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Does Buserelin and Lidocaine interact?

•Drug A: Buserelin •Drug B: Lidocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Lidocaine. •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): Lidocaine is an anesthetic of the amide group indicated 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): Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction. Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse. Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base. As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values. This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection. The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection. Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation. This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels. •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): Lidocaine is a local anesthetic of the amide type. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes. At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions. The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization. As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential. This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place. In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system. After absorption, lidocaine may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate, and force of contraction. •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, lidocaine is readily absorbed across mucous membranes and damaged skin but poorly through intact skin. The agent is quickly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream. And although lidocaine is also well absorbed across the gastrointestinal tract the oral bioavailability is only about 35% as a result of a high degree of first-pass metabolism. After injection into tissues, lidocaine is also rapidly absorbed and the absorption rate is affected by both vascularity and the presence of tissue and fat capable of binding lidocaine in the particular tissues. The concentration of lidocaine in the blood is subsequently affected by a variety of aspects, including its rate of absorption from the site of injection, the rate of tissue distribution, and the rate of metabolism and excretion. Subsequently, the systemic absorption of lidocaine is determined by the site of injection, the dosage given, and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site, and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of lidocaine injected and the resultant peak anesthetic blood levels. Nevertheless, it has been observed that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending also on lipid solubility and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. Additionally, lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. •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 determined for lidocaine is 0.7 to 1.5 L/kg. In particular, lidocaine is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or possibly even three-compartment model. There is a rapid disappearance (alpha phase) which is believed to be related to uptake by rapidly equilibrating tissues (tissues with high vascular perfusion, for example). The slower phase is related to distribution to slowly equilibrating tissues (beta phase) and to its metabolism and excretion (gamma phase). Lidocaine's distribution is ultimately throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of the agent. The highest percentage of this drug will be found in skeletal muscle, mainly due to the mass of muscle rather than an affinity. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding recorded for lidocaine is about 60 to 80% and is dependent upon the plasma concentration of alpha-1-acid glycoprotein. Such percentage protein binding bestows lidocaine with a medium duration of action when placed in comparison to other local anesthetic agents. •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): Lidocaine is metabolized predominantly and rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine HCl. Approximately 90% of lidocaine HCl administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. •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 excretion of unchanged lidocaine and its metabolites occurs predominantly via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of lidocaine occurs by non-ionic diffusion. •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 lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean systemic clearance observed for intravenously administered lidocaine in a study of 15 adults was approximately 0.64 +/- 0.18 L/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): Symptoms of overdose and/or acute systemic toxicity involves central nervous system toxicity that presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for neurotic behavior. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anesthetics. Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome. Pregnancy Category B has been established for the use of lidocaine in pregnancy, although there are no formal, adequate, and well-controlled studies in pregnant women. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place. Ultimately, although animal studies have revealed no evidence of harm to the fetus, lidocaine should not be administered during early pregnancy unless the benefits are considered to outweigh the risks. Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother. The ratio of umbilical to maternal venous concentration is 0.5 to 0.6. The fetus appears to be capable of metabolizing lidocaine at term. The elimination half-life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult. Elevated lidocaine levels may persist in the newborn for at least 48 hours after delivery. Fetal bradycardia or tachycardia, neonatal bradycardia, hypotonia or respiratory depression may occur. Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to the recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman. Dosages in children should be reduced, commensurate with age, body weight and physical condition. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Agoneaze, Akten, Alivio, Anestacon, Anodyne Lpt, Astero, Cathejell, Curacaine, Depo-medrol With Lidocaine, Dermacinrx Lido V Pak, Dermacinrx Phn Pak, Dermacinrx Prikaan, Diphen, Emla, Fortacin, Glydo, Instillagel, Kenalog, Lido Bdk, Lido-prilo Caine Pack, Lidocan, Lidodan, Lidoderm, Lidopac, Lidopril, Lidopro, Lidosol, Lidothol, Lidotral, Lignospan, Marcaine, Max-freeze, Medi-derm With Lidocaine, Neo-bex, Octocaine, Octocaine With Epinephrine, Oraqix, P-care, P-care X, Pliaglis, Prilolid, Prizotral, Procomycin, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Relador, Synera, Triple Antibiotic, Venipuncture Px1, Viadur, Xylocaine, Xylocaine With Epinephrine, Xylocard, Xylonor, Zingo, Ztlido •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lidocaína Lidocaina Lidocaine Lidocainum Lignocaine •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): Lidocaine 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 Lidocaine interact? Information: •Drug A: Buserelin •Drug B: Lidocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Lidocaine. •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): Lidocaine is an anesthetic of the amide group indicated 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): Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction. Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse. Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base. As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values. This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection. The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection. Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation. This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels. •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): Lidocaine is a local anesthetic of the amide type. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes. At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions. The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization. As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential. This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place. In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system. After absorption, lidocaine may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate, and force of contraction. •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, lidocaine is readily absorbed across mucous membranes and damaged skin but poorly through intact skin. The agent is quickly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream. And although lidocaine is also well absorbed across the gastrointestinal tract the oral bioavailability is only about 35% as a result of a high degree of first-pass metabolism. After injection into tissues, lidocaine is also rapidly absorbed and the absorption rate is affected by both vascularity and the presence of tissue and fat capable of binding lidocaine in the particular tissues. The concentration of lidocaine in the blood is subsequently affected by a variety of aspects, including its rate of absorption from the site of injection, the rate of tissue distribution, and the rate of metabolism and excretion. Subsequently, the systemic absorption of lidocaine is determined by the site of injection, the dosage given, and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site, and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of lidocaine injected and the resultant peak anesthetic blood levels. Nevertheless, it has been observed that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending also on lipid solubility and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. Additionally, lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. •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 determined for lidocaine is 0.7 to 1.5 L/kg. In particular, lidocaine is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or possibly even three-compartment model. There is a rapid disappearance (alpha phase) which is believed to be related to uptake by rapidly equilibrating tissues (tissues with high vascular perfusion, for example). The slower phase is related to distribution to slowly equilibrating tissues (beta phase) and to its metabolism and excretion (gamma phase). Lidocaine's distribution is ultimately throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of the agent. The highest percentage of this drug will be found in skeletal muscle, mainly due to the mass of muscle rather than an affinity. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding recorded for lidocaine is about 60 to 80% and is dependent upon the plasma concentration of alpha-1-acid glycoprotein. Such percentage protein binding bestows lidocaine with a medium duration of action when placed in comparison to other local anesthetic agents. •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): Lidocaine is metabolized predominantly and rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine HCl. Approximately 90% of lidocaine HCl administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. •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 excretion of unchanged lidocaine and its metabolites occurs predominantly via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of lidocaine occurs by non-ionic diffusion. •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 lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean systemic clearance observed for intravenously administered lidocaine in a study of 15 adults was approximately 0.64 +/- 0.18 L/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): Symptoms of overdose and/or acute systemic toxicity involves central nervous system toxicity that presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for neurotic behavior. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anesthetics. Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome. Pregnancy Category B has been established for the use of lidocaine in pregnancy, although there are no formal, adequate, and well-controlled studies in pregnant women. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place. Ultimately, although animal studies have revealed no evidence of harm to the fetus, lidocaine should not be administered during early pregnancy unless the benefits are considered to outweigh the risks. Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother. The ratio of umbilical to maternal venous concentration is 0.5 to 0.6. The fetus appears to be capable of metabolizing lidocaine at term. The elimination half-life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult. Elevated lidocaine levels may persist in the newborn for at least 48 hours after delivery. Fetal bradycardia or tachycardia, neonatal bradycardia, hypotonia or respiratory depression may occur. Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to the recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman. Dosages in children should be reduced, commensurate with age, body weight and physical condition. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Agoneaze, Akten, Alivio, Anestacon, Anodyne Lpt, Astero, Cathejell, Curacaine, Depo-medrol With Lidocaine, Dermacinrx Lido V Pak, Dermacinrx Phn Pak, Dermacinrx Prikaan, Diphen, Emla, Fortacin, Glydo, Instillagel, Kenalog, Lido Bdk, Lido-prilo Caine Pack, Lidocan, Lidodan, Lidoderm, Lidopac, Lidopril, Lidopro, Lidosol, Lidothol, Lidotral, Lignospan, Marcaine, Max-freeze, Medi-derm With Lidocaine, Neo-bex, Octocaine, Octocaine With Epinephrine, Oraqix, P-care, P-care X, Pliaglis, Prilolid, Prizotral, Procomycin, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Relador, Synera, Triple Antibiotic, Venipuncture Px1, Viadur, Xylocaine, Xylocaine With Epinephrine, Xylocard, Xylonor, Zingo, Ztlido •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lidocaína Lidocaina Lidocaine Lidocainum Lignocaine •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): Lidocaine 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 Linagliptin interact?

•Drug A: Buserelin •Drug B: Linagliptin •Severity: MODERATE •Description: The therapeutic efficacy of Linagliptin 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): Linagliptin is indicated for the treatment of type II diabetes in addition to diet and exercise. It should not be used to treat type I diabetes or in diabetic ketoacidosis. An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively 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): A 5mg oral dose of linagliptin results in >80% inhibition of dipeptidyl peptidase 4 (DPP-4) for ≥24 hours. Inhibition of DPP-4 increases the concentration of glucagon-like peptide 1 (GLP-1), leading to decreased glycosylated hemoglobin and fasting plasma glucose. •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): Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this enzyme slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP). GLP-1 and GIP stimulate the release of insulin from beta cells in the pancreas while inhibiting release of glucagon from pancreatic beta cells. These effects together reduce the breakdown of glycogen in the liver and increase insulin release in response to glucose. •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 of linagliptin is 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): A single intravenous dose of 5mg results in a volume of distribution of 1110L. However an intravenous infusion of 0.5-10mg results in a volume of distribution of 380-1540L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Linagliptin is 99% protein bound at a concentration of 1nmol/L and 75-89% protein bound at a concentration of >30nmol/L. •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): An oral dose of linagliptin is excreted primarily in the feces. 90% of an oral dose is excreted unchanged in the urine and feces. The predominant metabolite in the plasma is CD1790 and the predominant metabolite recovered after excretion was M489(1). Other metabolites are produced through oxidation, oxidative degradation, N-acetylation, glucuronidation, and cysteine adduct formation. Other metabolites have been identified through mass spectrometry though no structures were determined. Metabolism of linagliptin is mediated by cytochrome P450 3A4, aldo-keto reductases, and carbonyl reductases. •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): 84.7% of linagliptin is eliminated in the feces and 5.4% is 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 half life of linagliptin is 155 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance of linagliptin is 374mL/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): No dosage adjustment is necessary based on race, age, weight, sex, renal impairment, or hepatic impairment. Studies of efficacy and safety in pediatric populations were not included in the original drug approval but recent clinical trials show linagliptin to be well tolerated in patients 10 to 18 years old. Animal studies showed an increased risk of lymphoma in female rats at over 200 times the clinical dose. Aside from this effect, linagliptin was not shown to be mutagenic, clastogenic, or have an effect on fertility. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Glyxambi, Jentadueto, Tradjenta, Trajenta, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linagliptin Linagliptina •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): Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to manage 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 Linagliptin interact? Information: •Drug A: Buserelin •Drug B: Linagliptin •Severity: MODERATE •Description: The therapeutic efficacy of Linagliptin 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): Linagliptin is indicated for the treatment of type II diabetes in addition to diet and exercise. It should not be used to treat type I diabetes or in diabetic ketoacidosis. An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively 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): A 5mg oral dose of linagliptin results in >80% inhibition of dipeptidyl peptidase 4 (DPP-4) for ≥24 hours. Inhibition of DPP-4 increases the concentration of glucagon-like peptide 1 (GLP-1), leading to decreased glycosylated hemoglobin and fasting plasma glucose. •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): Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this enzyme slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP). GLP-1 and GIP stimulate the release of insulin from beta cells in the pancreas while inhibiting release of glucagon from pancreatic beta cells. These effects together reduce the breakdown of glycogen in the liver and increase insulin release in response to glucose. •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 of linagliptin is 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): A single intravenous dose of 5mg results in a volume of distribution of 1110L. However an intravenous infusion of 0.5-10mg results in a volume of distribution of 380-1540L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Linagliptin is 99% protein bound at a concentration of 1nmol/L and 75-89% protein bound at a concentration of >30nmol/L. •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): An oral dose of linagliptin is excreted primarily in the feces. 90% of an oral dose is excreted unchanged in the urine and feces. The predominant metabolite in the plasma is CD1790 and the predominant metabolite recovered after excretion was M489(1). Other metabolites are produced through oxidation, oxidative degradation, N-acetylation, glucuronidation, and cysteine adduct formation. Other metabolites have been identified through mass spectrometry though no structures were determined. Metabolism of linagliptin is mediated by cytochrome P450 3A4, aldo-keto reductases, and carbonyl reductases. •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): 84.7% of linagliptin is eliminated in the feces and 5.4% is 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 half life of linagliptin is 155 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance of linagliptin is 374mL/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): No dosage adjustment is necessary based on race, age, weight, sex, renal impairment, or hepatic impairment. Studies of efficacy and safety in pediatric populations were not included in the original drug approval but recent clinical trials show linagliptin to be well tolerated in patients 10 to 18 years old. Animal studies showed an increased risk of lymphoma in female rats at over 200 times the clinical dose. Aside from this effect, linagliptin was not shown to be mutagenic, clastogenic, or have an effect on fertility. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Glyxambi, Jentadueto, Tradjenta, Trajenta, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linagliptin Linagliptina •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): Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to manage 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 Liraglutide interact?

•Drug A: Buserelin •Drug B: Liraglutide •Severity: MODERATE •Description: The therapeutic efficacy of Liraglutide 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): Saxenda, a formulation of liraglutide intended for weight loss, is indicated as an adjunct to diet and exercise for chronic weight management in adult patients who are obese (BMI≥30 kg/m ), or who are overweight (BMI≥27 kg/m ) and have at least one weight-related comorbidity. It is also indicated for chronic weight management in pediatric patients ≥12 years old who weigh ≥60 kg and have an initial BMI corresponding to obesity based on international cut-offs. Victoza, a formulation of liraglutide used in diabetes, is indicated as an adjunct to diet and exercise to improve glycemic control in patients ≥10 years old with type 2 diabetes mellitus. It is also indicated to reduce the risk of major adverse cardiovascular events in adult patients with type 2 diabetes and established cardiovascular disease. Liraglutide is also available in combination with insulin degludec as an adjunct to diet and exercise to improve glycemic control in adult patients 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): Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at position 26 of the GLP-1 molecule, enabling it to bind reversibly to albumin within the subcutaneous tissue and bloodstream and be released slowly over time. Binding with albumin results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1. The effect of liraglutide is the increased secretion of insulin and decreased secretion of glucagon in response to glucose as well as slower gastric emptying. Liraglutide also does not adversely affect glucagon secretion in response to low blood sugar. •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): Liraglutide is an acylated synthetic glucagon-like peptide-1 analog. Liraglutide is an agonist of the glucagon-like peptide-1 receptor which is coupled to adenylate cyclase. The increase in cyclic AMP stimulates the glucose dependant release of insulin, inhibits the glucose dependant release of glucagon, and slows gastric emptying to increase control of blood sugar. •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 liraglutide after subcutaneous injection is approximately 55% and maximum concentrations are reached after 11.7 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): 13L. •Protein binding (Drug A): 15% •Protein binding (Drug B): >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): Liraglutide is less sensitive to metabolism than the endogenous GLP-1 and so is more slowly metabolized by dipeptidyl peptidase-4 and neutral endopeptidase to various smaller polypeptides which have not all been structurally determined. A portion of Liraglutide may be completely metabolized to carbon dioxide and water. •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): 6% excreted in urine and 5% 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): Terminal half life of 13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 1.2L/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 clinical significance of race or ethnicity on the safety or efficacy of liraglutide. Geriatric patients do not experience clinically significant differences in pharmacokinetics though patients at an especially advanced age may be more susceptible to adverse effects. Female patients have reduced clearance of liraglutide but no dose adjustment is necessary. The risk and benefit of liraglutide in pregnancy must be weighed before prescribing. In animal studies, liraglutide is associated with an increased risk of embryonic death and fetal abnormalities though an HbA1c > 7 is also associated with a 20-25% risk of birth defects. In animal studies, liraglutide is present in the milk of lactating rats at half the plasma concentration of the mother but these results may not translate to humans. Because it is not known if liraglutide is present in breast milk and the effects on infants are also unknown, the risk and benefit of liraglutide in breastfeeding must be considered before prescribing. Liraglutide was shown to be safe and effective in patients up to 160kg in weight but has not been studied in patients at a higher weight. A patient's weight significantly affects the pharmacokinetics of liraglutide. Liraglutide has not been investigated for use in pediatric patients. No dosage adjustments are necessary in patients with renal impairment but studies have not been performed in patients with end stage renal disease. There are no recommendations on dosage adjustment in patients with hepatic impairment, though caution should still be exercised when prescribing to this population. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Saxenda, Victoza, Xultophy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Liraglutida Liraglutide Liraglutide recombinant Liraglutidum •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): Liraglutide is a GLP-1 analog used in the management of type 2 diabetes mellitus and prevention of cardiovascular complications associated with diabetes.

