to receptor dimerization, which facilitates activation of JAK-STAT signaling pathways within the cytosol. Activated STAT (signal transducers and activators of transcription) proteins are then translocated to the nucleus where they serve as transcription factors which regulate the activation of specific genes involved in cell division or differentiation. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aranesp •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Darbepoetin alfa is a recombinant form of human erythropoietin used to increase differentiation of progenitor cells to red blood cells in the treatment of anemia. Output: Erythropoiesis-stimulating agents are often combined with antineoplastic agents to prevent and treat the complications of chemotherapy, which often leads to anemia due to inhibition of cell growth. The combination of erythropoiesis-stimulating agents and antineoplastic agents has proven beneficial in some malignancies, however, erythropoiesis-stimulating agents can increase the risk of thrombosis. Malignancy may also increase the risk of thrombosis through various mechanisms, resulting in additive thrombotic effects. The concomitant use of antineoplastic agents in patients with multiple myeloma treated with lenalidomide, thalidomide or pomalidomide have specifically led to an increased risk and severity of thrombosis, and this interaction is worsened by corticosteroid use. Cisplatin has been identified by Health Canada as a pro-thrombotic agent, therefore, concomitant administration with erythropoiesis-stimulating drugs may lead to thrombotic events. The severity of the interaction is moderate.

Does Buserelin and Dasatinib interact?

•Drug A: Buserelin •Drug B: Dasatinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Dasatinib is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dasatinib is indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, as well as adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Dasatinib is also indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase or newly diagnosed Ph+ ALL in combination with chemotherapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dasatinib is an orally available small-molecule multikinase inhibitor. During clinical trials, less than 1% of patients treated with dasatinib had QTc prolongation as an adverse reaction, and 1% experienced a QTcF higher than 500 ms. The use of dasatinib is also associated with myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, severe dermatologic reactions, tumor lysis syndrome and hepatotoxicity. It may also cause embryo-fetal toxicity and lead to adverse reactions associated with bone growth and development in pediatric patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dasatinib is a tyrosine kinase inhibitor with several targets. At nanomolar concentrations, it inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. In patients with chronic myeloid leukemia (CML), the tyrosine kinase activity of BCR-ABL is deregulated, leading to the growth, proliferation and survival of cancerous hematopoietic cells. Dasatinib binds to the active and inactive conformation of the ABL kinase domain with a higher affinity than imatinib. In chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL, dasatinib inhibits cell growth. Also, dasatinib has in vitro activity against leukemic cell lines that are either sensitive or resistant to imatinib. It has been suggested that dasatinib is able to overcome imatinib resistance caused by BCR-ABL kinase domain mutations because it does not require interaction with some of the residues involved in those mutations. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dasatinib has a dose-proportional pharmacokinetic profile and a linear elimination between 15 mg/day (0.15 times the lowest approved recommended dose) and 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg once a day, dasatinib has a C max and AUC of 82.2 ng/mL and 397 ng/mL*hr, respectively. In healthy adult subjects given dasatinib as dispersed tablets in juice, the adjusted geometric mean ratio compared to intact tablets was 0.97 for C max, and 0.84 for AUC. The T max of dasatinib is between 0.5 and 6 hours following oral administration. Following a single dose of 100 mg, a high-fat meal increases the AUC of dasatinib by 14%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Dasatinib has an apparent volume of distribution of 2505 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro, the binding of dasatinib to human plasma proteins is approximately 96%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In humans, dasatinib is mainly metabolized by CYP3A4, although flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites. Five pharmacologically active dasatinib metabolites have been identified: M4, M5, M6, M20 and M24. M4, M20, and M24 are mainly generated by CYP3A4, M5 is generated by FMO3, and M6 is generated by a cytosolic oxidoreductase. M4 is equipotent to dasatinib and represents approximately 5% of the AUC. However, it is unlikely to play a major role in the observed pharmacology of dasatinib. M5 and M6 are more than 10 times less active than dasatinib and are considered minor circulating metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dasatinib is mainly eliminated via feces. Within 10 days, 4% of dasatinib is recovered in urine, while 85% is recovered in feces. Approximately 0.1% and 19% of the administered dasatinib dose was recovered unchanged in urine and feces, respectively, and the rest was recovered as metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life of dasatinib is 3-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of dasatinib does not vary over time. Dasatinib has an apparent oral clearance of 363.8 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose cases with dasatinib occurred in isolated cases during clinical studies. Patients that received 280 mg of dasatinib per day for 1 week developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression, patients that ingest more than the recommended dosage should be monitored closely for myelosuppression and receive appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. In rodents, ventricular necrosis and valvular/ventricular/atrial hemorrhage were detected at single doses higher than or equal to 100 mg/kg (600 mg/m ). In monkeys receiving single doses higher than or equal to 10 mg/kg (120 mg/m ), there was a tendency for increased systolic and diastolic blood pressure. In rats, the oral LD 50 of dasatinib is 50-100 mg/kg, and in monkeys, it is 25-45 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sprycel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Anh. dasatinib BMS dasatinib Dasatinib Dasatinib (anh.) Dasatinibum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dasatinib is a tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dasatinib interact? Information: •Drug A: Buserelin •Drug B: Dasatinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Dasatinib is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dasatinib is indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, as well as adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Dasatinib is also indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase or newly diagnosed Ph+ ALL in combination with chemotherapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dasatinib is an orally available small-molecule multikinase inhibitor. During clinical trials, less than 1% of patients treated with dasatinib had QTc prolongation as an adverse reaction, and 1% experienced a QTcF higher than 500 ms. The use of dasatinib is also associated with myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, severe dermatologic reactions, tumor lysis syndrome and hepatotoxicity. It may also cause embryo-fetal toxicity and lead to adverse reactions associated with bone growth and development in pediatric patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dasatinib is a tyrosine kinase inhibitor with several targets. At nanomolar concentrations, it inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. In patients with chronic myeloid leukemia (CML), the tyrosine kinase activity of BCR-ABL is deregulated, leading to the growth, proliferation and survival of cancerous hematopoietic cells. Dasatinib binds to the active and inactive conformation of the ABL kinase domain with a higher affinity than imatinib. In chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL, dasatinib inhibits cell growth. Also, dasatinib has in vitro activity against leukemic cell lines that are either sensitive or resistant to imatinib. It has been suggested that dasatinib is able to overcome imatinib resistance caused by BCR-ABL kinase domain mutations because it does not require interaction with some of the residues involved in those mutations. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Dasatinib has a dose-proportional pharmacokinetic profile and a linear elimination between 15 mg/day (0.15 times the lowest approved recommended dose) and 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg once a day, dasatinib has a C max and AUC of 82.2 ng/mL and 397 ng/mL*hr, respectively. In healthy adult subjects given dasatinib as dispersed tablets in juice, the adjusted geometric mean ratio compared to intact tablets was 0.97 for C max, and 0.84 for AUC. The T max of dasatinib is between 0.5 and 6 hours following oral administration. Following a single dose of 100 mg, a high-fat meal increases the AUC of dasatinib by 14%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Dasatinib has an apparent volume of distribution of 2505 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro, the binding of dasatinib to human plasma proteins is approximately 96%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): In humans, dasatinib is mainly metabolized by CYP3A4, although flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites. Five pharmacologically active dasatinib metabolites have been identified: M4, M5, M6, M20 and M24. M4, M20, and M24 are mainly generated by CYP3A4, M5 is generated by FMO3, and M6 is generated by a cytosolic oxidoreductase. M4 is equipotent to dasatinib and represents approximately 5% of the AUC. However, it is unlikely to play a major role in the observed pharmacology of dasatinib. M5 and M6 are more than 10 times less active than dasatinib and are considered minor circulating metabolites. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dasatinib is mainly eliminated via feces. Within 10 days, 4% of dasatinib is recovered in urine, while 85% is recovered in feces. Approximately 0.1% and 19% of the administered dasatinib dose was recovered unchanged in urine and feces, respectively, and the rest was recovered as metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The terminal half-life of dasatinib is 3-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of dasatinib does not vary over time. Dasatinib has an apparent oral clearance of 363.8 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose cases with dasatinib occurred in isolated cases during clinical studies. Patients that received 280 mg of dasatinib per day for 1 week developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression, patients that ingest more than the recommended dosage should be monitored closely for myelosuppression and receive appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. In rodents, ventricular necrosis and valvular/ventricular/atrial hemorrhage were detected at single doses higher than or equal to 100 mg/kg (600 mg/m ). In monkeys receiving single doses higher than or equal to 10 mg/kg (120 mg/m ), there was a tendency for increased systolic and diastolic blood pressure. In rats, the oral LD 50 of dasatinib is 50-100 mg/kg, and in monkeys, it is 25-45 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Sprycel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Anh. dasatinib BMS dasatinib Dasatinib Dasatinib (anh.) Dasatinibum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dasatinib is a tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Degarelix interact?