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 Liraglutide interact? Information: •Drug A: Buserelin •Drug B: Liraglutide •Severity: MODERATE •Description: The therapeutic efficacy of Liraglutide 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): Saxenda, a formulation of liraglutide intended for weight loss, is indicated as an adjunct to diet and exercise for chronic weight management in adult patients who are obese (BMI≥30 kg/m ), or who are overweight (BMI≥27 kg/m ) and have at least one weight-related comorbidity. It is also indicated for chronic weight management in pediatric patients ≥12 years old who weigh ≥60 kg and have an initial BMI corresponding to obesity based on international cut-offs. Victoza, a formulation of liraglutide used in diabetes, is indicated as an adjunct to diet and exercise to improve glycemic control in patients ≥10 years old with type 2 diabetes mellitus. It is also indicated to reduce the risk of major adverse cardiovascular events in adult patients with type 2 diabetes and established cardiovascular disease. Liraglutide is also available in combination with insulin degludec as an adjunct to diet and exercise to improve glycemic control in adult patients 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): Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at position 26 of the GLP-1 molecule, enabling it to bind reversibly to albumin within the subcutaneous tissue and bloodstream and be released slowly over time. Binding with albumin results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1. The effect of liraglutide is the increased secretion of insulin and decreased secretion of glucagon in response to glucose as well as slower gastric emptying. Liraglutide also does not adversely affect glucagon secretion in response to low blood sugar. •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): Liraglutide is an acylated synthetic glucagon-like peptide-1 analog. Liraglutide is an agonist of the glucagon-like peptide-1 receptor which is coupled to adenylate cyclase. The increase in cyclic AMP stimulates the glucose dependant release of insulin, inhibits the glucose dependant release of glucagon, and slows gastric emptying to increase control of blood sugar. •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 liraglutide after subcutaneous injection is approximately 55% and maximum concentrations are reached after 11.7 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): 13L. •Protein binding (Drug A): 15% •Protein binding (Drug B): >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): Liraglutide is less sensitive to metabolism than the endogenous GLP-1 and so is more slowly metabolized by dipeptidyl peptidase-4 and neutral endopeptidase to various smaller polypeptides which have not all been structurally determined. A portion of Liraglutide may be completely metabolized to carbon dioxide and water. •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): 6% excreted in urine and 5% 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): Terminal half life of 13 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 1.2L/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 clinical significance of race or ethnicity on the safety or efficacy of liraglutide. Geriatric patients do not experience clinically significant differences in pharmacokinetics though patients at an especially advanced age may be more susceptible to adverse effects. Female patients have reduced clearance of liraglutide but no dose adjustment is necessary. The risk and benefit of liraglutide in pregnancy must be weighed before prescribing. In animal studies, liraglutide is associated with an increased risk of embryonic death and fetal abnormalities though an HbA1c > 7 is also associated with a 20-25% risk of birth defects. In animal studies, liraglutide is present in the milk of lactating rats at half the plasma concentration of the mother but these results may not translate to humans. Because it is not known if liraglutide is present in breast milk and the effects on infants are also unknown, the risk and benefit of liraglutide in breastfeeding must be considered before prescribing. Liraglutide was shown to be safe and effective in patients up to 160kg in weight but has not been studied in patients at a higher weight. A patient's weight significantly affects the pharmacokinetics of liraglutide. Liraglutide has not been investigated for use in pediatric patients. No dosage adjustments are necessary in patients with renal impairment but studies have not been performed in patients with end stage renal disease. There are no recommendations on dosage adjustment in patients with hepatic impairment, though caution should still be exercised when prescribing to this population. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Saxenda, Victoza, Xultophy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Liraglutida Liraglutide Liraglutide recombinant Liraglutidum •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): Liraglutide is a GLP-1 analog used in the management of type 2 diabetes mellitus and prevention of cardiovascular complications associated with diabetes. 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 Lixisenatide interact?

•Drug A: Buserelin •Drug B: Lixisenatide •Severity: MODERATE •Description: The therapeutic efficacy of Lixisenatide 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): Lixisenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type II diabetes mellitus. It is also available in combination with insulin glargine for the same indication. •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): Lixisenatide acts as an agonist at the GLP-1 receptor. In the pancreas, this agonism results in increased glucose-stimulated insulin exocytosis by beta islet cells. This produces a reduction in blood glucose due to increased glucose uptake by tissues. GLP-1 receptor activation in the GI tract results in delayed gastric emptying which is thought to mediate the effects of lixisenatide on postprandial blood glucose. •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 activation of the GLP-1 receptor by lixisenatide results in the activation of adenylyl cyclase. This increases the concentration of cyclic adenosine monophosphate in the cell leading to the activation of protein kinase A (PKA) as well as Epac1 and Epac2. PKA, Epac1, and Epac2 are involved the in release of Ca2+ from the endoplasmic reticulum which is known as the "amplification" pathway which increases insulin release when the triggering pathway is activated. By activating this amplification pathway lixisenatide increases glucose stimulated insulin secretion. •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 subcutaneous administration, the median T max of lixisenatide ranged from 1-3.5 hours, with no clinically relevant differences in the rate of absorption noted between possible injection sites (i.e. thigh, abdomen, or arm). •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 following subcutaneous administration is approximately 100 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Lixisenatide is approximately 55% 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): Lixisenatide is likely catabolized via non-specific proteolytic degradation. •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): Lixisenatide is presumably eliminated via glomerular filtration and proteolytic degradation. •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 the administration of multiple doses in patients with type II diabetes mellitus, the mean terminal half-life of lixisenatide was approximately 3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance of lixisenatide is approximately 35 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): Thyroid C-cell adenomas occurred in rats when exposed to >15 times human exposure of 20mcg/day. Overdose is associated with GI side effects typical of GLP-1 receptor agonists. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Adlyxin Starter Kit, Lyxumia, Soliqua •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lixisenatida Lixisénatide Lixisenatide •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): Lixisenatide is a GLP-1 receptor agonist used for 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 Lixisenatide interact? Information: •Drug A: Buserelin •Drug B: Lixisenatide •Severity: MODERATE •Description: The therapeutic efficacy of Lixisenatide 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): Lixisenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type II diabetes mellitus. It is also available in combination with insulin glargine for the same indication. •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): Lixisenatide acts as an agonist at the GLP-1 receptor. In the pancreas, this agonism results in increased glucose-stimulated insulin exocytosis by beta islet cells. This produces a reduction in blood glucose due to increased glucose uptake by tissues. GLP-1 receptor activation in the GI tract results in delayed gastric emptying which is thought to mediate the effects of lixisenatide on postprandial blood glucose. •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 activation of the GLP-1 receptor by lixisenatide results in the activation of adenylyl cyclase. This increases the concentration of cyclic adenosine monophosphate in the cell leading to the activation of protein kinase A (PKA) as well as Epac1 and Epac2. PKA, Epac1, and Epac2 are involved the in release of Ca2+ from the endoplasmic reticulum which is known as the "amplification" pathway which increases insulin release when the triggering pathway is activated. By activating this amplification pathway lixisenatide increases glucose stimulated insulin secretion. •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 subcutaneous administration, the median T max of lixisenatide ranged from 1-3.5 hours, with no clinically relevant differences in the rate of absorption noted between possible injection sites (i.e. thigh, abdomen, or arm). •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 following subcutaneous administration is approximately 100 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Lixisenatide is approximately 55% 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): Lixisenatide is likely catabolized via non-specific proteolytic degradation. •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): Lixisenatide is presumably eliminated via glomerular filtration and proteolytic degradation. •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 the administration of multiple doses in patients with type II diabetes mellitus, the mean terminal half-life of lixisenatide was approximately 3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance of lixisenatide is approximately 35 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): Thyroid C-cell adenomas occurred in rats when exposed to >15 times human exposure of 20mcg/day. Overdose is associated with GI side effects typical of GLP-1 receptor agonists. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Adlyxin Starter Kit, Lyxumia, Soliqua •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lixisenatida Lixisénatide Lixisenatide •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): Lixisenatide is a GLP-1 receptor agonist used for 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 Lofexidine interact?

•Drug A: Buserelin •Drug B: Lofexidine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lofexidine. •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): Lofexidine is indicated for mitigation of symptoms associated with acute withdrawal from opioids and for facilitation of the completion of opioid discontinuation treatment. It is the first non-opioid medication for the symptomatic management of opioid discontinuation. Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence. This condition is extremely unpleasant lasting several days with some of the main features being abdominal pain, nausea, diarrhea, mydriasis, lacrimation, and piloerection. These symptoms are often observed after abrupt reductions in the opioid dose and can be resolved by re-administration of the opioid. •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, lofexidine presented more severe opioid withdrawal effects than observed with methadone. On the other hand, in clinical trials of methadone withdrawal, lofexidine effectively reduced withdrawal symptoms, especially hypotension. The clinical reports have also indicated that lofexidine presents a better outcome when used briefly. In phase 3 clinical trials, lofexidine was shown to generate a significantly higher completion rate of opioid discontinuation. Some pharmacological studies were performed and there were no off-target effects reported. •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): Lofexidine is a potent alpha2-adrenergic receptor agonist with some moderate agonistic affinity towards Alpha-1A adrenergic receptor and 5-HT1a, 5-HT7, 5HT2c and 5HT1d receptors. The alpha2-adrenergic receptor is normally targeted by norepinephrine and its activation inhibits the synthesis of cAMP which in turn leads to potassium efflux and suppression of neural firing and inhibition of norepinephrine release. All of this activity can reduce the heart rate, blood pressure, and attenuate sympathetic stress response. Opioids inhibit cAMP in the noradrenergic neurons and their discontinuation produces a rise in the level of cAMP. This will generate an increase in norepinephrine which is associated with the symptoms of withdrawal. The magnitude of the effect is augmented by chronic opioid use due to the compensatory mechanisms of continuous negative feedback. Therefore, chronic opioid use translates into an exacerbated production of cAMP and norepinephrine release. Lofexidine replaces the opioid-driven inhibition of cAMP production by activating the alpha2-adrenergic receptor and moderating the symptoms of opioid withdrawal. This effect is performed without interacting with opioid receptors which mediate other activities of opioid dependence or addiction. •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): Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration. The bioavailability is registered to be even higher than 72%. About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 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): Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose. •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): Lofexidine metabolic ratio is highly variable among people. It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are 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): The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%. From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose. •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 elimination half-life of lofexidine is 11 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total elimination clearance following intravenous administration is 17.6 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): Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lucemyra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lofexidina Lofexidine Lofexidinum •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): Lofexidine is a centrally acting alpha2-adrenergic agonist used for the symptomatic treatment of acute opioid withdrawal syndrome to facilitate abrupt opioid discontinuation in adults.

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 Lofexidine interact? Information: •Drug A: Buserelin •Drug B: Lofexidine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lofexidine. •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): Lofexidine is indicated for mitigation of symptoms associated with acute withdrawal from opioids and for facilitation of the completion of opioid discontinuation treatment. It is the first non-opioid medication for the symptomatic management of opioid discontinuation. Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence. This condition is extremely unpleasant lasting several days with some of the main features being abdominal pain, nausea, diarrhea, mydriasis, lacrimation, and piloerection. These symptoms are often observed after abrupt reductions in the opioid dose and can be resolved by re-administration of the opioid. •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, lofexidine presented more severe opioid withdrawal effects than observed with methadone. On the other hand, in clinical trials of methadone withdrawal, lofexidine effectively reduced withdrawal symptoms, especially hypotension. The clinical reports have also indicated that lofexidine presents a better outcome when used briefly. In phase 3 clinical trials, lofexidine was shown to generate a significantly higher completion rate of opioid discontinuation. Some pharmacological studies were performed and there were no off-target effects reported. •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): Lofexidine is a potent alpha2-adrenergic receptor agonist with some moderate agonistic affinity towards Alpha-1A adrenergic receptor and 5-HT1a, 5-HT7, 5HT2c and 5HT1d receptors. The alpha2-adrenergic receptor is normally targeted by norepinephrine and its activation inhibits the synthesis of cAMP which in turn leads to potassium efflux and suppression of neural firing and inhibition of norepinephrine release. All of this activity can reduce the heart rate, blood pressure, and attenuate sympathetic stress response. Opioids inhibit cAMP in the noradrenergic neurons and their discontinuation produces a rise in the level of cAMP. This will generate an increase in norepinephrine which is associated with the symptoms of withdrawal. The magnitude of the effect is augmented by chronic opioid use due to the compensatory mechanisms of continuous negative feedback. Therefore, chronic opioid use translates into an exacerbated production of cAMP and norepinephrine release. Lofexidine replaces the opioid-driven inhibition of cAMP production by activating the alpha2-adrenergic receptor and moderating the symptoms of opioid withdrawal. This effect is performed without interacting with opioid receptors which mediate other activities of opioid dependence or addiction. •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): Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration. The bioavailability is registered to be even higher than 72%. About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 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): Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose. •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): Lofexidine metabolic ratio is highly variable among people. It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are 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): The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%. From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose. •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 elimination half-life of lofexidine is 11 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total elimination clearance following intravenous administration is 17.6 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): Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lucemyra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lofexidina Lofexidine Lofexidinum •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): Lofexidine is a centrally acting alpha2-adrenergic agonist used for the symptomatic treatment of acute opioid withdrawal syndrome to facilitate abrupt opioid discontinuation in adults. 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 Lomefloxacin interact?

•Drug A: Buserelin •Drug B: Lomefloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lomefloxacin. •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 bacterial infections of the respiratory tract (chronic bronchitis) and urinary tract, and as a pre-operative prophylactic to prevent urinary tract infection caused by: S.pneumoniae, H.influenzae, S.aureus, P.aeruginosa, E. cloacae, P. mirabilis, C. civersus, S. asprphyticus, E.coli, and K.pneumoniae. •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): Lomefloxacin is a fluoroquinolone antibiotic used to treat chronic bronchitis, as well as complicated and uncomplicated urinary tract infections. It is also used as a prophylactic or preventative treatment to prevent urinary tract infections in patients undergoing transrectal or transurethral surgical procedures. Flouroquinolones such as lomefloxacin possess excellent activity against gram-negative aerobic bacteria such as E.coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also posses effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. •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): Lomefloxacin is a bactericidal fluoroquinolone agent with activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of lomefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited. •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 nearly complete with approximately 95% to 98% of a single oral dose being 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): 10% •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): Minimally metabolized although 5 metabolites have been identified in human urine. 65% appears as the parent drug in urine and 9% as the glucuronide 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): The urinary excretion of lomefloxacin was virtually complete within 72 hours after cessation of dosing, with approximately 65% of the dose being recovered as parent drug and 9% as its glucuronide 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): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 271 mL/min/1.73 m2 [creatinine clearance of 110 mL/min/1.73 m2] 31 mL/min/1.73 m2 [creatinine clearance of 0 mL/min/1.73 m2] •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 include peripheral neuropathy, nervousness, agitation, anxiety, and phototoxic events (rash, itching, burning) due to sunlight exposure. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Maxaquin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): LFLX Lomefloxacin Lomefloxacine Lomefloxacino Lomefloxacinum •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): Lomefloxacin is a fluoroquinolone used to prevent and treat a wide variety of infections in the body.

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 Lomefloxacin interact? Information: •Drug A: Buserelin •Drug B: Lomefloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lomefloxacin. •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 bacterial infections of the respiratory tract (chronic bronchitis) and urinary tract, and as a pre-operative prophylactic to prevent urinary tract infection caused by: S.pneumoniae, H.influenzae, S.aureus, P.aeruginosa, E. cloacae, P. mirabilis, C. civersus, S. asprphyticus, E.coli, and K.pneumoniae. •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): Lomefloxacin is a fluoroquinolone antibiotic used to treat chronic bronchitis, as well as complicated and uncomplicated urinary tract infections. It is also used as a prophylactic or preventative treatment to prevent urinary tract infections in patients undergoing transrectal or transurethral surgical procedures. Flouroquinolones such as lomefloxacin possess excellent activity against gram-negative aerobic bacteria such as E.coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also posses effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. •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): Lomefloxacin is a bactericidal fluoroquinolone agent with activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of lomefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited. •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 nearly complete with approximately 95% to 98% of a single oral dose being 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): 10% •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): Minimally metabolized although 5 metabolites have been identified in human urine. 65% appears as the parent drug in urine and 9% as the glucuronide 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): The urinary excretion of lomefloxacin was virtually complete within 72 hours after cessation of dosing, with approximately 65% of the dose being recovered as parent drug and 9% as its glucuronide 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): 8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 271 mL/min/1.73 m2 [creatinine clearance of 110 mL/min/1.73 m2] 31 mL/min/1.73 m2 [creatinine clearance of 0 mL/min/1.73 m2] •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 include peripheral neuropathy, nervousness, agitation, anxiety, and phototoxic events (rash, itching, burning) due to sunlight exposure. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Maxaquin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): LFLX Lomefloxacin Lomefloxacine Lomefloxacino Lomefloxacinum •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): Lomefloxacin is a fluoroquinolone used to prevent and treat a wide variety of infections in the body. 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 Loperamide interact?

•Drug A: Buserelin •Drug B: Loperamide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Loperamide. •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): Loperamide is indicated for the relief of diarrhea, including Travelers’ Diarrhea. As an off-label use, it is often used to manage chemotherapy-related 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): Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na -gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death. •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): Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes. Loperamide acts on the mu-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools. •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): Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation. The drug bioavailability is less than 1%. Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2.5 hours after the liquid formulation of the drug. •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): Loperamide has a large volume of distribution. Although highly lipophilic, loperamide does not cross the blood-brain barrier and generally acts peripherally. •Protein binding (Drug A): 15% •Protein binding (Drug B): Based on literature information, the plasma protein binding of loperamide is about 95%. •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): Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation. Metabolites of loperamide are pharmacologically 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): Loperamide and its metabolites in the systemic circulation undergo biliary excretion. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. Only 1% of an absorbed dose 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): The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 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): Oral LD50 is 185 mg/kg in rats. Loperamide overdose can lead to a range of cardiac and non-cardiac effects. Chronic ingestion of doses ranging from 70 mg to 1600 mg daily - which is four to 100 times the recommended dose - resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death. These cases included instances of loperamide misuse and abuse. In case of cardiac effects, it is recommended that loperamide is discontinued and therapies to manage and prevent cardiac arrhythmias are initiated. Cases of loperamide overdose may cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus. Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diamode, Imodium, Imodium Multi-symptom Relief •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): Loperamide is a long acting antidiarrheal used to control nonspecific diarrhea and chronic diarrhea caused by inflammatory bowel disease, or gastroenteritis.

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 Loperamide interact? Information: •Drug A: Buserelin •Drug B: Loperamide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Loperamide. •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): Loperamide is indicated for the relief of diarrhea, including Travelers’ Diarrhea. As an off-label use, it is often used to manage chemotherapy-related 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): Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na -gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death. •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): Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes. Loperamide acts on the mu-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools. •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): Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation. The drug bioavailability is less than 1%. Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2.5 hours after the liquid formulation of the drug. •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): Loperamide has a large volume of distribution. Although highly lipophilic, loperamide does not cross the blood-brain barrier and generally acts peripherally. •Protein binding (Drug A): 15% •Protein binding (Drug B): Based on literature information, the plasma protein binding of loperamide is about 95%. •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): Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation. Metabolites of loperamide are pharmacologically 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): Loperamide and its metabolites in the systemic circulation undergo biliary excretion. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. Only 1% of an absorbed dose 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): The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 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): Oral LD50 is 185 mg/kg in rats. Loperamide overdose can lead to a range of cardiac and non-cardiac effects. Chronic ingestion of doses ranging from 70 mg to 1600 mg daily - which is four to 100 times the recommended dose - resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death. These cases included instances of loperamide misuse and abuse. In case of cardiac effects, it is recommended that loperamide is discontinued and therapies to manage and prevent cardiac arrhythmias are initiated. Cases of loperamide overdose may cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus. Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diamode, Imodium, Imodium Multi-symptom Relief •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): Loperamide is a long acting antidiarrheal used to control nonspecific diarrhea and chronic diarrhea caused by inflammatory bowel disease, or gastroenteritis. 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 Loratadine interact?

•Drug A: Buserelin •Drug B: Loratadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Loratadine 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): Loratadine is a 2nd generation antihistamine and is used to manage symptoms of allergic rhinitis, wheal formation, urticaria, and other allergic dermatologic conditions. •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): Like other 2nd generation antihistamines, loratadine is selective for peripheral H1 receptors. Loratadine does not penetrate effectively into the central nervous system and has poor affinity for CNS H1-receptors. These qualities result in a lack of CNS depressant effects such as drowsiness, sedation, and impaired psychomotor 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): Histamine release is a key mediator in allergic rhinitis and urticaria. As a result, loratadine exerts it's effect by targeting H1 histamine receptors. Loratadine binds to H1 histamine receptors found on the surface of epithelial cells, endothelial cells, eosinophils, neutrophils, airway cells, and vascular smooth muscle cells among others. H1 histamine receptors fall under the wider umbrella of G-protein coupled receptors, and exist in a state of equilibrium between the active and inactive forms. Histamine binding to the H1-receptor facilitates cross linking between transmembrane domains III and V, stabilizing the active form of the receptor. On the other hand, antihistamines bind to a different site on the H1 receptor favouring the inactive form. Hence, loratadine can more accurately be classified as an "inverse agonist" as opposed to a "histamine antagonist", and can prevent or reduce the severity of histamine mediated 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): Loratadine is rapidly absorbed and achieves peak plasma concentration in 1-2 hours, while it's main metabolite achieves peak plasma concentration in 3-4 hours. In the rapid dissolve formulation, the pharmacokinetic parameters of loratadine are as follows: Cmax = 2.56 ng/ml, Tmax = 1.14 hrs, AUC = 6.14 ng x hr/ml. In the rapid dissolve formulation, the pharmacokinetic parameters of descarboethoxyloratadine are as follows: Cmax = 3.72 ng/ml, Tmax = 1.97 hr, AUC = 49.1 ng x hr/ml. In the conventional formulation, the pharmacokinetic parameters of loratadine are as follows: Cmax = 2.11 ng/ml, Tmax = 1.00 hr, AUC = 4.64 ng x hr/ml In the conventional formulation, the pharmacokinetic parameters of descarboethoxyloratadine are as follows: Cmax = 3.66 ng/ml, Tmax = 1.97 hr, AUC = 48.4 ng x hr/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 volume of distribution of loratadine is 120 L/Kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): 97 - 99% of the loratadine 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): Loratadine undergoes extensive first pass metabolism in the liver and is primarily metabolized by CYP3A4, CYP2D6, CYP1A1 and CYP2C19. Less involved CYP enzymes include CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A5. CYP3A4 and CYP2D6 are mainly responsible for metabolizing loratadine to descarboethoxyloratadine. This primary metabolite is 4 times more pharmacologically active than loratadine. In addition, a study demonstrates that descarboethoxyloratadine is first glucuronidated by UGT2B10, then hydroxylated by CYP2C8 to form 3-hydroxydesloratadine. Further glucuronidation of 3-hydroxydesloratadine facilitates excretion. •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): Over a 10 day period, 40% of loratadine is excreted in the urine, and 42% is eliminated in the faeces. •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 is approximately 10 hours for loratadine and 20 hours for descarboethoxyloratadine. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of loratadine after single oral doses of 20 mg and 40 mg are 12 L/h/kg and 9 L/h/kg respectively. P-glycoprotein is involved in the clearance of many 2nd generation antihistamines, including loratadine, from the central nervous system. 1st generation antihistamines are not cleared by P-glycoprotein, which may help explain why they have a different central nervous system adverse effect profile compared to their 2nd generation counterparts. It appears that an antihistamine with higher affinity for p-glycoprotein will have a lower incidence of CNS adverse effects. •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): Second generation antihistamines such as loratadine have very few adverse effects; however, insomnia, headache, fatigue, drowsiness and rash have been reported. Symptoms of loratadine overdose include gastrointestinal side effects, agitation, drowsiness, tachycardia, and headache. It is advised to obtain an ECG in the event of loratadine overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Alavert, Alavert D, Allerclear, Claritin, Claritin-D, Diphen, Loradamed, Wal-itin, Wal-itin 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): Loratadine is a second generation antihistamine used to manage the symptoms of allergic rhinitis.

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 Loratadine interact? Information: •Drug A: Buserelin •Drug B: Loratadine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Loratadine 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): Loratadine is a 2nd generation antihistamine and is used to manage symptoms of allergic rhinitis, wheal formation, urticaria, and other allergic dermatologic conditions. •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): Like other 2nd generation antihistamines, loratadine is selective for peripheral H1 receptors. Loratadine does not penetrate effectively into the central nervous system and has poor affinity for CNS H1-receptors. These qualities result in a lack of CNS depressant effects such as drowsiness, sedation, and impaired psychomotor 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): Histamine release is a key mediator in allergic rhinitis and urticaria. As a result, loratadine exerts it's effect by targeting H1 histamine receptors. Loratadine binds to H1 histamine receptors found on the surface of epithelial cells, endothelial cells, eosinophils, neutrophils, airway cells, and vascular smooth muscle cells among others. H1 histamine receptors fall under the wider umbrella of G-protein coupled receptors, and exist in a state of equilibrium between the active and inactive forms. Histamine binding to the H1-receptor facilitates cross linking between transmembrane domains III and V, stabilizing the active form of the receptor. On the other hand, antihistamines bind to a different site on the H1 receptor favouring the inactive form. Hence, loratadine can more accurately be classified as an "inverse agonist" as opposed to a "histamine antagonist", and can prevent or reduce the severity of histamine mediated 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): Loratadine is rapidly absorbed and achieves peak plasma concentration in 1-2 hours, while it's main metabolite achieves peak plasma concentration in 3-4 hours. In the rapid dissolve formulation, the pharmacokinetic parameters of loratadine are as follows: Cmax = 2.56 ng/ml, Tmax = 1.14 hrs, AUC = 6.14 ng x hr/ml. In the rapid dissolve formulation, the pharmacokinetic parameters of descarboethoxyloratadine are as follows: Cmax = 3.72 ng/ml, Tmax = 1.97 hr, AUC = 49.1 ng x hr/ml. In the conventional formulation, the pharmacokinetic parameters of loratadine are as follows: Cmax = 2.11 ng/ml, Tmax = 1.00 hr, AUC = 4.64 ng x hr/ml In the conventional formulation, the pharmacokinetic parameters of descarboethoxyloratadine are as follows: Cmax = 3.66 ng/ml, Tmax = 1.97 hr, AUC = 48.4 ng x hr/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 volume of distribution of loratadine is 120 L/Kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): 97 - 99% of the loratadine 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): Loratadine undergoes extensive first pass metabolism in the liver and is primarily metabolized by CYP3A4, CYP2D6, CYP1A1 and CYP2C19. Less involved CYP enzymes include CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A5. CYP3A4 and CYP2D6 are mainly responsible for metabolizing loratadine to descarboethoxyloratadine. This primary metabolite is 4 times more pharmacologically active than loratadine. In addition, a study demonstrates that descarboethoxyloratadine is first glucuronidated by UGT2B10, then hydroxylated by CYP2C8 to form 3-hydroxydesloratadine. Further glucuronidation of 3-hydroxydesloratadine facilitates excretion. •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): Over a 10 day period, 40% of loratadine is excreted in the urine, and 42% is eliminated in the faeces. •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 is approximately 10 hours for loratadine and 20 hours for descarboethoxyloratadine. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of loratadine after single oral doses of 20 mg and 40 mg are 12 L/h/kg and 9 L/h/kg respectively. P-glycoprotein is involved in the clearance of many 2nd generation antihistamines, including loratadine, from the central nervous system. 1st generation antihistamines are not cleared by P-glycoprotein, which may help explain why they have a different central nervous system adverse effect profile compared to their 2nd generation counterparts. It appears that an antihistamine with higher affinity for p-glycoprotein will have a lower incidence of CNS adverse effects. •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): Second generation antihistamines such as loratadine have very few adverse effects; however, insomnia, headache, fatigue, drowsiness and rash have been reported. Symptoms of loratadine overdose include gastrointestinal side effects, agitation, drowsiness, tachycardia, and headache. It is advised to obtain an ECG in the event of loratadine overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Alavert, Alavert D, Allerclear, Claritin, Claritin-D, Diphen, Loradamed, Wal-itin, Wal-itin 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): Loratadine is a second generation antihistamine used to manage the symptoms of allergic rhinitis. 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 Losartan interact?

•Drug A: Buserelin •Drug B: Losartan •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Losartan 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): Losartan is indicated to treat hypertension in patients older than 6 years, reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage), and to treat diabetic nephropathy with elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension. Losartan with hydrochlorothiazide is indicated to treat hypertension and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage). •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): Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium 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): Losartan reversibly and competitively prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT 1 receptor with 1000 times more affinity than they bind to the AT 2 receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT 1 and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor and induce vasoconstriction, raising blood pressure. •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): Losartan is approximately 33% orally bioavailable. Losartan has a T max of 1 hour and the active metabolite has a T max of 3-4 hours. Taking losartan with food decreases the C max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C max of 200-250ng/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 volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174). •Protein binding (Drug A): 15% •Protein binding (Drug B): Losartan is 98.6-98.8% protein bound and the active metabolite (E-3174) is 99.7% protein bound in serum. •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): Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17. •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): A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% 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 terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/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): The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D. Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cozaar, Hyzaar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Losartan •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): Losartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy, and is used to reduce the risk of stroke.

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 Losartan interact? Information: •Drug A: Buserelin •Drug B: Losartan •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Losartan 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): Losartan is indicated to treat hypertension in patients older than 6 years, reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage), and to treat diabetic nephropathy with elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension. Losartan with hydrochlorothiazide is indicated to treat hypertension and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage). •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): Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium 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): Losartan reversibly and competitively prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT 1 receptor with 1000 times more affinity than they bind to the AT 2 receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT 1 and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor and induce vasoconstriction, raising blood pressure. •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): Losartan is approximately 33% orally bioavailable. Losartan has a T max of 1 hour and the active metabolite has a T max of 3-4 hours. Taking losartan with food decreases the C max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C max of 200-250ng/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 volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174). •Protein binding (Drug A): 15% •Protein binding (Drug B): Losartan is 98.6-98.8% protein bound and the active metabolite (E-3174) is 99.7% protein bound in serum. •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): Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17. •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): A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% 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 terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/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): The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D. Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cozaar, Hyzaar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Losartan •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): Losartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy, and is used to reduce the risk of stroke. 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 Lurasidone interact?

•Drug A: Buserelin •Drug B: Lurasidone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lurasidone. •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): Lurasidone is indicated for the treatment of schizophrenia in patients ≥13 years old. It is also indicated as a monotherapy for the treatment of bipolar depression in patients ≥10 years old, or in combination with lithium or valproate for the treatment of bipolar depression 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): Lurasidone is a benzothiazol derivative that is an antagonist and binds with high affinity to Dopamine-2 (D2) (Ki = 0.994 nM), 5-HT2A (Ki = 0.47 nM) receptors, and 5-HT7 receptors (Ki = 0.495 nM). It also binds with moderate affinity to alpha-2C adrenergic receptors (Ki = 10.8 nM) and is a partial agonist at 5-HT1A receptors (Ki = 6.38 nM). Its actions on histaminergic and muscarinic receptors are negligible. •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): Lurasidone is an atypical antipsychotic that is a D2 and 5-HT2A (mixed serotonin and dopamine activity) to improve cognition. It is thought that antagonism of serotonin receptors can improve negative symptoms of psychoses and reduce the extrapyramidal side effects that are often associated with typical antipsychotics. •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): Lurasidone is readily absorbed and quickly reaches maximal concentrations (Cmax) within 1-4 hours. When taken with food, there is a two-fold increase in exposure and time to maximal concentration is increased by 0.5-1.5 hours. This occurs regardless of fat or caloric content. Bioavailability = 9-19%. •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): 6173 L •Protein binding (Drug A): 15% •Protein binding (Drug B): ~99% bound to serum 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): Lurasidone is metabolized by CYP3A4 in which its major active metabolite is referred to as ID-14283 (25% of parent exposure). Its two minor metabolites are referred to as ID14326 and ID11614 which make up 3% and 1% of parent exposure respectively. Its two non-active metabolites are referred to as ID-20219 and ID-20220. •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 (~9%) and feces (~80%) •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): 40 mg dose= 18 hours 120 mg - 160 mg dose = 29-37 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 3902 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): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Latuda •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): Lurasidone is an atypical antipsychotic used to treat schizophrenia and depressive episodes associated with bipolar I disorder.

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 Lurasidone interact? Information: •Drug A: Buserelin •Drug B: Lurasidone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Lurasidone. •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): Lurasidone is indicated for the treatment of schizophrenia in patients ≥13 years old. It is also indicated as a monotherapy for the treatment of bipolar depression in patients ≥10 years old, or in combination with lithium or valproate for the treatment of bipolar depression 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): Lurasidone is a benzothiazol derivative that is an antagonist and binds with high affinity to Dopamine-2 (D2) (Ki = 0.994 nM), 5-HT2A (Ki = 0.47 nM) receptors, and 5-HT7 receptors (Ki = 0.495 nM). It also binds with moderate affinity to alpha-2C adrenergic receptors (Ki = 10.8 nM) and is a partial agonist at 5-HT1A receptors (Ki = 6.38 nM). Its actions on histaminergic and muscarinic receptors are negligible. •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): Lurasidone is an atypical antipsychotic that is a D2 and 5-HT2A (mixed serotonin and dopamine activity) to improve cognition. It is thought that antagonism of serotonin receptors can improve negative symptoms of psychoses and reduce the extrapyramidal side effects that are often associated with typical antipsychotics. •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): Lurasidone is readily absorbed and quickly reaches maximal concentrations (Cmax) within 1-4 hours. When taken with food, there is a two-fold increase in exposure and time to maximal concentration is increased by 0.5-1.5 hours. This occurs regardless of fat or caloric content. Bioavailability = 9-19%. •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): 6173 L •Protein binding (Drug A): 15% •Protein binding (Drug B): ~99% bound to serum 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): Lurasidone is metabolized by CYP3A4 in which its major active metabolite is referred to as ID-14283 (25% of parent exposure). Its two minor metabolites are referred to as ID14326 and ID11614 which make up 3% and 1% of parent exposure respectively. Its two non-active metabolites are referred to as ID-20219 and ID-20220. •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 (~9%) and feces (~80%) •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): 40 mg dose= 18 hours 120 mg - 160 mg dose = 29-37 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 3902 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): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Latuda •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): Lurasidone is an atypical antipsychotic used to treat schizophrenia and depressive episodes associated with bipolar I disorder. 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 Macimorelin interact?