•Drug A: Buserelin •Drug B: Degarelix •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Degarelix is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In Canada and the US, degarelix is indicated for the treatment of advanced prostate cancer in patients requiring androgen deprivation therapy. In the EU, it is more specifically indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer, and for treatment of high-risk localized and locally advanced hormone-dependent prostate cancer, in combination with radiotherapy or as a neo-adjuvant prior to radiotherapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Degarelix is a synthetic derivative of GnRH decapeptide, the ligand of the GnRH receptor. Gonadotropin and androgen production result from the binding of endogenous GnRH to the GnRH receptor. Degarelix antagonizes the GnRH receptor which in turn blocks the release of LH and FSH from the pituitary. LF and FSH decreases in a concentration-dependent manner. The reduction in LH leads to a decrease in testosterone release from the testes. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Degarelix competitively inhibits GnRH receptors in the pituitary gland, preventing the release of luteinizing hormone (LH) and follicle stimulating hormone. Reduced LH suppresses testosterone release, which slows the growth and reduces the size of prostate cancers. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Degarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Central compartment: 8.88 - 11.4 L; Peripheral compartment: 40.9 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 90% of the drug is bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): 70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fecal (70% to 80%) and renal (20%-30% of unchanged drug) •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Terminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most commonly observed adverse reactions (> 10%) during degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Firmagon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Degarelix is a GnRH receptor antagonist used in the management of advanced prostate cancer.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Degarelix interact? Information: •Drug A: Buserelin •Drug B: Degarelix •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Degarelix is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): In Canada and the US, degarelix is indicated for the treatment of advanced prostate cancer in patients requiring androgen deprivation therapy. In the EU, it is more specifically indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer, and for treatment of high-risk localized and locally advanced hormone-dependent prostate cancer, in combination with radiotherapy or as a neo-adjuvant prior to radiotherapy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Degarelix is a synthetic derivative of GnRH decapeptide, the ligand of the GnRH receptor. Gonadotropin and androgen production result from the binding of endogenous GnRH to the GnRH receptor. Degarelix antagonizes the GnRH receptor which in turn blocks the release of LH and FSH from the pituitary. LF and FSH decreases in a concentration-dependent manner. The reduction in LH leads to a decrease in testosterone release from the testes. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Degarelix competitively inhibits GnRH receptors in the pituitary gland, preventing the release of luteinizing hormone (LH) and follicle stimulating hormone. Reduced LH suppresses testosterone release, which slows the growth and reduces the size of prostate cancers. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Degarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Central compartment: 8.88 - 11.4 L; Peripheral compartment: 40.9 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 90% of the drug is bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): 70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Fecal (70% to 80%) and renal (20%-30% of unchanged drug) •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Terminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most commonly observed adverse reactions (> 10%) during degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Firmagon •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Degarelix is a GnRH receptor antagonist used in the management of advanced prostate cancer. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Delafloxacin interact?

•Drug A: Buserelin •Drug B: Delafloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Delafloxacin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Delafloxacin is indicated for the treatment of acute bacterial skin and skin structure infections caused by the Gram-positive organisms Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis as well as the Gram-negative organisms Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Delafloxacin is a fluoroquinolone antibacterial drug which kills bacterial cells. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Delafloxacin inhibits the activity of bacterial DNA topoisomerase IV and DNA gyrase (topoisomerase II). This interferes with bacterial DNA replication by preventing the relaxation of positive supercoils introduced as part of the elongation process. The resultant strain inhibits further elongation. Delafloxacin exerts concentration-dependent bacteriocidal activity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The median time to peak plasma concentration for orally administered Delafloxacin is 0.75 (0.5-4.0) hours after a single dose and 1.00 (0.5-6.0) hours for steady state dosing. The median time to peak plasma concentration for intravenously administered Delafloxacin is 1.00 (1.0-1.2) hours for a single dose and 1.0 (1.0-1.0) hour for steady state dosing. The absolute bioavailability for orally administed Delafloxacin is 58.8%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady sate volume of distrubution of Delafloxacin is 30-48 liters. •Protein binding (Drug A): 15% •Protein binding (Drug B): Delafloxacin is 84% bound to human plasma proteins. It primarily binds to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Delafoxacin is primarily metabolized via glucuronidation mediated by UDP glucuronosyltransferase 1-1, UDP-glucuronosyltransferase 1-3, and UDP-glucuronosyltransferase 2B15. Less than 1% is metabolized via oxidation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a single intravenous dose, 65% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 28% excreted unchanged in the feces. After a single oral dose, 50% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 48% excreted unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean half life of elimination of Delafloxacin is 3.7 hours after a single intravenous administration. The mean half life of elimination for multple oral administrations is 4.2-8.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total clearance of Delafloxacin is 16.3 liters per hour. Renal clearance accounts for 35-45% of total clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common adverse reactions noted with Delafloxacin were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Fluoroquinolones are associated with increased frequency of tendon rupture and tendonitis, increased risk of peipheral neuropathy, excacerbation of myasthenia gravis, and development of Clostridium difficile-associated diarrhea. Fluoroquinolones are also associated with an increased risk of central nervous system reactions (CNS), including: convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Baxdela •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Delafloxacin is a fluoroquinolone antibiotic used to treat skin and skin structure infections.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Delafloxacin interact? Information: •Drug A: Buserelin •Drug B: Delafloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Delafloxacin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Delafloxacin is indicated for the treatment of acute bacterial skin and skin structure infections caused by the Gram-positive organisms Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis as well as the Gram-negative organisms Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Delafloxacin is a fluoroquinolone antibacterial drug which kills bacterial cells. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Delafloxacin inhibits the activity of bacterial DNA topoisomerase IV and DNA gyrase (topoisomerase II). This interferes with bacterial DNA replication by preventing the relaxation of positive supercoils introduced as part of the elongation process. The resultant strain inhibits further elongation. Delafloxacin exerts concentration-dependent bacteriocidal activity. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The median time to peak plasma concentration for orally administered Delafloxacin is 0.75 (0.5-4.0) hours after a single dose and 1.00 (0.5-6.0) hours for steady state dosing. The median time to peak plasma concentration for intravenously administered Delafloxacin is 1.00 (1.0-1.2) hours for a single dose and 1.0 (1.0-1.0) hour for steady state dosing. The absolute bioavailability for orally administed Delafloxacin is 58.8%. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The steady sate volume of distrubution of Delafloxacin is 30-48 liters. •Protein binding (Drug A): 15% •Protein binding (Drug B): Delafloxacin is 84% bound to human plasma proteins. It primarily binds to serum albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Delafoxacin is primarily metabolized via glucuronidation mediated by UDP glucuronosyltransferase 1-1, UDP-glucuronosyltransferase 1-3, and UDP-glucuronosyltransferase 2B15. Less than 1% is metabolized via oxidation. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): After a single intravenous dose, 65% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 28% excreted unchanged in the feces. After a single oral dose, 50% of Delafloxacin was excreted in the urine either unchanged or as glucuronide metabolites with 48% excreted unchanged in the feces. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The mean half life of elimination of Delafloxacin is 3.7 hours after a single intravenous administration. The mean half life of elimination for multple oral administrations is 4.2-8.5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean total clearance of Delafloxacin is 16.3 liters per hour. Renal clearance accounts for 35-45% of total clearance. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): The most common adverse reactions noted with Delafloxacin were nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Fluoroquinolones are associated with increased frequency of tendon rupture and tendonitis, increased risk of peipheral neuropathy, excacerbation of myasthenia gravis, and development of Clostridium difficile-associated diarrhea. Fluoroquinolones are also associated with an increased risk of central nervous system reactions (CNS), including: convulsions and increased intracranial pressure (including pseudotumor cerebri) and toxic psychosis. Fluoroquinolones may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or acts. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Baxdela •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Delafloxacin is a fluoroquinolone antibiotic used to treat skin and skin structure infections. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Delamanid interact?