•Drug A: Buserelin •Drug B: Macimorelin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Macimorelin. •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): Indicated for the diagnosis of adult growth hormone deficiency (AGHD). •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): Maximum GH levels from stimulation are observed between 30 to 90 minutes after administration of macimorelin. Increase in the QTcF interval may be observed from macimorelin administration. •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): Ghrelin is an endogenous ligand for the GH secretagogue receptor that is also called the ghrelin receptor (GHS-R1a). Upon activation of the receptor, ghrelin serves to increase growth hormone (GH) secretion. Macimorelin mimics the actions of ghrelin by stimulating GH release. As a synthetic agonist, it activates growth hormone secretagogue receptors present in the pituitary and hypothalamus. •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): Macimorelin is a novel, synthetic ghrelin agonist, which is readily absorbed from the gastrointestinal tract. The maximum plasma concentration (Cmax) was observed between 0.5 and 1.5 hours following oral administration of 0.5mg/kg macimorelin to patients with AGHD under fasting for at least 8 hours. Higher doses of drug demonstrate a dose-proportional increase in plasma concentrations. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, 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): Following a single oral dose of 0.5 mg/kg macimorelin, the mean volume of distribution of the central compartment is 5,733.4 ± 565.7L. •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): Macimorelin predominantly undergoes CYP3A4-mediated metabolism according to an in vitro human liver microsomes study. •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 mean terminal half-life (T1/2) is 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following a single oral dose of 0.5 mg/kg macimorelin, the mean clearance over the fraction absorbed (Cl/F) was 37,411.0 ± 4,554.6 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): Macimorelin has not shown to demonstrate mutagenic properties according to bacterial assays. It also did not induce any mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation. Studies assessing the carcinogenic potential or effect on fertility of macimorelin have not been conducted. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Macrilen •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): Macimorelin is a medication used to treat adult growth hormone deficiency.

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 Macimorelin interact? Information: •Drug A: Buserelin •Drug B: Macimorelin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Macimorelin. •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): Indicated for the diagnosis of adult growth hormone deficiency (AGHD). •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): Maximum GH levels from stimulation are observed between 30 to 90 minutes after administration of macimorelin. Increase in the QTcF interval may be observed from macimorelin administration. •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): Ghrelin is an endogenous ligand for the GH secretagogue receptor that is also called the ghrelin receptor (GHS-R1a). Upon activation of the receptor, ghrelin serves to increase growth hormone (GH) secretion. Macimorelin mimics the actions of ghrelin by stimulating GH release. As a synthetic agonist, it activates growth hormone secretagogue receptors present in the pituitary and hypothalamus. •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): Macimorelin is a novel, synthetic ghrelin agonist, which is readily absorbed from the gastrointestinal tract. The maximum plasma concentration (Cmax) was observed between 0.5 and 1.5 hours following oral administration of 0.5mg/kg macimorelin to patients with AGHD under fasting for at least 8 hours. Higher doses of drug demonstrate a dose-proportional increase in plasma concentrations. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, 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): Following a single oral dose of 0.5 mg/kg macimorelin, the mean volume of distribution of the central compartment is 5,733.4 ± 565.7L. •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): Macimorelin predominantly undergoes CYP3A4-mediated metabolism according to an in vitro human liver microsomes study. •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 mean terminal half-life (T1/2) is 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following a single oral dose of 0.5 mg/kg macimorelin, the mean clearance over the fraction absorbed (Cl/F) was 37,411.0 ± 4,554.6 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): Macimorelin has not shown to demonstrate mutagenic properties according to bacterial assays. It also did not induce any mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation. Studies assessing the carcinogenic potential or effect on fertility of macimorelin have not been conducted. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Macrilen •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): Macimorelin is a medication used to treat adult growth hormone deficiency. 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 Maprotiline interact?

•Drug A: Buserelin •Drug B: Maprotiline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Maprotiline 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 depression, including the depressed phase of bipolar depression, psychotic depression, and involutional melancholia, and may also be helpful in treating certain patients suffering severe depressive neurosis. •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): Maprotiline is a tetracyclic antidepressant. Although its main therapeutic use is in the treatment of depression, it has also been shown to exert a sedative effect on the anxiety component that often accompanies depression. In one sleep study, it was shown that maprotiline increases the duration of the REM sleep phase in depressed patients, compared to imipramine which reduced the REM sleep phase. Maprotiline is a strong inhibitor of noradrenaline reuptake in the brain and peripheral tissues, however it is worthy to note that it is a weak inhibitor of serotonergic uptake. In addition, it displays strong antihistaminic action (which may explain its sedative effects) as well as weak anticholinergic action. Maprotiline also has lower alpha adrenergic blocking activity than amitriptyline. •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): Maprotiline exerts its antidepressant action by inhibition of presynaptic uptake of catecholamines, thereby increasing their concentration at the synaptic clefts of the brain. In single doses, the effect of maprotiline on the EEG revealed a rise in the alpha-wave density, a reduction of the alpha-wave frequency and an increase in the alpha-wave amplitude. However, as with other tricyclic antidepressants, maprotiline lowers the convulsive threshold. Maprotiline acts as an antagonist at central presynaptic α 2 -adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Maprotiline is also a moderate peripheral α 1 adrenergic antagonist, which may explain the occasional orthostatic hypotension reported in association with its use. Maprotiline also inhibits the amine transporter, delaying the reuptake of noradrenaline and norepinephrine. Lastly, maprotiline is a strong inhibitor of the histamine H 1 receptor, which explains its sedative actions. •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): Slowly, but completely absorbed from the GI tract 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): Maprotiline and its metabolites may be detected in the lungs, liver, brain, and kidneys; lower concentrations may be found in the adrenal glands, heart and muscle. Maprotiline is readily distributed into breast milk to similar concentrations as those in maternal blood. •Protein binding (Drug A): 15% •Protein binding (Drug B): 88% •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. Maprotiline is metabolized by N -demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. It is slowly metabolized primarily to desmethylmaprotiline, a pharmacologically active metabolite. Desmethylmaprotiline may undergo further metabolism to maprotiline- N -oxide. •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 60% of a single orally administered dose is excreted in urine as conjugated metabolites within 21 days; 30% is eliminated 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): Average ~ 51 hours (range: 27-58 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): LD 50 =~900 mg/kg (Orally in rats); LD 50 =90 mg/kg (Orally in women); Signs of overdose include motor unrest, muscular twitching and rigidity, tremor, ataxia, convulsions, hyperpyrexia, vertigo, mydriasis, vomiting, cyanosis, hypotension, shock, tachycardia, cardiac arrhythmias, impaired cardiac conduction, respiratory depression, and disturbances of consciousness up to deep coma. •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): Maprotiline is a tetracyclic antidepressant used to treat depressive illness, major depressive disorder, bipolar disorder, and anxiety associated with 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 Maprotiline interact? Information: •Drug A: Buserelin •Drug B: Maprotiline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Maprotiline 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 depression, including the depressed phase of bipolar depression, psychotic depression, and involutional melancholia, and may also be helpful in treating certain patients suffering severe depressive neurosis. •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): Maprotiline is a tetracyclic antidepressant. Although its main therapeutic use is in the treatment of depression, it has also been shown to exert a sedative effect on the anxiety component that often accompanies depression. In one sleep study, it was shown that maprotiline increases the duration of the REM sleep phase in depressed patients, compared to imipramine which reduced the REM sleep phase. Maprotiline is a strong inhibitor of noradrenaline reuptake in the brain and peripheral tissues, however it is worthy to note that it is a weak inhibitor of serotonergic uptake. In addition, it displays strong antihistaminic action (which may explain its sedative effects) as well as weak anticholinergic action. Maprotiline also has lower alpha adrenergic blocking activity than amitriptyline. •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): Maprotiline exerts its antidepressant action by inhibition of presynaptic uptake of catecholamines, thereby increasing their concentration at the synaptic clefts of the brain. In single doses, the effect of maprotiline on the EEG revealed a rise in the alpha-wave density, a reduction of the alpha-wave frequency and an increase in the alpha-wave amplitude. However, as with other tricyclic antidepressants, maprotiline lowers the convulsive threshold. Maprotiline acts as an antagonist at central presynaptic α 2 -adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Maprotiline is also a moderate peripheral α 1 adrenergic antagonist, which may explain the occasional orthostatic hypotension reported in association with its use. Maprotiline also inhibits the amine transporter, delaying the reuptake of noradrenaline and norepinephrine. Lastly, maprotiline is a strong inhibitor of the histamine H 1 receptor, which explains its sedative actions. •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): Slowly, but completely absorbed from the GI tract 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): Maprotiline and its metabolites may be detected in the lungs, liver, brain, and kidneys; lower concentrations may be found in the adrenal glands, heart and muscle. Maprotiline is readily distributed into breast milk to similar concentrations as those in maternal blood. •Protein binding (Drug A): 15% •Protein binding (Drug B): 88% •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. Maprotiline is metabolized by N -demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. It is slowly metabolized primarily to desmethylmaprotiline, a pharmacologically active metabolite. Desmethylmaprotiline may undergo further metabolism to maprotiline- N -oxide. •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 60% of a single orally administered dose is excreted in urine as conjugated metabolites within 21 days; 30% is eliminated 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): Average ~ 51 hours (range: 27-58 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): LD 50 =~900 mg/kg (Orally in rats); LD 50 =90 mg/kg (Orally in women); Signs of overdose include motor unrest, muscular twitching and rigidity, tremor, ataxia, convulsions, hyperpyrexia, vertigo, mydriasis, vomiting, cyanosis, hypotension, shock, tachycardia, cardiac arrhythmias, impaired cardiac conduction, respiratory depression, and disturbances of consciousness up to deep coma. •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): Maprotiline is a tetracyclic antidepressant used to treat depressive illness, major depressive disorder, bipolar disorder, and anxiety associated with 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 Mecasermin interact?

•Drug A: Buserelin •Drug B: Mecasermin •Severity: MODERATE •Description: The therapeutic efficacy of Mecasermin 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 long-term treatment of growth failure in pediatric patients with Primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. It is not indicated to treat Secondary IGFD resulting from GH deficiency, malnutrition, hypothyroidism or other causes; it is not a substitute for GH 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): Mecasermin is a biosynthetic (recombinant DNA origin) form of human insulin-like growth factor 1 (IGF-1) designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized statural growth. Growth hormones (GH) bind to growth hormone receptors (GHR) in the liver and other tissues, which stimulates the synthesis of IGF-1. In target tissues, IGF-1 activates the IGF-1 receptor, resulting in intracellular signals that stimulate growth. Although many actions of the GH are mediated through IGF-1, the precise roles of GH and IGF-1 have not been fully elucidated. Patients with severe primary IGF-1 deficiency (Primary IGFD) fail to produce adequate levels of IGF-1, due to disruption of the GH pathway used to promote IGF-1 release (possible GH pathway disruptions include mutations in the GHR, post-GHR signaling pathway, and IGF-1 gene defects). •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): Mecasermin supplies recombinant-DNA-origin IGF-1, which binds to the Type I IGF-1 receptor. This receptor exerts intra-cellular signaling activity in a number of processes involved in statural growth, including mitogenesis in multiple tissue types, chondrocyte growth and division along cartilage growth plates, and increases in organ growth. •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): While the bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects has been reported to be close to 100%, the absolute bioavailability of mecasermin given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined. •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): 0.257 ± 0.073 L/kg [subjects with severe Primary IGFD] at a dose of 0.045mg/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. •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): Information on the metabolism of Mecasermin is not readily available, however it is likely to be metabolized by the liver and kidney like other injectable peptide drugs. •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): Information on the elimination of Mecasermin is not readily available, however it is likely to be metabolized by the liver and kidney like other injectable peptide drugs. •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 life of 5.8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of Mecasermin is inversely proportional to IGF binding protein 3 (IGFBP-3) * Clearance is estimated to be 0.04L/hr/kg at 0.5 micrograms/mL of IGFBP-3 * Clearance is estimated to be 0.01L/hr/kg at 3 micrograms/mL of IGFBP-3 (the median level of IGFBP-3 for patients with normal IGF-1 levels) •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 of Mecasermin leads to hypoglycemia. One case of acute overdose was treated with IV glucose. Long-term overdosage may result in signs and symptoms of acromegaly. The effects of Mecasermin in human pregnancy has not been studied, however effects on fetal development in animal studies were only seen at doses higher than the maximum recommended human dose based on body surface area. Studies on excretion of the drug in human milk, use in patients under 2 years, use in patients over 65 years, or use in patients with renal or hepatic impairment have not been performed. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Increlex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): INSULIN-LIKE GROWTH FACTOR 1 INSULIN-LIKE GROWTH FACTOR I (HUMAN) Mecasermin Mecasermin recombinant Mecasermina RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-I RH-OLIGOPEPTIDE-2 VEXXON-IGF-1 •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): Mecasermin is a recombinant insulin-like growth factor-1 used for the long-term treatment of growth failure in pediatric patients with primary IGF-1 deficiency or with growth hormone gene deletion due to the development of neutralizing antibodies to GH.

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 Mecasermin interact? Information: •Drug A: Buserelin •Drug B: Mecasermin •Severity: MODERATE •Description: The therapeutic efficacy of Mecasermin 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 long-term treatment of growth failure in pediatric patients with Primary IGFD or with GH gene deletion who have developed neutralizing antibodies to GH. It is not indicated to treat Secondary IGFD resulting from GH deficiency, malnutrition, hypothyroidism or other causes; it is not a substitute for GH 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): Mecasermin is a biosynthetic (recombinant DNA origin) form of human insulin-like growth factor 1 (IGF-1) designed to replace natural IGF-1 in pediatric patients who are deficient, promoting normalized statural growth. Growth hormones (GH) bind to growth hormone receptors (GHR) in the liver and other tissues, which stimulates the synthesis of IGF-1. In target tissues, IGF-1 activates the IGF-1 receptor, resulting in intracellular signals that stimulate growth. Although many actions of the GH are mediated through IGF-1, the precise roles of GH and IGF-1 have not been fully elucidated. Patients with severe primary IGF-1 deficiency (Primary IGFD) fail to produce adequate levels of IGF-1, due to disruption of the GH pathway used to promote IGF-1 release (possible GH pathway disruptions include mutations in the GHR, post-GHR signaling pathway, and IGF-1 gene defects). •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): Mecasermin supplies recombinant-DNA-origin IGF-1, which binds to the Type I IGF-1 receptor. This receptor exerts intra-cellular signaling activity in a number of processes involved in statural growth, including mitogenesis in multiple tissue types, chondrocyte growth and division along cartilage growth plates, and increases in organ growth. •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): While the bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects has been reported to be close to 100%, the absolute bioavailability of mecasermin given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined. •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): 0.257 ± 0.073 L/kg [subjects with severe Primary IGFD] at a dose of 0.045mg/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. •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): Information on the metabolism of Mecasermin is not readily available, however it is likely to be metabolized by the liver and kidney like other injectable peptide drugs. •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): Information on the elimination of Mecasermin is not readily available, however it is likely to be metabolized by the liver and kidney like other injectable peptide drugs. •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 life of 5.8 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of Mecasermin is inversely proportional to IGF binding protein 3 (IGFBP-3) * Clearance is estimated to be 0.04L/hr/kg at 0.5 micrograms/mL of IGFBP-3 * Clearance is estimated to be 0.01L/hr/kg at 3 micrograms/mL of IGFBP-3 (the median level of IGFBP-3 for patients with normal IGF-1 levels) •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 of Mecasermin leads to hypoglycemia. One case of acute overdose was treated with IV glucose. Long-term overdosage may result in signs and symptoms of acromegaly. The effects of Mecasermin in human pregnancy has not been studied, however effects on fetal development in animal studies were only seen at doses higher than the maximum recommended human dose based on body surface area. Studies on excretion of the drug in human milk, use in patients under 2 years, use in patients over 65 years, or use in patients with renal or hepatic impairment have not been performed. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Increlex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): INSULIN-LIKE GROWTH FACTOR 1 INSULIN-LIKE GROWTH FACTOR I (HUMAN) Mecasermin Mecasermin recombinant Mecasermina RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-I RH-OLIGOPEPTIDE-2 VEXXON-IGF-1 •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): Mecasermin is a recombinant insulin-like growth factor-1 used for the long-term treatment of growth failure in pediatric patients with primary IGF-1 deficiency or with growth hormone gene deletion due to the development of neutralizing antibodies to GH. 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 Mefloquine interact?

•Drug A: Buserelin •Drug B: Mefloquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Mefloquine 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): Mefloquine is indicated for the treatment of mild to moderate cases of malaria caused by Plasmodium falciparum and Plasmodium vivax. It is effective against chloroquine-resistant forms of Plasmodium falciparum. Mefloquine is also indicated for the prophylaxis of malaria caused by Plasmodium falciparum and Plasmodium vivax, including chloroquine-resistant forms of Plasmodium falciparum. •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): Sporozoites located in the salivary glands of mosquitoes infected with malaria parasites are introduced into the bloodstream of a human host during mosquito feeding. These sporozoites rapidly invade the liver, where they mature into liver-stage schizonts, rupturing and releasing 2,000 - 40,000 merozoites that invade red blood cells. Mefloquine is an antimalarial drug acting as a blood schizonticide, preventing and treating malaria. •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 mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects. There are other studies in the literature with limited in vitro data on mefloquine's mechanism of action. •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): Mefloquine is readily absorbed from the gastrointestinal tract; food significantly increases absorption and increases bioavailability by 40%. The bioavailability of tablets compared with the oral solution preparation of mefloquine is over 85%. Cmax is achieved in 6 to 24 hours in healthy volunteers after a single dose. Average blood concentrations range between 50 to 110 ng/ml/mg/kg. A weekly dose of 250 mg leads to steady-state plasma concentrations of 1000 to 2000 μg/L, after 7 to 10 weeks of 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): The apparent volume of distribution is in healthy adults is about 20 L/kg with wide tissue distribution. Various estimates of the total apparent volume of distribution range from 13.3 to 40.9L/kg. Mefloquine can accumulate in erythrocytes that have been infected with malaria parasites. •Protein binding (Drug A): 15% •Protein binding (Drug B): The binding of mefloquine to plasma proteins is over 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): Mefloquine is heavily metabolized in the liver by the CYP3A4 enzyme. Two metabolites have been identified; the main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, which inactive against plasmodium falciparum. The second metabolite, an alcohol, is found in small quantities. •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): Mefloquine is believed to be excreted in the bile and feces. In healthy volunteers who have achieved steady-state concentrations of mefloquine, the unchanged drug was excreted at 9% of the ingested dose, and excretion of its carboxylic metabolite under was measured at 4% of the ingested dose. Concentrations of other metabolites could not be determined. •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 mefloquine ranges from 0.9 - 13.8 days, according to one pharmacokinetic review. In various studies of healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with a mean half-life of approximately 21 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The systemic clearance of mefloquine ranges from 0.022 to 0.073 L/h/kg, with an increased clearance during pregnancy. Prescribing information mentions a clearance rate of 30 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): The oral TDLO of mefloquine in humans is 11 mg/kg/2W (intermittent) and 880 mg/kg in the rat. Intraperitoneal LD50 in the rat is 130 mg/kg. Symptoms of an overdose with mefloquine may manifest as a worsening of adverse effects. In the case of an overdose, symptomatic and supportive care should be provided. There is no known antidote for an overdose with mefloquine. Monitor cardiac function by ECG, follow neuropsychiatric status for at least 24 hours, and provide treatment as required. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Mefloquin Mefloquina Méfloquine Mefloquine Mefloquinum •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): Mefloquine is an antimalarial agent used in the prophylaxis and treatment of malaria caused by Plasmodium falciparum and Plasmodium vivax.

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 Mefloquine interact? Information: •Drug A: Buserelin •Drug B: Mefloquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Mefloquine 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): Mefloquine is indicated for the treatment of mild to moderate cases of malaria caused by Plasmodium falciparum and Plasmodium vivax. It is effective against chloroquine-resistant forms of Plasmodium falciparum. Mefloquine is also indicated for the prophylaxis of malaria caused by Plasmodium falciparum and Plasmodium vivax, including chloroquine-resistant forms of Plasmodium falciparum. •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): Sporozoites located in the salivary glands of mosquitoes infected with malaria parasites are introduced into the bloodstream of a human host during mosquito feeding. These sporozoites rapidly invade the liver, where they mature into liver-stage schizonts, rupturing and releasing 2,000 - 40,000 merozoites that invade red blood cells. Mefloquine is an antimalarial drug acting as a blood schizonticide, preventing and treating malaria. •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 mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects. There are other studies in the literature with limited in vitro data on mefloquine's mechanism of action. •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): Mefloquine is readily absorbed from the gastrointestinal tract; food significantly increases absorption and increases bioavailability by 40%. The bioavailability of tablets compared with the oral solution preparation of mefloquine is over 85%. Cmax is achieved in 6 to 24 hours in healthy volunteers after a single dose. Average blood concentrations range between 50 to 110 ng/ml/mg/kg. A weekly dose of 250 mg leads to steady-state plasma concentrations of 1000 to 2000 μg/L, after 7 to 10 weeks of 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): The apparent volume of distribution is in healthy adults is about 20 L/kg with wide tissue distribution. Various estimates of the total apparent volume of distribution range from 13.3 to 40.9L/kg. Mefloquine can accumulate in erythrocytes that have been infected with malaria parasites. •Protein binding (Drug A): 15% •Protein binding (Drug B): The binding of mefloquine to plasma proteins is over 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): Mefloquine is heavily metabolized in the liver by the CYP3A4 enzyme. Two metabolites have been identified; the main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, which inactive against plasmodium falciparum. The second metabolite, an alcohol, is found in small quantities. •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): Mefloquine is believed to be excreted in the bile and feces. In healthy volunteers who have achieved steady-state concentrations of mefloquine, the unchanged drug was excreted at 9% of the ingested dose, and excretion of its carboxylic metabolite under was measured at 4% of the ingested dose. Concentrations of other metabolites could not be determined. •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 mefloquine ranges from 0.9 - 13.8 days, according to one pharmacokinetic review. In various studies of healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with a mean half-life of approximately 21 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The systemic clearance of mefloquine ranges from 0.022 to 0.073 L/h/kg, with an increased clearance during pregnancy. Prescribing information mentions a clearance rate of 30 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): The oral TDLO of mefloquine in humans is 11 mg/kg/2W (intermittent) and 880 mg/kg in the rat. Intraperitoneal LD50 in the rat is 130 mg/kg. Symptoms of an overdose with mefloquine may manifest as a worsening of adverse effects. In the case of an overdose, symptomatic and supportive care should be provided. There is no known antidote for an overdose with mefloquine. Monitor cardiac function by ECG, follow neuropsychiatric status for at least 24 hours, and provide treatment as required. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Mefloquin Mefloquina Méfloquine Mefloquine Mefloquinum •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): Mefloquine is an antimalarial agent used in the prophylaxis and treatment of malaria caused by Plasmodium falciparum and Plasmodium vivax. 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 Meloxicam interact?

•Drug A: Buserelin •Drug B: Meloxicam •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Meloxicam. •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): Meloxicam is indicated for the symptomatic treatment of arthritis and osteoarthritis. In addition, it is indicated for the pauciarticular and polyarticular course of Juvenile Rheumatoid Arthritis (JRA) in patients aged 2 years old or above. Off-label uses include the treatment of dental or post-surgical pain. In addition to the above, meloxicam has also been studied in the treatment of neuropathic pain. Meloxicam, in combination with bupivacaine, 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. •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): Meloxicam is an anti-inflammatory, analgesic analgesic with antipyretic effects in fever. Prostaglandins are substances that contribute to inflammation. This drug also exerts preferential actions against COX-2, which may reduce the possible gastrointestinal effects of this drug. In humans, meloxicam has demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP), as well as aquaporin-1 expression. As with other NSAIDS, prolonged use of meloxicum can result in renal or cardiovascular impairment or thrombotic cardiovascular events. A note on gastrointestinal effects As meloxicam preferentially inhibits COX-2, it is thought to cause less gastrointestinal irritation compared to other NSAIDS. Despite this, it still carries a risk of gastric inflammation, bleeding and ulceration. In one study, patients on meloxicam suffered from gastrointestinal symptoms at a rate of 13% compared to 19% of those on diclofenac. GI events were found to be less severe in the meloxicam-treated 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): Meloxicam inhibits prostaglandin synthetase (cylooxygenase 1 and 2) enzymes leading to a decreased synthesis of prostaglandins, which normally mediate painful inflammatory symptoms. As prostaglandins sensitize neuronal pain receptors, inhibition of their synthesis leads to analgesic and inflammatory effects. Meloxicam preferentially inhibits COX-2, but also exerts some activity against COX-1, causing gastrointestinal irritation. •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 absolute bioavailability oral capsules after a dose was 89% in one pharmacokinetic study. Cmax was reached 5–6 hours after administration of a single dose given after the first meal of the day. The Cmax doubled when the drug was administered in the fasting state. Despite this, meloxicam can be taken without regard to food, unlike many other NSAIDS. Meloxicam formulated for instillation with bupivacaine produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 1.8 mg of meloxicam produced a C max of 26 ± 14 ng/mL, a median T max of 18 h, and an AUC ∞ of 2079 ± 1631 ng*h/mL. For a 9 mg dose used in herniorrhaphy, the corresponding values were 225 ± 96 ng/mL, 54 h, and the AUC ∞ was not reported. Lastly, a 12 mg dose used in total knee arthroplasty produced values of 275 ± 134 ng/mL, 36 h, and 25,673 ± 17,666 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): The volume of distribution of meloxicam is 10-15L. Because of its high binding to albumin, it is likely to be distributed in highly perfused tissues, such as the liver and kidney. Meloxicam concentrations in synovial fluid, measured after an oral dose, is estimated at 40% to 50% of the concentrations measured in the plasma. This drug is known to cross the placenta in humans. •Protein binding (Drug A): 15% •Protein binding (Drug B): Meloxicam is about 99.4% protein bound, 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): Meloxicam is almost completely metabolized. CYP2C9 is the main enzyme responsible for the metabolism of meloxicam with minor contributions from CYP3A4. Meloxicam has 4 major metabolites with no activity determined. About 60% of the ingested dose is metabolized to 5'-carboxy meloxicam from hepatic cytochrome enzyme oxidation of an intermediate metabolite, 5’-hydroxymethylmeloxicam. Two other metabolites are likely produced via peroxidation. •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): Meloxicam is mainly eliminated through metabolism. Its metabolites are cleared through renal and fecal elimination. Less than <0.25% of a dose is eliminated in the urine as unchanged drug. About 1.6% of the parent drug is excreted 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 half-life of meloxicam is approximately 20 hours, which is considerably longer than most other NSAIDS. It can therefore be dosed without the need for slow-release formulations. Meloxicam applied together with bupivacaine for postsurgical analgesia had a median half-life of 33-42 hours, depending on dose and application site. •Clearance (Drug A): No clearance available •Clearance (Drug B): After an oral dose, the total clearance of meloxicam is 0.42–0.48 L/h. The FDA label indicates a plasma clearance from 7 to 9 mL/min. No dose changes are required in mild to moderate renal or hepatic impairment. The use of meloxicam in patients with severe renal or hepatic impairment has not been studied. FDA prescribing information advises against it. •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 in rats is 98 mg/kg. Signs and symptoms of overdose with meloxicam may include shallow breathing, seizure, decreased urine output, gastrointestinal irritation, nausea, vomiting, gastrointestinal bleeding, and black tarry stools. In the case of an overdose, offer supportive treatment and attempt to remove gastrointestinal contents. Cholestyramine has been shown to enhance the elimination of meloxicam. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anjeso, Mobic, Qmiiz, Vivlodex, Zynrelef •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): Meloxicam is an NSAID used to treat osteoarthritis in adults, rheumatoid arthritis in adults, and juvenile rheumatoid arthritis in pediatrics.

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 Meloxicam interact? Information: •Drug A: Buserelin •Drug B: Meloxicam •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Meloxicam. •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): Meloxicam is indicated for the symptomatic treatment of arthritis and osteoarthritis. In addition, it is indicated for the pauciarticular and polyarticular course of Juvenile Rheumatoid Arthritis (JRA) in patients aged 2 years old or above. Off-label uses include the treatment of dental or post-surgical pain. In addition to the above, meloxicam has also been studied in the treatment of neuropathic pain. Meloxicam, in combination with bupivacaine, 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. •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): Meloxicam is an anti-inflammatory, analgesic analgesic with antipyretic effects in fever. Prostaglandins are substances that contribute to inflammation. This drug also exerts preferential actions against COX-2, which may reduce the possible gastrointestinal effects of this drug. In humans, meloxicam has demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP), as well as aquaporin-1 expression. As with other NSAIDS, prolonged use of meloxicum can result in renal or cardiovascular impairment or thrombotic cardiovascular events. A note on gastrointestinal effects As meloxicam preferentially inhibits COX-2, it is thought to cause less gastrointestinal irritation compared to other NSAIDS. Despite this, it still carries a risk of gastric inflammation, bleeding and ulceration. In one study, patients on meloxicam suffered from gastrointestinal symptoms at a rate of 13% compared to 19% of those on diclofenac. GI events were found to be less severe in the meloxicam-treated 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): Meloxicam inhibits prostaglandin synthetase (cylooxygenase 1 and 2) enzymes leading to a decreased synthesis of prostaglandins, which normally mediate painful inflammatory symptoms. As prostaglandins sensitize neuronal pain receptors, inhibition of their synthesis leads to analgesic and inflammatory effects. Meloxicam preferentially inhibits COX-2, but also exerts some activity against COX-1, causing gastrointestinal irritation. •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 absolute bioavailability oral capsules after a dose was 89% in one pharmacokinetic study. Cmax was reached 5–6 hours after administration of a single dose given after the first meal of the day. The Cmax doubled when the drug was administered in the fasting state. Despite this, meloxicam can be taken without regard to food, unlike many other NSAIDS. Meloxicam formulated for instillation with bupivacaine produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 1.8 mg of meloxicam produced a C max of 26 ± 14 ng/mL, a median T max of 18 h, and an AUC ∞ of 2079 ± 1631 ng*h/mL. For a 9 mg dose used in herniorrhaphy, the corresponding values were 225 ± 96 ng/mL, 54 h, and the AUC ∞ was not reported. Lastly, a 12 mg dose used in total knee arthroplasty produced values of 275 ± 134 ng/mL, 36 h, and 25,673 ± 17,666 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): The volume of distribution of meloxicam is 10-15L. Because of its high binding to albumin, it is likely to be distributed in highly perfused tissues, such as the liver and kidney. Meloxicam concentrations in synovial fluid, measured after an oral dose, is estimated at 40% to 50% of the concentrations measured in the plasma. This drug is known to cross the placenta in humans. •Protein binding (Drug A): 15% •Protein binding (Drug B): Meloxicam is about 99.4% protein bound, 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): Meloxicam is almost completely metabolized. CYP2C9 is the main enzyme responsible for the metabolism of meloxicam with minor contributions from CYP3A4. Meloxicam has 4 major metabolites with no activity determined. About 60% of the ingested dose is metabolized to 5'-carboxy meloxicam from hepatic cytochrome enzyme oxidation of an intermediate metabolite, 5’-hydroxymethylmeloxicam. Two other metabolites are likely produced via peroxidation. •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): Meloxicam is mainly eliminated through metabolism. Its metabolites are cleared through renal and fecal elimination. Less than <0.25% of a dose is eliminated in the urine as unchanged drug. About 1.6% of the parent drug is excreted 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 half-life of meloxicam is approximately 20 hours, which is considerably longer than most other NSAIDS. It can therefore be dosed without the need for slow-release formulations. Meloxicam applied together with bupivacaine for postsurgical analgesia had a median half-life of 33-42 hours, depending on dose and application site. •Clearance (Drug A): No clearance available •Clearance (Drug B): After an oral dose, the total clearance of meloxicam is 0.42–0.48 L/h. The FDA label indicates a plasma clearance from 7 to 9 mL/min. No dose changes are required in mild to moderate renal or hepatic impairment. The use of meloxicam in patients with severe renal or hepatic impairment has not been studied. FDA prescribing information advises against it. •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 in rats is 98 mg/kg. Signs and symptoms of overdose with meloxicam may include shallow breathing, seizure, decreased urine output, gastrointestinal irritation, nausea, vomiting, gastrointestinal bleeding, and black tarry stools. In the case of an overdose, offer supportive treatment and attempt to remove gastrointestinal contents. Cholestyramine has been shown to enhance the elimination of meloxicam. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Anjeso, Mobic, Qmiiz, Vivlodex, Zynrelef •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): Meloxicam is an NSAID used to treat osteoarthritis in adults, rheumatoid arthritis in adults, and juvenile rheumatoid arthritis in pediatrics. 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 Mepivacaine interact?

•Drug A: Buserelin •Drug B: Mepivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Mepivacaine. •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 analgesia and anesthesia by local infiltration, peripheral nerve block techniques, and central neural techniques including epidural and caudal 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): Mepivicaine is an amide local anesthetic. Mepivicaine as a reasonably rapid onset and medium duration and is known by the proprietary names as Carbocaine and Polocaine. Mepivicaine is used in local infiltration and regional anesthesia. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. •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 the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. 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: pain, temperature, touch, proprioception, and 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): Absorbed locally. The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. •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): Mepivacaine is approximately 75% bound to plasma proteins. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to 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): Rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as 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): It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine.The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile 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 half-life of mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 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 mean seizure dosage of mepivacaine in rhesus monkeys was found to be 18.8 mg/kg with mean arterial plasma concentration of 24.4 µg/mL. The intravenous and subcutaneous LD 50 in mice is 23 mg/kg to 35 mg/kg and 280 mg/kg respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Carbocaine, Carbocaine With Neocobefrin, Isocaine, Isocaine With Levonordefrin, Polocaine, Scandonest, Scandonest L, Scandonest Plain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): DL-Mepivacaine Mepivacaina Mepivacaine Mepivacainum •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): Mepivacaine is a local anesthetic used for local or regional analgesia or 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 Mepivacaine interact? Information: •Drug A: Buserelin •Drug B: Mepivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Mepivacaine. •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 analgesia and anesthesia by local infiltration, peripheral nerve block techniques, and central neural techniques including epidural and caudal 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): Mepivicaine is an amide local anesthetic. Mepivicaine as a reasonably rapid onset and medium duration and is known by the proprietary names as Carbocaine and Polocaine. Mepivicaine is used in local infiltration and regional anesthesia. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. •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 the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. 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: pain, temperature, touch, proprioception, and 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): Absorbed locally. The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. •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): Mepivacaine is approximately 75% bound to plasma proteins. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to 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): Rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as 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): It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine.The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile 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 half-life of mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 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 mean seizure dosage of mepivacaine in rhesus monkeys was found to be 18.8 mg/kg with mean arterial plasma concentration of 24.4 µg/mL. The intravenous and subcutaneous LD 50 in mice is 23 mg/kg to 35 mg/kg and 280 mg/kg respectively. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Carbocaine, Carbocaine With Neocobefrin, Isocaine, Isocaine With Levonordefrin, Polocaine, Scandonest, Scandonest L, Scandonest Plain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): DL-Mepivacaine Mepivacaina Mepivacaine Mepivacainum •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): Mepivacaine is a local anesthetic used for local or regional analgesia or 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 Mepyramine interact?

•Drug A: Buserelin •Drug B: Mepyramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Mepyramine 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 treatment of allergic conditions, symptomatic relief of hypersensitivity reaction, and treatment of pruritic skin 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): 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): Mepyramine is a histamine H1 receptor inverse agonist. It binds to a G protein-coupled form of the receptor and promotes a G protein-coupled inactive state of the H1 receptor that interferes with the Gq/11-mediated signaling. Mepyramine competes with histamine for binding at H 1 -receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The sedative properties of Mepyramine occur at the subcortical level of the CNS. •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): The signs and symptoms that are produced after the acute overdosage of Mepyramine include Convulsions, Coma, Ataxia, Hyperpyrexia, Tremor, Extrapyramidal effects, Excitement. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Midol Complete, Midol Cramps & Bodyaches, Pamprin Multi-symptom, Premsyn Pms, Vanacof-8 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Mepiramina Mepyramine Pyranisamine Pyrilamine •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): Mepyramine is an antihistamine agent used for the symptomatic treatment of allergy, hypersensitivity reactions, and pruritic skin disorders.