•Drug A: Buserelin •Drug B: Delamanid •Severity: MINOR •Description: Buserelin may increase the QTc-prolonging activities of Delamanid. •Extended Description: QT prolongation has been observed with delamanid treatment, which increases slowly over time in the first 6-10 weeks of treatment and remains stable therafter. The major delamanid metabolite, DM-6705, most likely contributes with this effect. Co-administration of delamanid with drugs potential to prolong QTc may lead to potentiated risk for QTc prolongation from an additive effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The minimum inhibitory concentrations (MIC) of delamanid against Mycobacterium tuberculosis isolates ranges from 0.006 to 0.024 g/mL. Among non-tuberculosis mycobacteria, delamanid has in vitro activity against M. kansasii and M. bovis. Delamanid has no in vitro activity against Gram negative or positive bacterial species and does not display cross-resistance to other anti-tuberculosis drugs. In murine models of chronic tuberculosis, the reduction of M. tuberculosis colony counts by delamanid was demonstrated in a dose-dependent manner. Repeated dosing of delamanid may cause QTc-prolongation via inhibition of cardiac potassium channel (hERG channel), and this effect is mostly contributed by the main metabolite of delamanid, DM-6705. Animal studies indicate that delamanid may attenuate vitamin K-dependent blood clotting, increase prothrombin time (PT), and activated partial thromboplastin time (APTT). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Delamanid is a prodrug that requires biotransformation via via the mycobacterial F420 coenzyme system, including the deazaflavin dependent nitroreductase (Rv3547), to mediate its antimycobacterial activity against both growing and nongrowing mycobacteria. Mutations in one of five coenzyme F420 genes, fgd, Rv3547, fbiA, fbiB, and fbiC has been proposed as the mechanism of resistance to delamanid. Upon activation, the radical intermediate formed between delamanid and desnitro-imidazooxazole derivative is thought to mediate antimycobacterial actions via inhibition of methoxy-mycolic and keto-mycolic acid synthesis, leading to depletion of mycobacterial cell wall components and destruction of the mycobacteria. Nitroimidazooxazole derivative is thought to generate reactive nitrogen species, including nitrogen oxide (NO). However unlike isoniazid, delamanid does not alpha-mycolic acid. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following a single oral dose administration of 100 mg delamanid, the peak plasma concentration was 135 ng/mL. Steady-state concentration is reached after 10-14 days. Delamanid plasma exposure increases less than proportionally with increasing dose. In animal models (dog, rat, mouse), the oral bioavailability of delamanid was reported to be 35%–60%. The absolute oral bioavailability in humans is estimated to range from 25 to 47%. Oral bioavailability in humans is enhanced when administered with a standard meal, by about 2.7 fold compared to fasting conditions because delamanid exhibits poor water solubility. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vz/F) is 2,100 L. Pharmacokinetic data in animals have shown excretion of delamanid and/or its metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4-fold higher than that of the blood. •Protein binding (Drug A): 15% •Protein binding (Drug B): Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Delamanid predominantly undergoes metabolism by albumin and to a lesser extent, CYP3A4.. The metabolism of delamanid may also be mediated by hepatic CYP1A1, CYP2D6, and CYP2E1 to a lesser extent [31966]. Four major metabolites (M1–M4) have been identified in plasma in patients receiving delamanid where M1 and M3 accounts for 13%–18% of the total plasma exposure in humans. While they do not retain significant pharmacological activity, they may still contribute to QT prolongation. This is especially true for the main metabolite of delamanid, M1 (DM-6705). Delamanid is predominantly metabolized by serum albumin to form M1 (DM-6705) via hydrolytic cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety. The formation of this major metabolite is suggested to be a crucial starting point in the metabolic pathway of delamanid. M1 (DM-6705) can be further catalyzed by three pathways. In the first metabolic pathway, DM-6705 undergoes hydroxylation of the oxazole moiety to form M2 ((4RS,5S)-DM-6720), followed by CYP3A4-mediated oxidation of hydroxyl group and tautomerization of oxazole to an imino-ketone metabolite, M3 ((S)-DM-6718). The second metabolic pathway involves the hydrolysis and deamination of the oxazole amine to form M4 (DM-6704) followed by hydroxylation to M6 ((4R,5S)-DM-6721) and M7 ((4S,5S)-DM-6722) and oxidation of oxazole to another ketone metabolite, M8 ((S)-DM-6717). The third pathway involves the hydrolytic cleavage of the oxazole ring to form M5 (DM-6706). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Delamanid is excreted primarily in the stool, with less than 5% excretion in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life ranges from 30 to 38 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): While there have been no cases of delamanid overdose, some adverse reactions were observed at a higher frequency and the rate of QT prolongation increased in a dose-related manner. Treatment of overdose should involve immediate measures to remove delamanid from the gastrointestinal tract and supportive care as required. Frequent ECG monitoring should be performed. Studies of genotoxicity and carcinogenic potential reveal no significant effects on humans. Delamanid and/or its metabolites have the potential to affect cardiac repolarisation via blockade of hERG potassium channels. During repeat-dose studies in dogs, foamy macrophages were observed in lymphoid tissue of various organs with delamanid treatment although clinical relevance of this finding was not established. Repeat-dose toxicity studies in rabbits revealed an inhibitory effect of delamanid and/or its metabolites on clotting factors II, VII, IX, and X via inhibition of vitamin K production. Embryo-fetal toxicity was observed at maternally toxic dosages in reproductive studies involving rabbits. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole Delamanid •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Delamanid is an antibiotic used to treat multidrug resistant tuberculosis.

QT prolongation has been observed with delamanid treatment, which increases slowly over time in the first 6-10 weeks of treatment and remains stable therafter. The major delamanid metabolite, DM-6705, most likely contributes with this effect. Co-administration of delamanid with drugs potential to prolong QTc may lead to potentiated risk for QTc prolongation from an additive effect. The severity of the interaction is minor.

Question: Does Buserelin and Delamanid interact? Information: •Drug A: Buserelin •Drug B: Delamanid •Severity: MINOR •Description: Buserelin may increase the QTc-prolonging activities of Delamanid. •Extended Description: QT prolongation has been observed with delamanid treatment, which increases slowly over time in the first 6-10 weeks of treatment and remains stable therafter. The major delamanid metabolite, DM-6705, most likely contributes with this effect. Co-administration of delamanid with drugs potential to prolong QTc may lead to potentiated risk for QTc prolongation from an additive effect. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): The minimum inhibitory concentrations (MIC) of delamanid against Mycobacterium tuberculosis isolates ranges from 0.006 to 0.024 g/mL. Among non-tuberculosis mycobacteria, delamanid has in vitro activity against M. kansasii and M. bovis. Delamanid has no in vitro activity against Gram negative or positive bacterial species and does not display cross-resistance to other anti-tuberculosis drugs. In murine models of chronic tuberculosis, the reduction of M. tuberculosis colony counts by delamanid was demonstrated in a dose-dependent manner. Repeated dosing of delamanid may cause QTc-prolongation via inhibition of cardiac potassium channel (hERG channel), and this effect is mostly contributed by the main metabolite of delamanid, DM-6705. Animal studies indicate that delamanid may attenuate vitamin K-dependent blood clotting, increase prothrombin time (PT), and activated partial thromboplastin time (APTT). •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Delamanid is a prodrug that requires biotransformation via via the mycobacterial F420 coenzyme system, including the deazaflavin dependent nitroreductase (Rv3547), to mediate its antimycobacterial activity against both growing and nongrowing mycobacteria. Mutations in one of five coenzyme F420 genes, fgd, Rv3547, fbiA, fbiB, and fbiC has been proposed as the mechanism of resistance to delamanid. Upon activation, the radical intermediate formed between delamanid and desnitro-imidazooxazole derivative is thought to mediate antimycobacterial actions via inhibition of methoxy-mycolic and keto-mycolic acid synthesis, leading to depletion of mycobacterial cell wall components and destruction of the mycobacteria. Nitroimidazooxazole derivative is thought to generate reactive nitrogen species, including nitrogen oxide (NO). However unlike isoniazid, delamanid does not alpha-mycolic acid. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Following a single oral dose administration of 100 mg delamanid, the peak plasma concentration was 135 ng/mL. Steady-state concentration is reached after 10-14 days. Delamanid plasma exposure increases less than proportionally with increasing dose. In animal models (dog, rat, mouse), the oral bioavailability of delamanid was reported to be 35%–60%. The absolute oral bioavailability in humans is estimated to range from 25 to 47%. Oral bioavailability in humans is enhanced when administered with a standard meal, by about 2.7 fold compared to fasting conditions because delamanid exhibits poor water solubility. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution (Vz/F) is 2,100 L. Pharmacokinetic data in animals have shown excretion of delamanid and/or its metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4-fold higher than that of the blood. •Protein binding (Drug A): 15% •Protein binding (Drug B): Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Delamanid predominantly undergoes metabolism by albumin and to a lesser extent, CYP3A4.. The metabolism of delamanid may also be mediated by hepatic CYP1A1, CYP2D6, and CYP2E1 to a lesser extent [31966]. Four major metabolites (M1–M4) have been identified in plasma in patients receiving delamanid where M1 and M3 accounts for 13%–18% of the total plasma exposure in humans. While they do not retain significant pharmacological activity, they may still contribute to QT prolongation. This is especially true for the main metabolite of delamanid, M1 (DM-6705). Delamanid is predominantly metabolized by serum albumin to form M1 (DM-6705) via hydrolytic cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety. The formation of this major metabolite is suggested to be a crucial starting point in the metabolic pathway of delamanid. M1 (DM-6705) can be further catalyzed by three pathways. In the first metabolic pathway, DM-6705 undergoes hydroxylation of the oxazole moiety to form M2 ((4RS,5S)-DM-6720), followed by CYP3A4-mediated oxidation of hydroxyl group and tautomerization of oxazole to an imino-ketone metabolite, M3 ((S)-DM-6718). The second metabolic pathway involves the hydrolysis and deamination of the oxazole amine to form M4 (DM-6704) followed by hydroxylation to M6 ((4R,5S)-DM-6721) and M7 ((4S,5S)-DM-6722) and oxidation of oxazole to another ketone metabolite, M8 ((S)-DM-6717). The third pathway involves the hydrolytic cleavage of the oxazole ring to form M5 (DM-6706). •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Delamanid is excreted primarily in the stool, with less than 5% excretion in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half life ranges from 30 to 38 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): While there have been no cases of delamanid overdose, some adverse reactions were observed at a higher frequency and the rate of QT prolongation increased in a dose-related manner. Treatment of overdose should involve immediate measures to remove delamanid from the gastrointestinal tract and supportive care as required. Frequent ECG monitoring should be performed. Studies of genotoxicity and carcinogenic potential reveal no significant effects on humans. Delamanid and/or its metabolites have the potential to affect cardiac repolarisation via blockade of hERG potassium channels. During repeat-dose studies in dogs, foamy macrophages were observed in lymphoid tissue of various organs with delamanid treatment although clinical relevance of this finding was not established. Repeat-dose toxicity studies in rabbits revealed an inhibitory effect of delamanid and/or its metabolites on clotting factors II, VII, IX, and X via inhibition of vitamin K production. Embryo-fetal toxicity was observed at maternally toxic dosages in reproductive studies involving rabbits. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole Delamanid •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Delamanid is an antibiotic used to treat multidrug resistant tuberculosis. Output: QT prolongation has been observed with delamanid treatment, which increases slowly over time in the first 6-10 weeks of treatment and remains stable therafter. The major delamanid metabolite, DM-6705, most likely contributes with this effect. Co-administration of delamanid with drugs potential to prolong QTc may lead to potentiated risk for QTc prolongation from an additive effect. The severity of the interaction is minor.