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 Mepyramine interact? Information: •Drug A: Buserelin •Drug B: Mepyramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Mepyramine 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 treatment of allergic conditions, symptomatic relief of hypersensitivity reaction, and treatment of pruritic skin 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): 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): Mepyramine is a histamine H1 receptor inverse agonist. It binds to a G protein-coupled form of the receptor and promotes a G protein-coupled inactive state of the H1 receptor that interferes with the Gq/11-mediated signaling. Mepyramine competes with histamine for binding at H 1 -receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The sedative properties of Mepyramine occur at the subcortical level of the CNS. •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): The signs and symptoms that are produced after the acute overdosage of Mepyramine include Convulsions, Coma, Ataxia, Hyperpyrexia, Tremor, Extrapyramidal effects, Excitement. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Midol Complete, Midol Cramps & Bodyaches, Pamprin Multi-symptom, Premsyn Pms, Vanacof-8 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Mepiramina Mepyramine Pyranisamine Pyrilamine •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): Mepyramine is an antihistamine agent used for the symptomatic treatment of allergy, hypersensitivity reactions, and pruritic skin disorders. 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 Metformin interact?

•Drug A: Buserelin •Drug B: Metformin •Severity: MINOR •Description: The therapeutic efficacy of Metformin can be decreased when used in combination with Buserelin. •Extended Description: The subject drug is known to cause hyperglycemia as an off-target effect and can lead to loss of glycemic control. This may in turn counteract the glucose-lowering effects of metformin, which is an antidiabetic drug. However, the clinical relevance of this drug-drug interaction is unclear. •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): Metformin immediate-release formulations Metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years old with type 2 diabetes mellitus. Metformin extended-release tablet (XR) The extended-release formulation of metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Safety in children has not been determined to this date. Metformin combination products Metformin is a component of a variety of combination products with other anti-diabetic agents. It is indicated, along with diet and exercise, to improve glycemic control in adult patients with type 2 diabetes mellitus in combination with DPP-4 inhibitors ( sitagliptin, linagliptin, alogliptin, or saxagliptin ), in combination with SGLT2 inhibitors ( canagliflozin, empagliflozin, ertugliflozin, or dapagliflozin ), or in combination with pioglitazone. •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 Insulin is an important hormone that regulates blood glucose levels. Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin is unable to exert adequate effects on tissues and cells (i.e. insulin resistance) and insulin deficiency may also be present. Metformin reduces hepatic production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the sulfonylurea class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use. Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c) HbA1c is an important periodic measure of glycemic control used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo. Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only. •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): Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (also called gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control. After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting adenylate cyclase and decreasing the production of cyclic adenosine monophosphate (cAMP), a derivative of ATP used for cell signaling. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin. In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose. In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years. •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): Regular tablet absorption The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at <1 μg/mL. Extended-release tablet absorption After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar. Effect of food Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting. Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin. •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 (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Metformin is negligibly 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): Intravenous studies using a single dose of metformin in normal subjects show that metformin is excreted as unchanged drug in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. •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): This drug is substantially excreted by the kidney. Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion. •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 metformin is 6.2 hours in the plasma. The elimination half-life in the blood is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours. •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): Metformin (hydrochloride) toxicity data: Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg. A note on lactic acidosis Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis. There have been reported postmarketing cases of metformin-associated lactic acidosis, including some fatal cases. Such cases had a subtle onset and were accompanied by nonspecific symptoms including malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence. In certain cases, hypotension and resistant bradyarrhythmias have occurred with severe lactic acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), as well as an increased lactate:pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. A note on renal function In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased. Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels. A note on hypoglycemia When used alone, metformin does not cause hypoglycemia, however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin when they are used together. Use in pregnancy Available data from post-marketing studies have not indicated a clear association of metformin with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was ingested during pregnancy. Despite this, the abovementioned studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations, including small sample size and inconsistent study groups. Use in nursing A limited number of published studies indicate that metformin is present in human milk. There is insufficient information to confirm the effects of metformin on the nursing infant and no available data on the effects of metformin on the production of milk. The developmental and health benefits of breastfeeding should be considered as well as the mother’s clinical need for metformin and any possible adverse effects on the nursing child. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actoplus Met, Avandamet, Fortamet, Glucophage, Glucovance, Glumetza, Glycon, Invokamet, Janumet, Jentadueto, Kazano, Kombiglyze, Komboglyze, Qternmet, Riomet, Segluromet, Synjardy, Trijardy, Velmetia, Xigduo, Zituvimet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dimethylbiguanid Metformin Metformina Metformine Metforminum •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): Metformin is a biguanide antihyperglycemic used in conjunction with diet and exercise for glycemic control in type 2 diabetes mellitus. It is also used off-label for insulin resistance in polycystic ovary syndrome (PCOS).

The subject drug is known to cause hyperglycemia as an off-target effect and can lead to loss of glycemic control. This may in turn counteract the glucose-lowering effects of metformin, which is an antidiabetic drug. However, the clinical relevance of this drug-drug interaction is unclear. The severity of the interaction is minor.

Question: Does Buserelin and Metformin interact? Information: •Drug A: Buserelin •Drug B: Metformin •Severity: MINOR •Description: The therapeutic efficacy of Metformin can be decreased when used in combination with Buserelin. •Extended Description: The subject drug is known to cause hyperglycemia as an off-target effect and can lead to loss of glycemic control. This may in turn counteract the glucose-lowering effects of metformin, which is an antidiabetic drug. However, the clinical relevance of this drug-drug interaction is unclear. •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): Metformin immediate-release formulations Metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years old with type 2 diabetes mellitus. Metformin extended-release tablet (XR) The extended-release formulation of metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Safety in children has not been determined to this date. Metformin combination products Metformin is a component of a variety of combination products with other anti-diabetic agents. It is indicated, along with diet and exercise, to improve glycemic control in adult patients with type 2 diabetes mellitus in combination with DPP-4 inhibitors ( sitagliptin, linagliptin, alogliptin, or saxagliptin ), in combination with SGLT2 inhibitors ( canagliflozin, empagliflozin, ertugliflozin, or dapagliflozin ), or in combination with pioglitazone. •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 Insulin is an important hormone that regulates blood glucose levels. Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin is unable to exert adequate effects on tissues and cells (i.e. insulin resistance) and insulin deficiency may also be present. Metformin reduces hepatic production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the sulfonylurea class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use. Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c) HbA1c is an important periodic measure of glycemic control used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo. Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only. •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): Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (also called gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control. After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting adenylate cyclase and decreasing the production of cyclic adenosine monophosphate (cAMP), a derivative of ATP used for cell signaling. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin. In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose. In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years. •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): Regular tablet absorption The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at <1 μg/mL. Extended-release tablet absorption After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar. Effect of food Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting. Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin. •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 (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Metformin is negligibly 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): Intravenous studies using a single dose of metformin in normal subjects show that metformin is excreted as unchanged drug in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. •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): This drug is substantially excreted by the kidney. Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion. •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 metformin is 6.2 hours in the plasma. The elimination half-life in the blood is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours. •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): Metformin (hydrochloride) toxicity data: Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg. A note on lactic acidosis Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis. There have been reported postmarketing cases of metformin-associated lactic acidosis, including some fatal cases. Such cases had a subtle onset and were accompanied by nonspecific symptoms including malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence. In certain cases, hypotension and resistant bradyarrhythmias have occurred with severe lactic acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), as well as an increased lactate:pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. A note on renal function In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased. Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels. A note on hypoglycemia When used alone, metformin does not cause hypoglycemia, however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin when they are used together. Use in pregnancy Available data from post-marketing studies have not indicated a clear association of metformin with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was ingested during pregnancy. Despite this, the abovementioned studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations, including small sample size and inconsistent study groups. Use in nursing A limited number of published studies indicate that metformin is present in human milk. There is insufficient information to confirm the effects of metformin on the nursing infant and no available data on the effects of metformin on the production of milk. The developmental and health benefits of breastfeeding should be considered as well as the mother’s clinical need for metformin and any possible adverse effects on the nursing child. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actoplus Met, Avandamet, Fortamet, Glucophage, Glucovance, Glumetza, Glycon, Invokamet, Janumet, Jentadueto, Kazano, Kombiglyze, Komboglyze, Qternmet, Riomet, Segluromet, Synjardy, Trijardy, Velmetia, Xigduo, Zituvimet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dimethylbiguanid Metformin Metformina Metformine Metforminum •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): Metformin is a biguanide antihyperglycemic used in conjunction with diet and exercise for glycemic control in type 2 diabetes mellitus. It is also used off-label for insulin resistance in polycystic ovary syndrome (PCOS). Output: The subject drug is known to cause hyperglycemia as an off-target effect and can lead to loss of glycemic control. This may in turn counteract the glucose-lowering effects of metformin, which is an antidiabetic drug. However, the clinical relevance of this drug-drug interaction is unclear. The severity of the interaction is minor.

Does Buserelin and Methadone interact?

•Drug A: Buserelin •Drug B: Methadone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Methadone. •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): Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Methadone is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services. •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): Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction. Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures. Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone. Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine. Dependence and Tolerance As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Cardiac Conduction Effects Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. Respiratory Depression and Overdose Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Incomplete Cross-tolerance between Methadone and other Opioids Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making the determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to morphine. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). Gastrointestinal Effects Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Sexual Function/Reproduction Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility. •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): Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from morphine (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity. Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer. The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects. While methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. •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): Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known. Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility. Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function. There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study. •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): Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L with monographs listing it between 1.0-8.0L/kg. As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone. Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels. •Protein binding (Drug A): 15% •Protein binding (Drug B): Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the 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): Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive. The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference. Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone]/[EDDP]. The SNPs CYP2B6*6, *9, *11, CYP2C19*2, *3, CYP3A4*1B, and CYP3A5*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6*6/*6 demonstrate diminished metabolism and clearance of methadone. See the pharmacogenomics section for further information. Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval. •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 methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. •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): Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours with official monographs listing it between 7-59 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours with approved monographs listing it between 1.4 to 126 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 severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diskets, Dolophine, Metadol, Metadol-D, Methadose •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metadona Methadone Methadonum •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): Methadone is an opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction.

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 Methadone interact? Information: •Drug A: Buserelin •Drug B: Methadone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Methadone. •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): Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Methadone is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services. •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): Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction. Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures. Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone. Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine. Dependence and Tolerance As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Cardiac Conduction Effects Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. Respiratory Depression and Overdose Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Incomplete Cross-tolerance between Methadone and other Opioids Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making the determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to morphine. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). Gastrointestinal Effects Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Sexual Function/Reproduction Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility. •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): Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from morphine (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity. Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer. The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects. While methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. •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): Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known. Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility. Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function. There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study. •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): Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L with monographs listing it between 1.0-8.0L/kg. As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone. Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels. •Protein binding (Drug A): 15% •Protein binding (Drug B): Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the 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): Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive. The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference. Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone]/[EDDP]. The SNPs CYP2B6*6, *9, *11, CYP2C19*2, *3, CYP3A4*1B, and CYP3A5*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6*6/*6 demonstrate diminished metabolism and clearance of methadone. See the pharmacogenomics section for further information. Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval. •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 methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. •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): Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours with official monographs listing it between 7-59 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours with approved monographs listing it between 1.4 to 126 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 severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diskets, Dolophine, Metadol, Metadol-D, Methadose •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metadona Methadone Methadonum •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): Methadone is an opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction. 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 Methotrimeprazine interact?

•Drug A: Buserelin •Drug B: Methotrimeprazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Methotrimeprazine 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 psychosis, particular those of schizophrenia, and manic phases of bipolar 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): Methotrimeprazine is a phenothiazine with pharmacological activity similar to that of both chlorpromazine and promethazine. It has the histamine-antagonist properties of the antihistamines together with central nervous system effects resembling those of chlorpromazine. (From Martindale, The Extra Pharmacopoeia, 30th ed, p604) •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): Methotrimeprazine's antipsychotic effect is largely due to its antagonism of dopamine receptors in the brain. In addition, its binding to 5HT2 receptors may also play a role. •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): Methotrimeprazine has an incomplete oral bioavailability, because it undergoes considerable first-pass-metabolism in the liver. Oral bioavailability is approximately 50 to 60%. •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. Methotrimeprazine is metabolized in the liver and degraded to a sulfoxid-, a glucuronid- and a demethyl-moiety. •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): Approximately 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): Symptoms of overdose include convulsions, spastic movements, and coma. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nozinan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Methoxytrimeprazine Levomepromazina Levomepromazine Lévomépromazine Levomepromazinum Methotrimeprazine •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): Methotrimeprazine is a phenothiazine used in the management of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder.

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 Methotrimeprazine interact? Information: •Drug A: Buserelin •Drug B: Methotrimeprazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Methotrimeprazine 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 psychosis, particular those of schizophrenia, and manic phases of bipolar 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): Methotrimeprazine is a phenothiazine with pharmacological activity similar to that of both chlorpromazine and promethazine. It has the histamine-antagonist properties of the antihistamines together with central nervous system effects resembling those of chlorpromazine. (From Martindale, The Extra Pharmacopoeia, 30th ed, p604) •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): Methotrimeprazine's antipsychotic effect is largely due to its antagonism of dopamine receptors in the brain. In addition, its binding to 5HT2 receptors may also play a role. •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): Methotrimeprazine has an incomplete oral bioavailability, because it undergoes considerable first-pass-metabolism in the liver. Oral bioavailability is approximately 50 to 60%. •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. Methotrimeprazine is metabolized in the liver and degraded to a sulfoxid-, a glucuronid- and a demethyl-moiety. •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): Approximately 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): Symptoms of overdose include convulsions, spastic movements, and coma. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nozinan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Methoxytrimeprazine Levomepromazina Levomepromazine Lévomépromazine Levomepromazinum Methotrimeprazine •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): Methotrimeprazine is a phenothiazine used in the management of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder. 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 Methoxy polyethylene glycol-epoetin beta interact?

•Drug A: Buserelin •Drug B: Methoxy polyethylene glycol-epoetin beta •Severity: MODERATE •Description: The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta 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 patients with anaemia associated with chronic kidney disease. Not a substitute for RBC transfusion if immediate correction of anemia is required. •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): Stimulates hemoglobin production by stimulating the erythropoetin receptor of erythroid progenitor cells in the bone marrow. Hemoglobin increase, following a single initial dose, occurs 7 to 15 days after. •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): Erythropoietin is a growth factor for erythroid development. It is produced in the kidney and released into the bloodstream in response to hypoxia, interacting with erythroid progenitor cells to increase red blood cell production. Production of endogenous erythropoietin is impaired in patients with chronic kidney disease (CKD), and erythropoietin deficiency is the primary cause of their anaemia. Administration of methoxy polyethylene glycol-epoetin beta acts like endogenous erythropoetin and stimulates erythropoetin receptor of the erythroid progenitor cells in the bone marrow. •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): Administered parenterally (subcutaneous or IV) therefore not 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): ~94.74 ml/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): No 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): Not metabolized. •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): Undergoes proteolysis at erythropoietin receptor •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 CKD patients on peritoneal dialysis with IV administration: 134 ± 65 hours In CKD patients on peritoneal dialysis with SC administration: 139 ± 67 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): In CKD patients on peritoneal dialysis: 0.49 ± 0.18 mL/hr/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): Overdosage can cause severe hypertension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Mircera •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): Methoxy polyethylene glycol-epoetin beta is a synthetic erythropoiesis stimulating agent (ESA) used to treat anemia associated with chronic kidney disease.

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 Methoxy polyethylene glycol-epoetin beta interact? Information: •Drug A: Buserelin •Drug B: Methoxy polyethylene glycol-epoetin beta •Severity: MODERATE •Description: The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta 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 patients with anaemia associated with chronic kidney disease. Not a substitute for RBC transfusion if immediate correction of anemia is required. •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): Stimulates hemoglobin production by stimulating the erythropoetin receptor of erythroid progenitor cells in the bone marrow. Hemoglobin increase, following a single initial dose, occurs 7 to 15 days after. •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): Erythropoietin is a growth factor for erythroid development. It is produced in the kidney and released into the bloodstream in response to hypoxia, interacting with erythroid progenitor cells to increase red blood cell production. Production of endogenous erythropoietin is impaired in patients with chronic kidney disease (CKD), and erythropoietin deficiency is the primary cause of their anaemia. Administration of methoxy polyethylene glycol-epoetin beta acts like endogenous erythropoetin and stimulates erythropoetin receptor of the erythroid progenitor cells in the bone marrow. •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): Administered parenterally (subcutaneous or IV) therefore not 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): ~94.74 ml/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): No 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): Not metabolized. •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): Undergoes proteolysis at erythropoietin receptor •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 CKD patients on peritoneal dialysis with IV administration: 134 ± 65 hours In CKD patients on peritoneal dialysis with SC administration: 139 ± 67 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): In CKD patients on peritoneal dialysis: 0.49 ± 0.18 mL/hr/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): Overdosage can cause severe hypertension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Mircera •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): Methoxy polyethylene glycol-epoetin beta is a synthetic erythropoiesis stimulating agent (ESA) used to treat anemia associated with chronic kidney disease. 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 Methsuximide interact?