Does Buserelin and Desflurane interact?

•Drug A: Buserelin •Drug B: Desflurane •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Desflurane is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Desflurane is indicated for the induction and maintenance of anesthesia in adults, as well as the maintenance of anesthesia in pediatric patients. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Desflurane is a general inhalation anesthetic. It has a short duration of action as it is rapidly cleared. Patients should be counselled regarding the risks of malignant hyperthermia, perioperative hyperkalemia, respiratory adverse reactions in pediatric patients, QTc prolongation, hepatobiliary disorders, pediatric neurotoxicity, and postoperative agitation in children. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of inhalational anesthetics is still not fully understood. They can block excitatory ion channels and increase the activity of inhibitory ion channels. The most notable agonism is at the GABA A channel. Desflurane is also an agonist of glycine receptors, antagonist of glutamate receptors, inducer of potassium voltage gated channels, and inhibits both NADH-ubiquinone oxioreductase chain 1 and calcium transporting ATPases. An older school of thought is the unitary theory of general anesthetic action, suggesting that desflurane affects the lipid bilayer of cells. Studies of other halogenated inhalational anesthetics have shown that the lipid bilayer spreads out more thinly as the anesthetic incorporates into the bilayer. However, the anesthetic does not bind to lipid heads or acyl chains of hydrocarbons in the bilayer. The effect of incorporating into the lipid bilayer is not well described. By incorporating into the lipid bilayer, anesthetics may introduce disorder in the lipids, leading to some indirect effect on ion channels. However, this theory remains controversial. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Data regarding the C max, T max, and AUC of desflurane are not readily available. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Desflurane has a median volume of distribution of 612 mL/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Desflurane is bound to human serum albumin in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Desflurane is minimally defluorinated by CYP2E1, to the extent that serum fluoride levels do not increase above baseline levels. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Initially, desflurane is rapidly eliminated from the lungs. A small amount of the metabolite trifluoroacetic acid is eliminated in the urine and only 0.02% of an inhaled dose is recovered as urinary metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Desflurane has a terminal elimination half life of 8.16 ± 3.15 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): A 26 g dose of desflurane is 90% eliminated from the brain after 33 hours. The metabolite trifluoroacetic acid has a urinary clearance rate of 0.169 ± 0.107 µmol/L. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing a desflurane overdose may experience deepening anesthesia, cardiac or respiratory depression. In the event of an overdose, patients may require symptomatic and supportive treatment to maintain airway, breathing, and circulation. Discontinue desflurane. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Suprane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desflurane Desflurano Desfluranum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Desflurane is a general inhalation anesthetic for inpatient and outpatient surgery in adults.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Desflurane interact? Information: •Drug A: Buserelin •Drug B: Desflurane •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Desflurane is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Desflurane is indicated for the induction and maintenance of anesthesia in adults, as well as the maintenance of anesthesia in pediatric patients. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Desflurane is a general inhalation anesthetic. It has a short duration of action as it is rapidly cleared. Patients should be counselled regarding the risks of malignant hyperthermia, perioperative hyperkalemia, respiratory adverse reactions in pediatric patients, QTc prolongation, hepatobiliary disorders, pediatric neurotoxicity, and postoperative agitation in children. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The mechanism of inhalational anesthetics is still not fully understood. They can block excitatory ion channels and increase the activity of inhibitory ion channels. The most notable agonism is at the GABA A channel. Desflurane is also an agonist of glycine receptors, antagonist of glutamate receptors, inducer of potassium voltage gated channels, and inhibits both NADH-ubiquinone oxioreductase chain 1 and calcium transporting ATPases. An older school of thought is the unitary theory of general anesthetic action, suggesting that desflurane affects the lipid bilayer of cells. Studies of other halogenated inhalational anesthetics have shown that the lipid bilayer spreads out more thinly as the anesthetic incorporates into the bilayer. However, the anesthetic does not bind to lipid heads or acyl chains of hydrocarbons in the bilayer. The effect of incorporating into the lipid bilayer is not well described. By incorporating into the lipid bilayer, anesthetics may introduce disorder in the lipids, leading to some indirect effect on ion channels. However, this theory remains controversial. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Data regarding the C max, T max, and AUC of desflurane are not readily available. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Desflurane has a median volume of distribution of 612 mL/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Desflurane is bound to human serum albumin in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Desflurane is minimally defluorinated by CYP2E1, to the extent that serum fluoride levels do not increase above baseline levels. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Initially, desflurane is rapidly eliminated from the lungs. A small amount of the metabolite trifluoroacetic acid is eliminated in the urine and only 0.02% of an inhaled dose is recovered as urinary metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Desflurane has a terminal elimination half life of 8.16 ± 3.15 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): A 26 g dose of desflurane is 90% eliminated from the brain after 33 hours. The metabolite trifluoroacetic acid has a urinary clearance rate of 0.169 ± 0.107 µmol/L. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Patients experiencing a desflurane overdose may experience deepening anesthesia, cardiac or respiratory depression. In the event of an overdose, patients may require symptomatic and supportive treatment to maintain airway, breathing, and circulation. Discontinue desflurane. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Suprane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desflurane Desflurano Desfluranum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Desflurane is a general inhalation anesthetic for inpatient and outpatient surgery in adults. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Desipramine interact?

•Drug A: Buserelin •Drug B: Desipramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Desipramine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 73-92% bound to plasma proteins •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7-60+ hours; 70% eliminated renally •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Male mice: LD50 = 290 mg/kg, female rats: LD50 = 320 mg/kg. Antagonism of the histamine H 1 and α 1 receptors can lead to sedation and hypotension. Antimuscarinic activity confers anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of desipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Norpramin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Déméthylimipramine Desipramin Desipramina Desipramine Désipramine Desipraminum Desmethylimipramine Monodemethylimipramine Norimipramine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Desipramine is a tricyclic antidepressant used in the treatment of depression.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Desipramine interact? Information: •Drug A: Buserelin •Drug B: Desipramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Desipramine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 73-92% bound to plasma proteins •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 7-60+ hours; 70% eliminated renally •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Male mice: LD50 = 290 mg/kg, female rats: LD50 = 320 mg/kg. Antagonism of the histamine H 1 and α 1 receptors can lead to sedation and hypotension. Antimuscarinic activity confers anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of desipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Norpramin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Déméthylimipramine Desipramin Desipramina Desipramine Désipramine Desipraminum Desmethylimipramine Monodemethylimipramine Norimipramine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Desipramine is a tricyclic antidepressant used in the treatment of depression. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Desloratadine interact?

•Drug A: Buserelin •Drug B: Desloratadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Desloratadine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms of seasonal allergic rhinitis, perennial (non-seasonal) allergic rhinitis. Desloratidine is also used for the sympomatic treatment of pruritus and urticaria (hives) associated with chronic idiopathic urticaria. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Desloratadine is a long-acting second-generation H 1 -receptor antagonist which has a selective and peripheral H1-antagonist action. Histamine is a chemical that causes many of the signs that are part of allergic reactions, such as the swelling of tissues. Histamine is released from histamine-storing cells (mast cells) and attaches to other cells that have receptors for histamine. The attachment of the histamine to the receptors causes the cell to be "activated," releasing other chemicals which produce the effects that we associate with allergies. Desloratadine blocks one type of receptor for histamine (the H1 receptor) and thus prevents activation of cells by histamine. Unlike most other antihistamines, Desloratadine does not enter the brain from the blood and, therefore, does not cause drowsiness. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Like other H1-blockers, Desloratadine competes with free histamine for binding at H 1 -receptors in the GI tract, uterus, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Desloratadine administered orally for ten days to healthy volunteers as a 5 mg tablet once daily resulted in a mean T max of approximately 3 hours, a mean steady-state C max of 4 ng/ml, and a mean steady-state AUC of 56.9 ng*hr/ml. A similar profile was observed using 10 ml of an oral solution containing 5 mg of desloratadine. Food was found not to affect desloratadine absorption. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Desloratadine is bound approximately 82 to 87% to plasma proteins, while its active metabolite, 3-hydroxydesloratadine, is bound approximately 85 to 89%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Desloratadine is metabolized to the active metabolite 3-hydroxydesloratadine, which is subsequently glucuronidated. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 87% of a C-desloratadine dose was equally recovered in urine and feces as metabolic products. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Desloratadine has a mean plasma elimination half-life of approximately 27 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Information regarding desloratadine overdose is limited, although somnolence has been reported. In case of overdose, symptomatic and supportive treatment, including removing the unabsorbed drug, is recommended; note, however, that desloratadine and its active metabolite 3-hydroxydesloratadine cannot be eliminated by hemodialysis. In animal studies, lethality was observed at or above doses of 250 mg/kg in rats and of 353 mg/kg in mice (oral LD 50 ), doses that represent 120 and 290 times the human exposure based on the recommended daily oral dose. In monkey, no deaths occurred at doses up to 250 mg/kg, representing an exposure roughly 810 times that of the recommended dose in humans. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aerius, Clarinex, Clarinex-D, Neoclarityn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Descarboethoxyloratadine Desloratadina Desloratadine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Desloratadine is a second generation tricyclic antihistamine used to treat seasonal and non seasonal allergic rhinitis, pruritus, and urticaria.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Desloratadine interact? Information: •Drug A: Buserelin •Drug B: Desloratadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Desloratadine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the relief of symptoms of seasonal allergic rhinitis, perennial (non-seasonal) allergic rhinitis. Desloratidine is also used for the sympomatic treatment of pruritus and urticaria (hives) associated with chronic idiopathic urticaria. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Desloratadine is a long-acting second-generation H 1 -receptor antagonist which has a selective and peripheral H1-antagonist action. Histamine is a chemical that causes many of the signs that are part of allergic reactions, such as the swelling of tissues. Histamine is released from histamine-storing cells (mast cells) and attaches to other cells that have receptors for histamine. The attachment of the histamine to the receptors causes the cell to be "activated," releasing other chemicals which produce the effects that we associate with allergies. Desloratadine blocks one type of receptor for histamine (the H1 receptor) and thus prevents activation of cells by histamine. Unlike most other antihistamines, Desloratadine does not enter the brain from the blood and, therefore, does not cause drowsiness. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Like other H1-blockers, Desloratadine competes with free histamine for binding at H 1 -receptors in the GI tract, uterus, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Desloratadine administered orally for ten days to healthy volunteers as a 5 mg tablet once daily resulted in a mean T max of approximately 3 hours, a mean steady-state C max of 4 ng/ml, and a mean steady-state AUC of 56.9 ng*hr/ml. A similar profile was observed using 10 ml of an oral solution containing 5 mg of desloratadine. Food was found not to affect desloratadine absorption. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): Desloratadine is bound approximately 82 to 87% to plasma proteins, while its active metabolite, 3-hydroxydesloratadine, is bound approximately 85 to 89%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Desloratadine is metabolized to the active metabolite 3-hydroxydesloratadine, which is subsequently glucuronidated. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Approximately 87% of a C-desloratadine dose was equally recovered in urine and feces as metabolic products. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Desloratadine has a mean plasma elimination half-life of approximately 27 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Information regarding desloratadine overdose is limited, although somnolence has been reported. In case of overdose, symptomatic and supportive treatment, including removing the unabsorbed drug, is recommended; note, however, that desloratadine and its active metabolite 3-hydroxydesloratadine cannot be eliminated by hemodialysis. In animal studies, lethality was observed at or above doses of 250 mg/kg in rats and of 353 mg/kg in mice (oral LD 50 ), doses that represent 120 and 290 times the human exposure based on the recommended daily oral dose. In monkey, no deaths occurred at doses up to 250 mg/kg, representing an exposure roughly 810 times that of the recommended dose in humans. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aerius, Clarinex, Clarinex-D, Neoclarityn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Descarboethoxyloratadine Desloratadina Desloratadine •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Desloratadine is a second generation tricyclic antihistamine used to treat seasonal and non seasonal allergic rhinitis, pruritus, and urticaria. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Deutetrabenazine interact?

•Drug A: Buserelin •Drug B: Deutetrabenazine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Deutetrabenazine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Deutetrabenazine is indicated in adults patients for the treatment of tardive dyskinesia and for chorea associated with Huntington's disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In clinical trials, there was an evidence of clinical effectiveness of deutetrabenazine in improving the symptoms of involuntary movements in patient with tardive dyskinesia by reducing the mean Abnormal Involuntary Movement Scale (AIMS) score. In a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects, single dose administration of 24 mg deutetrabenazine results in an approximately 4.5 msec mean increase in QTc. Effects at higher exposures to deutetrabenazine or its metabolites have not been evaluated. Deutetrabenazine and its metabolites were shown to bind to melanin-containing tissues including eyes, skin and fur in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The precise mechanism of action of deutetrabenazine in mediating its anti-chorea effects is not fully elucidated. Deutetrabenazine reversibly depletes the levels of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerve terminals via its active metabolites. The major circulating metabolites are α-dihydrotetrabenazine [HTBZ] and β-HTBZ that act as reversible inhibitors of VMAT2. Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic terminal and depletion of monoamine stores from nerve terminals. Deutetrabenazine contains the molecule deuterium, which is a naturally-occurring, nontoxic hydrogen isotope but with an increased mass relative to hydrogen. Placed at key positions, deuterium forms a stronger hydrogen bond with carbon that requires more energy for cleavage, thus attenuating CYP2D6-mediated metabolism without having any effect on the therapeutic target. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The extent of absorption is 80% with oral deutetrabenazine. As deutetrabenazine is extensively metabolized to its main active metabolites following administration, linear dose dependence of peak plasma concentrations (Cmax) and AUC was observed for the metabolites after single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Cmax of deuterated α-HTBZ and β-HTBZ are reached within 3-4 hours post-dosing. Food may increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex. Similar distribution pattern is expected for deutetrabenazine. •Protein binding (Drug A): 15% •Protein binding (Drug B): At doses ranging from 50 to 200 ng/mL in vitro, tetrabenazine protein binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Similar protein binding pattern is expected for deutetrabenazine and its metabolites. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, α-HTBZ and β­-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Deutetrabenazine is mainly excreted in the urine as metabolites. In healthy subjects, about 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. α-HTBZ and β-HTBZ metabolites accounted for less than 10% of the administered dose in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with Huntington's disease, the median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Adverse reactions associated with overdosage include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. In case of an overdose, general supportive and symptomatic measures are recommended while monitoring cardiac rhythm and vital signs. In managing overdosage, the possibility of multiple drug involvement should always be considered. No carcinogenicity studies were performed with deutetrabenazine. In p53+/– transgenic mice, there were no detectable tumors following oral administration of deutetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks. Findings from in vitro assays and in vivo mice micronucleus assay suggest that deutetrabenazine and its metabolites are unlikely to be mutagenic. The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of tetrabenazine had no effects on mating and reproductive systems of male and female rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Austedo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used for the symptomatic treatment of tardive dyskinesia and chorea associated with Huntington's disease.

The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Question: Does Buserelin and Deutetrabenazine interact? Information: •Drug A: Buserelin •Drug B: Deutetrabenazine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Deutetrabenazine. •Extended Description: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Deutetrabenazine is indicated in adults patients for the treatment of tardive dyskinesia and for chorea associated with Huntington's disease. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In clinical trials, there was an evidence of clinical effectiveness of deutetrabenazine in improving the symptoms of involuntary movements in patient with tardive dyskinesia by reducing the mean Abnormal Involuntary Movement Scale (AIMS) score. In a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects, single dose administration of 24 mg deutetrabenazine results in an approximately 4.5 msec mean increase in QTc. Effects at higher exposures to deutetrabenazine or its metabolites have not been evaluated. Deutetrabenazine and its metabolites were shown to bind to melanin-containing tissues including eyes, skin and fur in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): The precise mechanism of action of deutetrabenazine in mediating its anti-chorea effects is not fully elucidated. Deutetrabenazine reversibly depletes the levels of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerve terminals via its active metabolites. The major circulating metabolites are α-dihydrotetrabenazine [HTBZ] and β-HTBZ that act as reversible inhibitors of VMAT2. Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic terminal and depletion of monoamine stores from nerve terminals. Deutetrabenazine contains the molecule deuterium, which is a naturally-occurring, nontoxic hydrogen isotope but with an increased mass relative to hydrogen. Placed at key positions, deuterium forms a stronger hydrogen bond with carbon that requires more energy for cleavage, thus attenuating CYP2D6-mediated metabolism without having any effect on the therapeutic target. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): The extent of absorption is 80% with oral deutetrabenazine. As deutetrabenazine is extensively metabolized to its main active metabolites following administration, linear dose dependence of peak plasma concentrations (Cmax) and AUC was observed for the metabolites after single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Cmax of deuterated α-HTBZ and β-HTBZ are reached within 3-4 hours post-dosing. Food may increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex. Similar distribution pattern is expected for deutetrabenazine. •Protein binding (Drug A): 15% •Protein binding (Drug B): At doses ranging from 50 to 200 ng/mL in vitro, tetrabenazine protein binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Similar protein binding pattern is expected for deutetrabenazine and its metabolites. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, α-HTBZ and β­-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Deutetrabenazine is mainly excreted in the urine as metabolites. In healthy subjects, about 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. α-HTBZ and β-HTBZ metabolites accounted for less than 10% of the administered dose in the urine. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with Huntington's disease, the median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Adverse reactions associated with overdosage include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. In case of an overdose, general supportive and symptomatic measures are recommended while monitoring cardiac rhythm and vital signs. In managing overdosage, the possibility of multiple drug involvement should always be considered. No carcinogenicity studies were performed with deutetrabenazine. In p53+/– transgenic mice, there were no detectable tumors following oral administration of deutetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks. Findings from in vitro assays and in vivo mice micronucleus assay suggest that deutetrabenazine and its metabolites are unlikely to be mutagenic. The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of tetrabenazine had no effects on mating and reproductive systems of male and female rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Austedo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used for the symptomatic treatment of tardive dyskinesia and chorea associated with Huntington's disease. Output: The subject drug may prolong the QTc interval. The affected drug has a high risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is moderate.