•Drug A: Buserelin •Drug B: Methsuximide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Methsuximide 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 control of absence (petit mal) seizures that are refractory to other drugs. •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): Used in the treatment of epilepsy. Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. •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): Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. •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): 1.4-2.6 hours for mesuximide and 28-38 hours for the active metabolite. •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 overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. Levels greater than 40 µg/mL have caused toxicity and coma has been seen at levels of 150 µg/mL. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Celontin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): alpha-Methylphensuximide Mesuximida Mesuximide Mesuximidum Methsuximid Methsuximide Metosuccimmide •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): Methsuximide is a succinimide anticonvulsant that increases the seizure threshold. Primarily used for childhood absence seizures. Functions by suppressing paroxysmal spike-and-wave patterns associated with lapses of consciousness in absence seizures.

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 Methsuximide interact? Information: •Drug A: Buserelin •Drug B: Methsuximide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Methsuximide 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 control of absence (petit mal) seizures that are refractory to other drugs. •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): Used in the treatment of epilepsy. Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. •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): Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. •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): 1.4-2.6 hours for mesuximide and 28-38 hours for the active metabolite. •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 overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. Levels greater than 40 µg/mL have caused toxicity and coma has been seen at levels of 150 µg/mL. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Celontin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): alpha-Methylphensuximide Mesuximida Mesuximide Mesuximidum Methsuximid Methsuximide Metosuccimmide •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): Methsuximide is a succinimide anticonvulsant that increases the seizure threshold. Primarily used for childhood absence seizures. Functions by suppressing paroxysmal spike-and-wave patterns associated with lapses of consciousness in absence seizures. 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 Metoclopramide interact?

•Drug A: Buserelin •Drug B: Metoclopramide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Metoclopramide 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): Metoclopramide in the oral tablet form is used for symptomatic treatment of both acute and recurrent diabetic gastroparesis, in addition to the treatment of gastroesophageal reflux disease (GERD) in patients who have failed to respond to traditional therapy. A nasal spray formulation is also indicated to treat adults with acute, recurrent diabetic gastroparesis. In the intravenous injection form, it is indicated for the above conditions as well as for the prevention of vomiting that may follow emetogenic chemotherapy or nausea and vomiting after surgery. Intravenous metoclopramide facilitates intubation of the small bowel and stimulates gastric emptying and barium flow in patients who require radiological examination of the stomach or small intestine. In some cases, the delay of gastrointestinal emptying interferes with the radiographic visualization of the gastrointestinal tract, and metoclopramide is used to facilitate emptying in these cases, allowing for adequate diagnostic visualization. Some off-label uses of metoclopramide include the management of radiation-induced nausea and vomiting, gastric bezoars, intractable hiccups, and migraine 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): Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure. It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting. In addition, this drug increases gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions. Because of its antidopaminergic activity, metoclopramide can cause symptoms of tardive dyskinesia (TD), dystonia, and akathisia, and should therefore not be administered for longer than 12 weeks. •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): Metoclopramide causes antiemetic effects by inhibiting dopamine D2 and serotonin 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) located in the area postrema of the brain. Administration of this drug leads to prokinetic effects via inhibitory actions on presynaptic and postsynaptic D2 receptors, agonism of serotonin 5-HT4 receptors, and antagonism of muscarinic receptor inhibition. This action enhances the release of acetylcholine, causing increased lower esophageal sphincter (LES) and gastric tone, accelerating gastric emptying and transit through the gut. Metoclopramide antagonizes the dopamine D2 receptors. Dopamine exerts relaxant effect on the gastrointestinal tract through binding to muscular D2 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): Metoclopramide is rapidly absorbed in the gastrointestinal tract with an absorption rate of about 84%. The bioavailability of the oral preparation is reported to be about 40.7%, but can range from 30-100%. Nasal metoclopramide is 47% bioavailable. A 15mg dose reaches a C max of 41.0 ng/mL, with a T max of 1.25 h, and an AUC of 367 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): The volume of distribution of metoclopramide is approximately 3.5 L/kg. This implies a high level of tissue distribution. Metoclopramide crosses the placental barrier and can cause extrapyramidal symptoms in the fetus. •Protein binding (Drug A): 15% •Protein binding (Drug B): Metoclopramide is 30% bound to plasma proteins, mainly to 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): Metoclopramide undergoes first-pass metabolism and its metabolism varies according to the individual. This drug is metabolized by cytochrome P450 enzymes in the liver. CYP2D6 and CYP3A4 both contribute to its metabolism, with CYP2D6 being more heavily involved. CYP1A2 is also a minor contributing enzyme. The process of N-4 sulphate conjugation is a primary metabolic pathway of metoclopramide. •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): About 85% of an orally administered dose was measured in the urine within 72 hours during a pharmacokinetic study. An average of 18% to 22% of 10-20 mg dose was recovered as free drug within 3 days of administration. •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 metoclopramide in people with healthy renal function ranges from 5 to 6 hours but is prolonged in patients with renal impairment. Downward dose adjustment should be considered. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of metoclopramide is 0.16 L/h/kg with a total clearance of 0.7 L/h/kg. Clinical studies showed that the clearance of metoclopramide may be reduced by up to 50% in patients with renal impairment. After high intravenous doses, total metoclopramide clearance ranged from 0.31 to 0.69 L/kg/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 rat oral LD50 of metoclopramide is 750 mg/kg. Some symptoms of an overdose with metoclopramide include drowsiness, disorientation, and extrapyramidal reactions. Drugs that manage Parkinson's disease or anticholinergic drugs or antihistamines with anticholinergic properties should be employed to treat extrapyramidal symptoms. Normally, these symptoms subside within 24 hours. Unintentional overdose in infants receiving the oral solution of metoclopramide resulted in seizures, extrapyramidal symptoms, in addition to a lethargic state. In addition, methemoglobinemia has been found to occur in premature and full-term neonates after a metoclopramide overdose. Intravenous methylene blue may treat metoclopramide-associated methemoglobinemia. It is important to note that methylene blue administration may lead to hemolytic anemia in patients who suffer from G6PD deficiency, which can result in fatality. Dialysis has not been shown to be effective in sufficiently eliminating metoclopramide in an overdose situation due to low plasma distribution of this drug. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Gimoti, Reglan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metoclopramida Metoclopramide Metoclopramidum •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): Metoclopramide is an antiemetic agent and dopamine D2 antagonist used in the treatment of gastroesophageal reflux disease, prevention of nausea and vomiting, and to stimulate gastric emptying.

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 Metoclopramide interact? Information: •Drug A: Buserelin •Drug B: Metoclopramide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Metoclopramide 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): Metoclopramide in the oral tablet form is used for symptomatic treatment of both acute and recurrent diabetic gastroparesis, in addition to the treatment of gastroesophageal reflux disease (GERD) in patients who have failed to respond to traditional therapy. A nasal spray formulation is also indicated to treat adults with acute, recurrent diabetic gastroparesis. In the intravenous injection form, it is indicated for the above conditions as well as for the prevention of vomiting that may follow emetogenic chemotherapy or nausea and vomiting after surgery. Intravenous metoclopramide facilitates intubation of the small bowel and stimulates gastric emptying and barium flow in patients who require radiological examination of the stomach or small intestine. In some cases, the delay of gastrointestinal emptying interferes with the radiographic visualization of the gastrointestinal tract, and metoclopramide is used to facilitate emptying in these cases, allowing for adequate diagnostic visualization. Some off-label uses of metoclopramide include the management of radiation-induced nausea and vomiting, gastric bezoars, intractable hiccups, and migraine 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): Metoclopramide increases gastric emptying by decreasing lower esophageal sphincter (LES) pressure. It also exerts effects on the area postrema of the brain, preventing and relieving the symptoms of nausea and vomiting. In addition, this drug increases gastrointestinal motility without increasing biliary, gastric, or pancreatic secretions. Because of its antidopaminergic activity, metoclopramide can cause symptoms of tardive dyskinesia (TD), dystonia, and akathisia, and should therefore not be administered for longer than 12 weeks. •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): Metoclopramide causes antiemetic effects by inhibiting dopamine D2 and serotonin 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) located in the area postrema of the brain. Administration of this drug leads to prokinetic effects via inhibitory actions on presynaptic and postsynaptic D2 receptors, agonism of serotonin 5-HT4 receptors, and antagonism of muscarinic receptor inhibition. This action enhances the release of acetylcholine, causing increased lower esophageal sphincter (LES) and gastric tone, accelerating gastric emptying and transit through the gut. Metoclopramide antagonizes the dopamine D2 receptors. Dopamine exerts relaxant effect on the gastrointestinal tract through binding to muscular D2 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): Metoclopramide is rapidly absorbed in the gastrointestinal tract with an absorption rate of about 84%. The bioavailability of the oral preparation is reported to be about 40.7%, but can range from 30-100%. Nasal metoclopramide is 47% bioavailable. A 15mg dose reaches a C max of 41.0 ng/mL, with a T max of 1.25 h, and an AUC of 367 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): The volume of distribution of metoclopramide is approximately 3.5 L/kg. This implies a high level of tissue distribution. Metoclopramide crosses the placental barrier and can cause extrapyramidal symptoms in the fetus. •Protein binding (Drug A): 15% •Protein binding (Drug B): Metoclopramide is 30% bound to plasma proteins, mainly to 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): Metoclopramide undergoes first-pass metabolism and its metabolism varies according to the individual. This drug is metabolized by cytochrome P450 enzymes in the liver. CYP2D6 and CYP3A4 both contribute to its metabolism, with CYP2D6 being more heavily involved. CYP1A2 is also a minor contributing enzyme. The process of N-4 sulphate conjugation is a primary metabolic pathway of metoclopramide. •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): About 85% of an orally administered dose was measured in the urine within 72 hours during a pharmacokinetic study. An average of 18% to 22% of 10-20 mg dose was recovered as free drug within 3 days of administration. •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 metoclopramide in people with healthy renal function ranges from 5 to 6 hours but is prolonged in patients with renal impairment. Downward dose adjustment should be considered. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of metoclopramide is 0.16 L/h/kg with a total clearance of 0.7 L/h/kg. Clinical studies showed that the clearance of metoclopramide may be reduced by up to 50% in patients with renal impairment. After high intravenous doses, total metoclopramide clearance ranged from 0.31 to 0.69 L/kg/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 rat oral LD50 of metoclopramide is 750 mg/kg. Some symptoms of an overdose with metoclopramide include drowsiness, disorientation, and extrapyramidal reactions. Drugs that manage Parkinson's disease or anticholinergic drugs or antihistamines with anticholinergic properties should be employed to treat extrapyramidal symptoms. Normally, these symptoms subside within 24 hours. Unintentional overdose in infants receiving the oral solution of metoclopramide resulted in seizures, extrapyramidal symptoms, in addition to a lethargic state. In addition, methemoglobinemia has been found to occur in premature and full-term neonates after a metoclopramide overdose. Intravenous methylene blue may treat metoclopramide-associated methemoglobinemia. It is important to note that methylene blue administration may lead to hemolytic anemia in patients who suffer from G6PD deficiency, which can result in fatality. Dialysis has not been shown to be effective in sufficiently eliminating metoclopramide in an overdose situation due to low plasma distribution of this drug. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Gimoti, Reglan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metoclopramida Metoclopramide Metoclopramidum •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): Metoclopramide is an antiemetic agent and dopamine D2 antagonist used in the treatment of gastroesophageal reflux disease, prevention of nausea and vomiting, and to stimulate gastric emptying. 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 Metronidazole interact?

•Drug A: Buserelin •Drug B: Metronidazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Metronidazole 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): Metronidazole is indicated for the treatment of confirmed trichomoniasis caused by Trichomonas vaginalis (except for in the first trimester of pregnancy) and the patient's sexual partners, bacterial vaginosis, certain types of amebiasis, and various anaerobic infections. The above anaerobic infections may occur on the skin and skin structures, the abdomen, the heart, reproductive organs, central nervous system, and the respiratory system. Some may also be present in the bloodstream in cases of septicemia. Common infections treated by metronidazole are Bacteroides species infections, Clostridium infections, and Fusobacterium infections, as well as Peptococcus and Peptostreptococcus infections. Topical formulations of metronidazole are indicated for the treatment of inflammatory lesions of rosacea. It is also used off-label in the treatment of Crohn's disease, as a prophylactic agent after surgery, and in the treatment of Helicobacter pylori infection. It has also been studied in the prevention of preterm births and to treat periodontal 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): Metronidazole treats amebiasis, trichomoniasis, and giardiasis, exerting both antibacterial and antiprotozoal activities. Metronidazole is an effective treatment for some anaerobic bacterial infections. Metronidazole has shown antibacterial activity against the majority of obligate anaerobes, however, during in vitro studies, it does not demonstrate significant action against facultative anaerobes or obligate aerobes. The nitro group reduction of metronidazole by anaerobic organisms is likely responsible for the drug's antimicrobial cytotoxic effects, causing DNA strand damage to microbes. A note on convulsions and neuropathy and carcinogenesis It is important to be aware of the risk of peripheral neuropathy and convulsions associated with metronidazole, especially at higher doses. If convulsions or numbness of an extremity occur, discontinue the drug immediately. Metronidazole has been found to be carcinogenic in mice and rats. The relevance to this effect in humans is unknown. It is advisable to only administer metronidazole when clinically necessary and only for its approved indications. •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 of action of metronidazole has not been fully established, however, it is possible that an intermediate in the reduction of metronidazole which is only made by anaerobic bacteria and protozoa, binds deoxyribonucleic acid and electron-transport proteins of organisms, blocking nucleic acid synthesis. After administration, metronidazole enters cells by passive diffusion. Following this, ferredoxin or flavodoxin reduce its nitro group to nitro radicals. The redox potential of the electron transport portions of anaerobic or microaerophilic microorganisms renders metronidazole selective to these organisms, which cause nitro group reduction, leading to the production of toxic metabolites. These include N-(2-hydroxyethyl) oxamic acid and acetamide, which may damage DNA of replicating organisms. •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 intravenous infusion of a 1.5g dose, peak concentration was reached within 1 hour and was peak level of 30-40 mg/L. When a multiple-dose regimen of 500mg three times a day administered intravenously, steady-state concentrations were achieved within about 3 days and peak concentration was measured at 26 mg/L. When administered orally in the tablet form, metronidazole is absorbed entirely absorbed, showing a bioavailability of greater than 90%. One resource indicates that Cmax after a single oral dose of 500mg metronidazole ranges from 8 to 13 mg/L, with a Tmax of 25 minutes to 4 hours. The AUC following a single 500mg oral dose of metronidazole was 122 ± 10.3 mg/L • h. A note on the absorption of topical preparations Insignificant percutaneous absorption of metronidazole occurs after the application of 1% metronidazole cream topically. Healthy volunteers applied one 100 mg dose of 14C-labelled metronidazole 2% cream to unbroken skin. After 12 hours, metronidazole was not detected in the plasma. Approximately 0.1% to 1% of the administered metronidazole was measured in the urine and feces. •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): Metronidazole is widely distributed throughout the body and various body fluids. They include the bile, saliva, breastmilk, cerebrospinal fluid, and the placenta. Steady-state volume distribution of metronidazole in adults ranges from 0.51 to 1.1 L/kg. It attains 60 to 100% of plasma concentrations in various tissues, such as the central nervous system, however, is not measured in high concentrations in the placental tissue. •Protein binding (Drug A): 15% •Protein binding (Drug B): Metronidazole is less than 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): Metronidazole undergoes hepatic metabolism via hydroxylation, oxidation, and glucuronidation. The metabolism of metronidazole yields 5 metabolites. The hydroxy metabolite, 1-(2-hydroxy-ethyl)-2-hydroxy methyl-5-nitroimidazole, is considered the major active metabolite. Unchanged metronidazole is found in the plasma along with small amounts of its 2- hydroxymethyl metabolite. Several metabolites of metronidazole are found in the urine. They are primarily a product of side-chain oxidation in addition to glucuronide conjugation. Only 20% of the dose found in the urine is accounted for by unchanged metronidazole. The two main oxidative metabolites of metronidazole are hydroxy and acetic acid 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): Metronidazole and metabolites are 60 to 80% eliminated in the urine, and 6-15% excreted 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 elimination half-life of metronidazole is 7.3 ± 1.0 after a single 500mg IV dose in healthy subjects. Another resource indicates that the elimination half-life for metronidazole ranges from 6 to 10 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Dose adjustments may be required in patients with hepatic impairment, as clearance is impaired in these patients. The clearance of metronidazole in the kidneys is estimated at 10 mL/min/1.73 m2. The total clearance from serum is about 2.1 to 6.4 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): LD50 information The oral LD50 of metronidazole in rats is 5000 mg/kg Overdose information Adverse effects that may be exaggerated with an overdose include peripheral neuropathy, central nervous system toxicity, seizures, disulfiram-like effect (if combined with alcohol) dark urine, a metallic taste in the mouth, nausea, epigastric discomfort, and vertigo, in addition to neutropenia. There is no specific antidote for metronidazole overdose. Symptomatic and supportive treatment should be employed in addition to the administration of activated charcoal to remove the unabsorbed drug from the gastrointestinal tract. In addition to the above measures, contact the local poison control center for updated information on the management of a metronidazole overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Flagyl, Flagystatin, Likmez, Metrocream, Metrogel, Metrolotion, Nidagel, Noritate, Nuvessa, Pylera, Rosadan, Vandazole •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metronidazol Métronidazole Metronidazole Metronidazolum •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): Metronidazole is a nitroimidazole used to treat trichomoniasis, amebiasis, inflammatory lesions of rosacea, and bacterial infections, as well as prevent postoperative 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 Metronidazole interact? Information: •Drug A: Buserelin •Drug B: Metronidazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Metronidazole 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): Metronidazole is indicated for the treatment of confirmed trichomoniasis caused by Trichomonas vaginalis (except for in the first trimester of pregnancy) and the patient's sexual partners, bacterial vaginosis, certain types of amebiasis, and various anaerobic infections. The above anaerobic infections may occur on the skin and skin structures, the abdomen, the heart, reproductive organs, central nervous system, and the respiratory system. Some may also be present in the bloodstream in cases of septicemia. Common infections treated by metronidazole are Bacteroides species infections, Clostridium infections, and Fusobacterium infections, as well as Peptococcus and Peptostreptococcus infections. Topical formulations of metronidazole are indicated for the treatment of inflammatory lesions of rosacea. It is also used off-label in the treatment of Crohn's disease, as a prophylactic agent after surgery, and in the treatment of Helicobacter pylori infection. It has also been studied in the prevention of preterm births and to treat periodontal 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): Metronidazole treats amebiasis, trichomoniasis, and giardiasis, exerting both antibacterial and antiprotozoal activities. Metronidazole is an effective treatment for some anaerobic bacterial infections. Metronidazole has shown antibacterial activity against the majority of obligate anaerobes, however, during in vitro studies, it does not demonstrate significant action against facultative anaerobes or obligate aerobes. The nitro group reduction of metronidazole by anaerobic organisms is likely responsible for the drug's antimicrobial cytotoxic effects, causing DNA strand damage to microbes. A note on convulsions and neuropathy and carcinogenesis It is important to be aware of the risk of peripheral neuropathy and convulsions associated with metronidazole, especially at higher doses. If convulsions or numbness of an extremity occur, discontinue the drug immediately. Metronidazole has been found to be carcinogenic in mice and rats. The relevance to this effect in humans is unknown. It is advisable to only administer metronidazole when clinically necessary and only for its approved indications. •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 of action of metronidazole has not been fully established, however, it is possible that an intermediate in the reduction of metronidazole which is only made by anaerobic bacteria and protozoa, binds deoxyribonucleic acid and electron-transport proteins of organisms, blocking nucleic acid synthesis. After administration, metronidazole enters cells by passive diffusion. Following this, ferredoxin or flavodoxin reduce its nitro group to nitro radicals. The redox potential of the electron transport portions of anaerobic or microaerophilic microorganisms renders metronidazole selective to these organisms, which cause nitro group reduction, leading to the production of toxic metabolites. These include N-(2-hydroxyethyl) oxamic acid and acetamide, which may damage DNA of replicating organisms. •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 intravenous infusion of a 1.5g dose, peak concentration was reached within 1 hour and was peak level of 30-40 mg/L. When a multiple-dose regimen of 500mg three times a day administered intravenously, steady-state concentrations were achieved within about 3 days and peak concentration was measured at 26 mg/L. When administered orally in the tablet form, metronidazole is absorbed entirely absorbed, showing a bioavailability of greater than 90%. One resource indicates that Cmax after a single oral dose of 500mg metronidazole ranges from 8 to 13 mg/L, with a Tmax of 25 minutes to 4 hours. The AUC following a single 500mg oral dose of metronidazole was 122 ± 10.3 mg/L • h. A note on the absorption of topical preparations Insignificant percutaneous absorption of metronidazole occurs after the application of 1% metronidazole cream topically. Healthy volunteers applied one 100 mg dose of 14C-labelled metronidazole 2% cream to unbroken skin. After 12 hours, metronidazole was not detected in the plasma. Approximately 0.1% to 1% of the administered metronidazole was measured in the urine and feces. •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): Metronidazole is widely distributed throughout the body and various body fluids. They include the bile, saliva, breastmilk, cerebrospinal fluid, and the placenta. Steady-state volume distribution of metronidazole in adults ranges from 0.51 to 1.1 L/kg. It attains 60 to 100% of plasma concentrations in various tissues, such as the central nervous system, however, is not measured in high concentrations in the placental tissue. •Protein binding (Drug A): 15% •Protein binding (Drug B): Metronidazole is less than 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): Metronidazole undergoes hepatic metabolism via hydroxylation, oxidation, and glucuronidation. The metabolism of metronidazole yields 5 metabolites. The hydroxy metabolite, 1-(2-hydroxy-ethyl)-2-hydroxy methyl-5-nitroimidazole, is considered the major active metabolite. Unchanged metronidazole is found in the plasma along with small amounts of its 2- hydroxymethyl metabolite. Several metabolites of metronidazole are found in the urine. They are primarily a product of side-chain oxidation in addition to glucuronide conjugation. Only 20% of the dose found in the urine is accounted for by unchanged metronidazole. The two main oxidative metabolites of metronidazole are hydroxy and acetic acid 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): Metronidazole and metabolites are 60 to 80% eliminated in the urine, and 6-15% excreted 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 elimination half-life of metronidazole is 7.3 ± 1.0 after a single 500mg IV dose in healthy subjects. Another resource indicates that the elimination half-life for metronidazole ranges from 6 to 10 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Dose adjustments may be required in patients with hepatic impairment, as clearance is impaired in these patients. The clearance of metronidazole in the kidneys is estimated at 10 mL/min/1.73 m2. The total clearance from serum is about 2.1 to 6.4 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): LD50 information The oral LD50 of metronidazole in rats is 5000 mg/kg Overdose information Adverse effects that may be exaggerated with an overdose include peripheral neuropathy, central nervous system toxicity, seizures, disulfiram-like effect (if combined with alcohol) dark urine, a metallic taste in the mouth, nausea, epigastric discomfort, and vertigo, in addition to neutropenia. There is no specific antidote for metronidazole overdose. Symptomatic and supportive treatment should be employed in addition to the administration of activated charcoal to remove the unabsorbed drug from the gastrointestinal tract. In addition to the above measures, contact the local poison control center for updated information on the management of a metronidazole overdose. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Flagyl, Flagystatin, Likmez, Metrocream, Metrogel, Metrolotion, Nidagel, Noritate, Nuvessa, Pylera, Rosadan, Vandazole •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metronidazol Métronidazole Metronidazole Metronidazolum •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): Metronidazole is a nitroimidazole used to treat trichomoniasis, amebiasis, inflammatory lesions of rosacea, and bacterial infections, as well as prevent postoperative 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 Mifepristone interact?