Does Buserelin and Dexbrompheniramine interact?

•Drug A: Buserelin •Drug B: Dexbrompheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Dexbrompheniramine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment and relief of symptoms of allergies, hay fever, and colds •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Dexbrompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dexbrompheniramine competitively binds to the histamine H 1 -receptor. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Antihistamines are well absorbed from the gastrointestinal tract after oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic (cytochrome P-450 system), some renal. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 25 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Signs of an overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ala-hist Ir, Ala-hist PE, Dologen, Dologesic Reformulated Jun 2016 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-brompheniramine Desbrofeniramina Dexbromfeniramina Dexbrompheniramin Dexbromphéniramine Dexbrompheniramine Dexbrompheniraminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dexbrompheniramine is an antihistamine used to treat allergy symptoms including upper respiratory tract symptoms.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dexbrompheniramine interact? Information: •Drug A: Buserelin •Drug B: Dexbrompheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Dexbrompheniramine is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For treatment and relief of symptoms of allergies, hay fever, and colds •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Dexbrompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dexbrompheniramine competitively binds to the histamine H 1 -receptor. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Antihistamines are well absorbed from the gastrointestinal tract after oral administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic (cytochrome P-450 system), some renal. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 25 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Signs of an overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ala-hist Ir, Ala-hist PE, Dologen, Dologesic Reformulated Jun 2016 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-brompheniramine Desbrofeniramina Dexbromfeniramina Dexbrompheniramin Dexbromphéniramine Dexbrompheniramine Dexbrompheniraminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dexbrompheniramine is an antihistamine used to treat allergy symptoms including upper respiratory tract symptoms. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dexchlorpheniramine maleate interact?

•Drug A: Buserelin •Drug B: Dexchlorpheniramine maleate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dexchlorpheniramine maleate. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dexchlorpheniramine can be used in the treatment of perennial and seasonal allergic rhinitis, vasomotor rhiniti, allergic conjunctivitis due to inhalant allergens and foods, mild uncomplicated allergic skin manifestations of urticaria and angioedema, amelioration of allergic reactions to blood or plasma, and dermographism. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In allergic reactions, an allergen binds to IgE antibodies on mast cells and basophils. Once this occurs IgE receptors crosslink with each other triggering a series of events that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Dexchlorpheniramine, is a histamine H1 antagonist of the alkylamine class. It competes with histamine for the normal H1-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract. Dexchlorpheniramine is the predominant active isomer of chlorpheniramine and is approximately twice as active as the racemic compound. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral bioavailability in rats 40.5% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 321L •Protein binding (Drug A): 15% •Protein binding (Drug B): Dexchlorpheniramine is bound to total plasma proteins 38%, to albumin 20% and to alpha-glycoprotein acid 23%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic metabolism. Major metabolism by CYP 2D6 and minor metabolism by 3A4, 2C11 and 2B1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal excretion •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 20-30 h •Clearance (Drug A): No clearance available •Clearance (Drug B): 9.8L/h •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Central nervous system depression •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rescon Tablets, Ryclora, Rymed-D •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dexchlorpheniramine maleate is a first generation antihistamine used to treat allergic and vasomotor rhinitis, allergic conjunctivitis, and mild urticaria and angioedema.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dexchlorpheniramine maleate interact? Information: •Drug A: Buserelin •Drug B: Dexchlorpheniramine maleate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dexchlorpheniramine maleate. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dexchlorpheniramine can be used in the treatment of perennial and seasonal allergic rhinitis, vasomotor rhiniti, allergic conjunctivitis due to inhalant allergens and foods, mild uncomplicated allergic skin manifestations of urticaria and angioedema, amelioration of allergic reactions to blood or plasma, and dermographism. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): In allergic reactions, an allergen binds to IgE antibodies on mast cells and basophils. Once this occurs IgE receptors crosslink with each other triggering a series of events that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Dexchlorpheniramine, is a histamine H1 antagonist of the alkylamine class. It competes with histamine for the normal H1-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract. Dexchlorpheniramine is the predominant active isomer of chlorpheniramine and is approximately twice as active as the racemic compound. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Oral bioavailability in rats 40.5% •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): 321L •Protein binding (Drug A): 15% •Protein binding (Drug B): Dexchlorpheniramine is bound to total plasma proteins 38%, to albumin 20% and to alpha-glycoprotein acid 23%. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic metabolism. Major metabolism by CYP 2D6 and minor metabolism by 3A4, 2C11 and 2B1. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Renal excretion •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): 20-30 h •Clearance (Drug A): No clearance available •Clearance (Drug B): 9.8L/h •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Central nervous system depression •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rescon Tablets, Ryclora, Rymed-D •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dexchlorpheniramine maleate is a first generation antihistamine used to treat allergic and vasomotor rhinitis, allergic conjunctivitis, and mild urticaria and angioedema. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Digitoxin interact?

•Drug A: Buserelin •Drug B: Digitoxin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Digitoxin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Digitoxin is a cardiac glycoside sometimes used in place of DIGOXIN. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting (From Martindale, The Extra Pharmacopoeia, 30th ed, p665). It is eliminated hepatically making it useful in patients with poor or erratic kidney function, although it is now rarely used in practice. Digitoxin lacks the strength of evidence that digoxin has in the management of heart failure. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Digitoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Digitoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Digitoxin exerts similar toxic effects to digoxin including anorexia, nausea, vomiting, diarrhoea, confusion, visual disturbances, and cardiac arrhythmias. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Digitoxin is a cardiac glycoside used in the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Digitoxin interact? Information: •Drug A: Buserelin •Drug B: Digitoxin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Digitoxin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): For the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Digitoxin is a cardiac glycoside sometimes used in place of DIGOXIN. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting (From Martindale, The Extra Pharmacopoeia, 30th ed, p665). It is eliminated hepatically making it useful in patients with poor or erratic kidney function, although it is now rarely used in practice. Digitoxin lacks the strength of evidence that digoxin has in the management of heart failure. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Digitoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Digitoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Digitoxin exerts similar toxic effects to digoxin including anorexia, nausea, vomiting, diarrhoea, confusion, visual disturbances, and cardiac arrhythmias. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Digitoxin is a cardiac glycoside used in the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Digoxin interact?

•Drug A: Buserelin •Drug B: Digoxin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Digoxin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Digoxin is indicated in the following conditions: 1) For the treatment of mild to moderate heart failure in adult patients. 2) To increase myocardial contraction in children diagnosed with heart failure. 3) To maintain control ventricular rate in adult patients diagnosed with chronic atrial fibrillation. In adults with heart failure, when it is clinically possible, digoxin should be administered in conjunction with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor for optimum effects. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Digoxin is a positive inotropic and negative chronotropic drug, meaning that it increases the force of the heartbeat and decreases the heart rate. The decrease in heart rate is particularly useful in cases of atrial fibrillation, a condition characterized by a fast and irregular heartbeat. The relief of heart failure symptoms during digoxin therapy has been demonstrated in clinical studies by increased exercise capacity and reduced hospitalization due to heart failure and reduced heart failure-related emergency medical visits. Digoxin has a narrow therapeutic window. A note on cardiovascular risk Digoxin poses a risk of rapid ventricular response that can cause ventricular fibrillation in patients with an accessory atrioventricular (AV) pathway. Cardiac arrest as a result of ventricular fibrillation is fatal. An increased risk of fatal severe or complete heart block is present in individuals with pre-existing sinus node disease and AV block who take digoxin. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the sodium pump. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function. Digoxin also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Digoxin is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased. A note on gut bacteria An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation. A note on malabsorption Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta. The apparent volume of distribution of digoxin is 475-500 L. A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys. It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): Digoxin protein binding is approximately 25%. It is mainly bound to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): About 13% of a digoxin dose is found to be metabolized in healthy subjects. Several urinary metabolites of digoxin exist, including dihydrodigoxin and digoxigenin bisdigitoxoside. Their glucuronidated and sulfated conjugates are thought to be produced through the process of hydrolysis, oxidation, and additionally, conjugation. The cytochrome P-450 system does not play a major role in digoxin metabolism, nor does this drug induce or inhibit the enzymes in this system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Digoxin has a half-life of 1.5-2 days in healthy subjects. The half-life in patients who do not pass urine, usually due to renal failure, is prolonged to 3.5-5 days. Since most of the drug is distributed extravascularly, dialysis and exchange transfusion are not optimal methods for the removal of digoxin. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels. One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m². Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral TDLO (human female): 100 ug/kg, Oral TDLO (human male): 75 ug/kg, Oral LD50 (rat): 28270 ug/kg Digoxin toxicity can occur in cases of supratherapeutic dose ingestion or as a result of chronic overexposure. Digoxin toxicity may be manifested by symptoms of nausea, vomiting, visual changes, in addition to arrhythmia. Older age, lower body weight, and decreased renal function or electrolyte abnormalities lead to an increased risk of digoxin toxicity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Digox, Lanoxin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Digossina Digoxin Digoxina Digoxine Digoxinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Digoxin is a cardiac glycoside used in the treatment of mild to moderate heart failure and for ventricular response rate control in chronic atrial fibrillation.

Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Digoxin interact? Information: •Drug A: Buserelin •Drug B: Digoxin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Digoxin is combined with Buserelin. •Extended Description: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Digoxin is indicated in the following conditions: 1) For the treatment of mild to moderate heart failure in adult patients. 2) To increase myocardial contraction in children diagnosed with heart failure. 3) To maintain control ventricular rate in adult patients diagnosed with chronic atrial fibrillation. In adults with heart failure, when it is clinically possible, digoxin should be administered in conjunction with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor for optimum effects. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Digoxin is a positive inotropic and negative chronotropic drug, meaning that it increases the force of the heartbeat and decreases the heart rate. The decrease in heart rate is particularly useful in cases of atrial fibrillation, a condition characterized by a fast and irregular heartbeat. The relief of heart failure symptoms during digoxin therapy has been demonstrated in clinical studies by increased exercise capacity and reduced hospitalization due to heart failure and reduced heart failure-related emergency medical visits. Digoxin has a narrow therapeutic window. A note on cardiovascular risk Digoxin poses a risk of rapid ventricular response that can cause ventricular fibrillation in patients with an accessory atrioventricular (AV) pathway. Cardiac arrest as a result of ventricular fibrillation is fatal. An increased risk of fatal severe or complete heart block is present in individuals with pre-existing sinus node disease and AV block who take digoxin. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the sodium pump. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function. Digoxin also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Digoxin is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased. A note on gut bacteria An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation. A note on malabsorption Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta. The apparent volume of distribution of digoxin is 475-500 L. A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys. It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): Digoxin protein binding is approximately 25%. It is mainly bound to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): About 13% of a digoxin dose is found to be metabolized in healthy subjects. Several urinary metabolites of digoxin exist, including dihydrodigoxin and digoxigenin bisdigitoxoside. Their glucuronidated and sulfated conjugates are thought to be produced through the process of hydrolysis, oxidation, and additionally, conjugation. The cytochrome P-450 system does not play a major role in digoxin metabolism, nor does this drug induce or inhibit the enzymes in this system. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): Digoxin has a half-life of 1.5-2 days in healthy subjects. The half-life in patients who do not pass urine, usually due to renal failure, is prolonged to 3.5-5 days. Since most of the drug is distributed extravascularly, dialysis and exchange transfusion are not optimal methods for the removal of digoxin. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels. One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m². Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Oral TDLO (human female): 100 ug/kg, Oral TDLO (human male): 75 ug/kg, Oral LD50 (rat): 28270 ug/kg Digoxin toxicity can occur in cases of supratherapeutic dose ingestion or as a result of chronic overexposure. Digoxin toxicity may be manifested by symptoms of nausea, vomiting, visual changes, in addition to arrhythmia. Older age, lower body weight, and decreased renal function or electrolyte abnormalities lead to an increased risk of digoxin toxicity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Digox, Lanoxin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Digossina Digoxin Digoxina Digoxine Digoxinum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Digoxin is a cardiac glycoside used in the treatment of mild to moderate heart failure and for ventricular response rate control in chronic atrial fibrillation. Output: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Diltiazem interact?

•Drug A: Buserelin •Drug B: Diltiazem •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Diltiazem. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Oral Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents. Indicated for use to improve exercise tolerance in patients with chronic stable angina. Indicated for the management of variant angina (Prinzmetal's angina). Intravenous Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate. Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. Off-label Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories. As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension. In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively. In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo. In the NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed. When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group. Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers. •Protein binding (Drug A): 15% •Protein binding (Drug B): Diltiazem is about 70-80% bound to plasma proteins, according to in vitro binding studies. About 40% of the drug is thought to bind to alpha-1-glycoprotein at clinically significant concentrations while about 30% of the drug is bound to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The plasma elimination half-life is approximately 3.0 to 4.5 hours following single and multiple oral doses. The half-life may slightly increase with dose and the extent of hepatic impairment. The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6 to 9 hours. The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection. The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Clinical Toxicity and Overdose The oral LD 50 ranges from 415 to 740mg/kg in mice and 560 to 810 mg/kg in rats. The oral LD 50 in dogs is considered to be in excess of 50 mg/kg. A dose of 360 mg/kg resulted in lethality in monkeys. The intravenous LD 50 is 60 mg/kg in mice and 38 mg/kg in rats. Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death. Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination. Bradycardia and heart block can be treated with atropine at doses ranging from 0.60 to 1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered. Cardiac pacing can also be used to treat fixed high-degree AV block. In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as isoproterenol, dopamine, or dobutamine. Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Non-clinical toxicity In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro bacterial assays. No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day. Pregnancy and Lactation In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths. There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women. The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus. Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother. Use in special populations As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cardizem, Cartia, Matzim, Taztia, Tiadylt, Tiazac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-cis-diltiazem Diltiazem Diltiazemum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Diltiazem is a calcium channel blocker used to treat hypertension and to manage chronic stable angina.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Diltiazem interact? Information: •Drug A: Buserelin •Drug B: Diltiazem •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Diltiazem. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Oral Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents. Indicated for use to improve exercise tolerance in patients with chronic stable angina. Indicated for the management of variant angina (Prinzmetal's angina). Intravenous Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate. Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. Off-label Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories. As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension. In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively. In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo. In the NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed. When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group. Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers. •Protein binding (Drug A): 15% •Protein binding (Drug B): Diltiazem is about 70-80% bound to plasma proteins, according to in vitro binding studies. About 40% of the drug is thought to bind to alpha-1-glycoprotein at clinically significant concentrations while about 30% of the drug is bound to albumin. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The plasma elimination half-life is approximately 3.0 to 4.5 hours following single and multiple oral doses. The half-life may slightly increase with dose and the extent of hepatic impairment. The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6 to 9 hours. The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection. The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Clinical Toxicity and Overdose The oral LD 50 ranges from 415 to 740mg/kg in mice and 560 to 810 mg/kg in rats. The oral LD 50 in dogs is considered to be in excess of 50 mg/kg. A dose of 360 mg/kg resulted in lethality in monkeys. The intravenous LD 50 is 60 mg/kg in mice and 38 mg/kg in rats. Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death. Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination. Bradycardia and heart block can be treated with atropine at doses ranging from 0.60 to 1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered. Cardiac pacing can also be used to treat fixed high-degree AV block. In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as isoproterenol, dopamine, or dobutamine. Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Non-clinical toxicity In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro bacterial assays. No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day. Pregnancy and Lactation In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths. There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women. The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus. Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother. Use in special populations As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cardizem, Cartia, Matzim, Taztia, Tiadylt, Tiazac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-cis-diltiazem Diltiazem Diltiazemum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Diltiazem is a calcium channel blocker used to treat hypertension and to manage chronic stable angina. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Dimenhydrinate interact?

•Drug A: Buserelin •Drug B: Dimenhydrinate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dimenhydrinate. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness. It has a short duration of action of 4-8 hours. Patients should be counselled regarding pronounced drowsiness, avoiding alcohol and other sedatives, and exercising caution when operating a motor vehicle or heavy machinery. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dimenhydrinate is a theoclate salt that separates into diphenhydramine and 8-chlorotheophylline. While the exact mechanism of action is unknown, diphenhydramine is theorized to reduce disturbances to equilibrium through antimuscarinic effects or histamine H1 antagonism. 8-chlorotheophylline may produce excitation through blocking adenosine receptors, reducing the drowsiness produced by diphenhydramine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): A 50 mg oral film coated tablet reaches a C max of 72.6 ng/mL with a T max of 2.7 hours. A 100 mg suppository reaches a C max of 112.2 ng/mL with a T max of 5.3 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of dimenhydrinate is 3-4 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Dimenhydrinate is 70-85% protein bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dimenhydrinate is a theoclate salt that separates into diphenhydramine and 8-chlorotheophylline. diphenhydramine can either be N-glucuronidated by UGTs to diphenhydramine N-glucuronide or N-demethylated by CYP2D6, CYP1A2, CYP2C9, and CYP2C19 to N-desmethyldiphenhydramine. N-desmethyldiphenhydramine can be N-demethylated again by the same enzymes to N,N-didesmethyldiphenhydramine, which undergoes oxidative deamination to form diphenylmethoxyacetic acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dimenhydrinate is predominantly eliminated in the urine. 1-3% of the dissociated diphenhydramine is eliminated in the urine unchanged, while 64% of diphenhydramine is eliminated in the urine as metabolites. The elimination of dimenhydrinate has not been fully studied. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The plasma elimination half life of dimenhydrinate is 5-8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Infants and children experiencing an overdose may lead to hallucinations, convulsions, or death. Adults experiencing an overdose may present with drowsiness, convulsions, coma, or respiratory depression. Treat overdoses with symptomatic and supportive measures including mechanically assisted ventilation. In mice the oral LD 50 is 203 mg/kg, while in rats it is 1320 mg/kg. The intraperitoneal LD 50 in mice is 149 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Dramamine, Driminate, Gravol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dimenhidrinato Dimenhydrinate Dimenhydrinatum Diphenhydramine theoclate •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dimenhydrinate is a medication used to prevent and treat nausea, vomiting, vertigo, and motion sickness.

The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Question: Does Buserelin and Dimenhydrinate interact? Information: •Drug A: Buserelin •Drug B: Dimenhydrinate •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Dimenhydrinate. •Extended Description: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness. It has a short duration of action of 4-8 hours. Patients should be counselled regarding pronounced drowsiness, avoiding alcohol and other sedatives, and exercising caution when operating a motor vehicle or heavy machinery. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Dimenhydrinate is a theoclate salt that separates into diphenhydramine and 8-chlorotheophylline. While the exact mechanism of action is unknown, diphenhydramine is theorized to reduce disturbances to equilibrium through antimuscarinic effects or histamine H1 antagonism. 8-chlorotheophylline may produce excitation through blocking adenosine receptors, reducing the drowsiness produced by diphenhydramine. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): A 50 mg oral film coated tablet reaches a C max of 72.6 ng/mL with a T max of 2.7 hours. A 100 mg suppository reaches a C max of 112.2 ng/mL with a T max of 5.3 hours. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): The volume of distribution of dimenhydrinate is 3-4 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Dimenhydrinate is 70-85% protein bound in plasma. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Dimenhydrinate is a theoclate salt that separates into diphenhydramine and 8-chlorotheophylline. diphenhydramine can either be N-glucuronidated by UGTs to diphenhydramine N-glucuronide or N-demethylated by CYP2D6, CYP1A2, CYP2C9, and CYP2C19 to N-desmethyldiphenhydramine. N-desmethyldiphenhydramine can be N-demethylated again by the same enzymes to N,N-didesmethyldiphenhydramine, which undergoes oxidative deamination to form diphenylmethoxyacetic acid. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): Dimenhydrinate is predominantly eliminated in the urine. 1-3% of the dissociated diphenhydramine is eliminated in the urine unchanged, while 64% of diphenhydramine is eliminated in the urine as metabolites. The elimination of dimenhydrinate has not been fully studied. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The plasma elimination half life of dimenhydrinate is 5-8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Infants and children experiencing an overdose may lead to hallucinations, convulsions, or death. Adults experiencing an overdose may present with drowsiness, convulsions, coma, or respiratory depression. Treat overdoses with symptomatic and supportive measures including mechanically assisted ventilation. In mice the oral LD 50 is 203 mg/kg, while in rats it is 1320 mg/kg. The intraperitoneal LD 50 in mice is 149 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Dramamine, Driminate, Gravol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dimenhidrinato Dimenhydrinate Dimenhydrinatum Diphenhydramine theoclate •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Dimenhydrinate is a medication used to prevent and treat nausea, vomiting, vertigo, and motion sickness. Output: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e.g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. The severity of the interaction is minor.

Does Buserelin and Diphenhydramine interact?

•Drug A: Buserelin •Drug B: Diphenhydramine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Diphenhydramine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea. Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for: i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated; ii) the active treatment of motion sickness; and iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response. Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center. Furthermore, H1 receptors are similar to muscarinic receptors. Consequently, diphenhydramine also acts as an antimuscarinic. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication. Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour. The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Diphenhydramine is widely distributed throughout the body, including the CNS. Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Some prescribing information records the protein binding of diphenhydramine as approximately 78% while others have suggested the medication is about 80 to 85% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Diphenhydramine undergoes rapid and extensive first-pass metabolism. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite). Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged. The metabolites are further conjugated with glycine and glutamine and excreted in urine. Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine. Only about 1% of a single dose is excreted unchanged in urine. The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life ranges from 2.4-9.3 hours in healthy adults. The terminal elimination half-life is prolonged in liver cirrhosis. •Clearance (Drug A): No clearance available •Clearance (Drug B): Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others. Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes. Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse. Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow. Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk. This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant. Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults. Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects. Avoid use in elderly patients with confusion. The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR). After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease. However, the mean plasma clearance and apparent volume of distribution were not significantly affected. LD 50 =500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Acetadryl, Advil PM, Aleve PM, Allegra Cooling Relief Anti-itch, Banophen, Benadryl, Benadryl Itch Stopping, Benadryl-D Allergy and Sinus, Calagel, Damylin With Codeine, Dimetapp Nighttime Cold & Congestion, Diphen, Diphenhist, Diphenist, Excedrin PM Triple Action, Goody's PM, Legatrin PM, Motrin PM, Nytol, Nytol Quickgels, Percogesic Reformulated Jan 2011, Siladryl, Simply Sleep, Sleepinal, Sominex, Triaminic Night Time Cold & Cough, Tylenol PM, Unisom, Unisom Sleep, Vanamine, Wal-dryl, Wal-som (doxylamine), Zzzquil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Difenhidramina Diphenhydramine Diphenhydraminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Diphenhydramine is a H1 receptor antihistamine used in the treatment of seasonal allergies, and various allergic reactions including sneezing, runny nose, itchy/watery eyes, itching of nose or throat, pruritus, urticaria, insect bites/stings, and allergic rashes.

The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.

Question: Does Buserelin and Diphenhydramine interact? Information: •Drug A: Buserelin •Drug B: Diphenhydramine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Diphenhydramine. •Extended Description: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. •Indication (Drug A): Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. •Indication (Drug B): Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea. Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for: i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated; ii) the active treatment of motion sickness; and iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents. •Pharmacodynamics (Drug A): The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. •Pharmacodynamics (Drug B): Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain. •Mechanism of action (Drug A): Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. •Mechanism of action (Drug B): Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response. Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center. Furthermore, H1 receptors are similar to muscarinic receptors. Consequently, diphenhydramine also acts as an antimuscarinic. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication. Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties. •Absorption (Drug A): Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. •Absorption (Drug B): Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour. The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration. •Volume of distribution (Drug A): Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. •Volume of distribution (Drug B): Diphenhydramine is widely distributed throughout the body, including the CNS. Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Some prescribing information records the protein binding of diphenhydramine as approximately 78% while others have suggested the medication is about 80 to 85% bound to plasma proteins. •Metabolism (Drug A): It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. •Metabolism (Drug B): Diphenhydramine undergoes rapid and extensive first-pass metabolism. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite). Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged. The metabolites are further conjugated with glycine and glutamine and excreted in urine. Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine. •Route of elimination (Drug A): Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. •Route of elimination (Drug B): The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine. Only about 1% of a single dose is excreted unchanged in urine. The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites. •Half-life (Drug A): The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. •Half-life (Drug B): The elimination half-life ranges from 2.4-9.3 hours in healthy adults. The terminal elimination half-life is prolonged in liver cirrhosis. •Clearance (Drug A): No clearance available •Clearance (Drug B): Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min. •Toxicity (Drug A): Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. •Toxicity (Drug B): Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others. Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes. Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse. Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow. Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk. This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant. Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults. Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects. Avoid use in elderly patients with confusion. The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR). After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease. However, the mean plasma clearance and apparent volume of distribution were not significantly affected. LD 50 =500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Acetadryl, Advil PM, Aleve PM, Allegra Cooling Relief Anti-itch, Banophen, Benadryl, Benadryl Itch Stopping, Benadryl-D Allergy and Sinus, Calagel, Damylin With Codeine, Dimetapp Nighttime Cold & Congestion, Diphen, Diphenhist, Diphenist, Excedrin PM Triple Action, Goody's PM, Legatrin PM, Motrin PM, Nytol, Nytol Quickgels, Percogesic Reformulated Jan 2011, Siladryl, Simply Sleep, Sleepinal, Sominex, Triaminic Night Time Cold & Cough, Tylenol PM, Unisom, Unisom Sleep, Vanamine, Wal-dryl, Wal-som (doxylamine), Zzzquil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Difenhidramina Diphenhydramine Diphenhydraminum •Summary (Drug A): Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. •Summary (Drug B): Diphenhydramine is a H1 receptor antihistamine used in the treatment of seasonal allergies, and various allergic reactions including sneezing, runny nose, itchy/watery eyes, itching of nose or throat, pruritus, urticaria, insect bites/stings, and allergic rashes. Output: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. The severity of the interaction is moderate.