•Drug A: Buserelin •Drug B: Mifepristone •Severity: MODERATE •Description: The therapeutic efficacy of Mifepristone 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 medical termination of intrauterine pregnancy through 49 days' pregnancy. Also indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery. •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): Mifepristone is a synthetic steroid with antiprogestational effects indicated for the medical termination of intrauterine pregnancy through 49 days' pregnancy. Doses of 1 mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins. Mifepristone also exhibits antiglucocorticoid and weak antiandrogenic activity. The activity of the glucocorticoid dexamethasone in rats was inhibited following doses of 10 to 25 mg/kg of mifepristone. Doses of 4.5 mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol. •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 anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results. In the treatment of Cushing's syndrome, Mifepristone blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar 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 absolute bioavailability of a 20 mg oral dose is 69% •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): 98% (bound to plasma proteins, albumin and a 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): Hepatic. Hepatic, by Cytochrome P450 3A4 isoenzyme to the N-monodemethylated metabolite (RU 42 633); RU 42 698, which results from the loss of two methyl groups from position 11 beta; and RU 42 698, which results from terminal hydroxylation of the 17–propynyl chain. •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: 83%; Renal: 9%. •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): 18 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): Nearly all of the women who receive mifepristone will report adverse reactions, and many can be expected to report more than one such reaction. About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure. Side effects include more heavy bleeding than a heavy menstrual period, abdominal pain, uterine cramping, nausea, vomiting, and diarrhea. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Korlym, Mifegymiso •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): Mifepristone is a cortisol receptor blocker used to treat Cushing's syndrome, and to terminate pregnancies up to 70 days gestation.

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 Mifepristone interact? Information: •Drug A: Buserelin •Drug B: Mifepristone •Severity: MODERATE •Description: The therapeutic efficacy of Mifepristone 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 medical termination of intrauterine pregnancy through 49 days' pregnancy. Also indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery. •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): Mifepristone is a synthetic steroid with antiprogestational effects indicated for the medical termination of intrauterine pregnancy through 49 days' pregnancy. Doses of 1 mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins. Mifepristone also exhibits antiglucocorticoid and weak antiandrogenic activity. The activity of the glucocorticoid dexamethasone in rats was inhibited following doses of 10 to 25 mg/kg of mifepristone. Doses of 4.5 mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol. •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 anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results. In the treatment of Cushing's syndrome, Mifepristone blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar 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 absolute bioavailability of a 20 mg oral dose is 69% •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): 98% (bound to plasma proteins, albumin and a 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): Hepatic. Hepatic, by Cytochrome P450 3A4 isoenzyme to the N-monodemethylated metabolite (RU 42 633); RU 42 698, which results from the loss of two methyl groups from position 11 beta; and RU 42 698, which results from terminal hydroxylation of the 17–propynyl chain. •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: 83%; Renal: 9%. •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): 18 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): Nearly all of the women who receive mifepristone will report adverse reactions, and many can be expected to report more than one such reaction. About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure. Side effects include more heavy bleeding than a heavy menstrual period, abdominal pain, uterine cramping, nausea, vomiting, and diarrhea. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Korlym, Mifegymiso •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): Mifepristone is a cortisol receptor blocker used to treat Cushing's syndrome, and to terminate pregnancies up to 70 days gestation. 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 Miglitol interact?

•Drug A: Buserelin •Drug B: Miglitol •Severity: MODERATE •Description: The therapeutic efficacy of Miglitol 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 use as an adjunct to diet to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) whose hyperglycemia cannot be managed with diet alone. •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): Miglitol, an oral alpha-glucosidase inhibitor, is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, miglitol reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time. Because its mechanism of action is different, the effect of miglitol to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, miglitol diminishes the insulinotropic and weight-increasing effects of sulfonylureas. Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance. •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 contrast to sulfonylureas, miglitol does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal a-glucoside hydrolase enzymes. Membrane-bound intestinal a-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia. •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 miglitol is saturable at high doses with 25 mg being completely absorbed while a 100-mg dose is only 50-70% absorbed. No evidence exists to show that systemic absorption of miglitol adds to its therapeutic effect. •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): 0.18 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of miglitol is negligible (<4.0%). •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): Miglitol is not metabolized in man or in any animal species studied. •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): Miglitol is not metabolized in man or in any animal species studied. It is eliminated by renal excretion as an 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): The elimination half-life of miglitol from plasma 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): Unlike sulfonylureas or insulin, an overdose will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdomi-nal discomfort. Because of the lack of extra-intestinal effects seen with miglitol, no serious systemic reactions are expected in the event of an overdose. •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): Miglitol is an oral alpha-glucosidase inhibitor used to improve glycemic control by delaying the digestion of carbohydrates.

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 Miglitol interact? Information: •Drug A: Buserelin •Drug B: Miglitol •Severity: MODERATE •Description: The therapeutic efficacy of Miglitol 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 use as an adjunct to diet to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) whose hyperglycemia cannot be managed with diet alone. •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): Miglitol, an oral alpha-glucosidase inhibitor, is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, miglitol reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time. Because its mechanism of action is different, the effect of miglitol to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, miglitol diminishes the insulinotropic and weight-increasing effects of sulfonylureas. Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance. •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 contrast to sulfonylureas, miglitol does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal a-glucoside hydrolase enzymes. Membrane-bound intestinal a-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia. •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 miglitol is saturable at high doses with 25 mg being completely absorbed while a 100-mg dose is only 50-70% absorbed. No evidence exists to show that systemic absorption of miglitol adds to its therapeutic effect. •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): 0.18 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of miglitol is negligible (<4.0%). •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): Miglitol is not metabolized in man or in any animal species studied. •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): Miglitol is not metabolized in man or in any animal species studied. It is eliminated by renal excretion as an 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): The elimination half-life of miglitol from plasma 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): Unlike sulfonylureas or insulin, an overdose will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdomi-nal discomfort. Because of the lack of extra-intestinal effects seen with miglitol, no serious systemic reactions are expected in the event of an overdose. •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): Miglitol is an oral alpha-glucosidase inhibitor used to improve glycemic control by delaying the digestion of carbohydrates. 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 Mirabegron interact?

•Drug A: Buserelin •Drug B: Mirabegron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Mirabegron. •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): Mirabegron is indicated for the treatment of overactive bladder (OAB) - with symptoms of urge urinary incontinence, urgency, and urinary frequency - either alone or in combination with solifenacin. It is also indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older and weighing 35kg or more. •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): Mirabegron exerts its pharmacologic effects by forcing bladder smooth muscle to relax, thereby expanding its capacity and relieving urgency. Mirabegron does not appear to adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in patients with lower urinary tract symptoms and bladder outlet obstruction (BOO), but should be used with in patients with BOO due to reports of significant urinary retention. Furthermore, mirabegron increases both blood pressure and heart rate in a dose-dependent manner and should therefore be used with caution in patients with severely uncontrolled hypertension or others for whom these increases may prove dangerous. •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): Mirabegron is a potent and selective agonist of beta-3 adrenergic receptors. The activation of beta-3 receptors relaxes detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle, which increases the bladder's storage capacity thereby alleviating feelings of urgency and frequency. •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 absolute bioavailability of orally administered mirabegron ranges from 29% at a dose of 25 mg to 35% at a dose of 50 mg. The T max for the extended-release tablet and suspension formulations are approximately 3.5 hours, while the T max for the granule formulation is 4-5 hours. Both C max and AUC increase more than dose proportionally - an increase in dose from 50mg to 100mg results in a 2.9- and 2.6-fold increase in C max and AUC, respectively, whereas an increase from 50mg to 200mg results in a 8.4- and 6.5-fold increase in C max and AUC, respectively. Steady-state concentrations of mirabegron are achieved after approximately 7 days of once-daily 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): Following intravenous administration, mirabegron has an apparent steady-state volume of distribution (Vd) of 1670 L indicating extensive distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): Mirabegron is approximately 71% protein-bound in plasma, primarily to 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): Mirabegron is extensively metabolized via a number of mechanisms, although unchanged parent drug is still the major circulating component following oral administration. Presumed metabolic pathways and their resultant metabolites include amide hydrolysis (M5, M16, M17), glucuronidation (mirabegron O-glucuronide, N-glucuronide, N-carbamoylglucuronide, M12), and secondary amine oxidation or dealkylation (M8, M9, M15), amongst others. The enzymes responsible for the oxidative metabolism of mirabegron are thought to be CYP3A4 and CYP2D6, while the UDP-glucuronosyltransferases responsible for conjugation reactions have been identified as UGT2B7, UGT1A3, and UGT1A8. Other enzymes that may be involved in the metabolism of mirabegron include butylcholinesterase and possibly alcohol dehydrogenase. •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): Of a 160mg radiolabeled dose administered to healthy volunteers, approximately 55% of the radioactivity was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in the urine while 0% was recovered in the feces. Renal elimination is achieved primarily via active tubular secretion with some contribution by glomerular filtration. •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 mirabegron in adults being treated for overactive bladder is approximately 50 hours. In pediatric patients receiving the granule formulation for the treatment of neurogenic detrusor overactivity, the mean terminal elimination half-life is approximately 26-31 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total plasma clearance following intravenous administration is approximately 57 L/h, with renal clearance accounting for roughly 25% at approximately 13 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): At doses of up to 400mg in healthy volunteers (~8x the recommended maximum), reported symptoms of overdose included palpitations and increased heart rate. Symptoms of chronic overdosage are similar in presentation and may also include a rise in systolic blood pressure. In cases of overdosage, employ standard symptomatic and supportive measures in addition to ECG monitoring. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Myrbetriq •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): Mirabegron is a beta-3 adrenergic agonist used to treat overactive bladder and neurogenic detrusor overactivity.

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 Mirabegron interact? Information: •Drug A: Buserelin •Drug B: Mirabegron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Mirabegron. •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): Mirabegron is indicated for the treatment of overactive bladder (OAB) - with symptoms of urge urinary incontinence, urgency, and urinary frequency - either alone or in combination with solifenacin. It is also indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older and weighing 35kg or more. •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): Mirabegron exerts its pharmacologic effects by forcing bladder smooth muscle to relax, thereby expanding its capacity and relieving urgency. Mirabegron does not appear to adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in patients with lower urinary tract symptoms and bladder outlet obstruction (BOO), but should be used with in patients with BOO due to reports of significant urinary retention. Furthermore, mirabegron increases both blood pressure and heart rate in a dose-dependent manner and should therefore be used with caution in patients with severely uncontrolled hypertension or others for whom these increases may prove dangerous. •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): Mirabegron is a potent and selective agonist of beta-3 adrenergic receptors. The activation of beta-3 receptors relaxes detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle, which increases the bladder's storage capacity thereby alleviating feelings of urgency and frequency. •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 absolute bioavailability of orally administered mirabegron ranges from 29% at a dose of 25 mg to 35% at a dose of 50 mg. The T max for the extended-release tablet and suspension formulations are approximately 3.5 hours, while the T max for the granule formulation is 4-5 hours. Both C max and AUC increase more than dose proportionally - an increase in dose from 50mg to 100mg results in a 2.9- and 2.6-fold increase in C max and AUC, respectively, whereas an increase from 50mg to 200mg results in a 8.4- and 6.5-fold increase in C max and AUC, respectively. Steady-state concentrations of mirabegron are achieved after approximately 7 days of once-daily 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): Following intravenous administration, mirabegron has an apparent steady-state volume of distribution (Vd) of 1670 L indicating extensive distribution. •Protein binding (Drug A): 15% •Protein binding (Drug B): Mirabegron is approximately 71% protein-bound in plasma, primarily to 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): Mirabegron is extensively metabolized via a number of mechanisms, although unchanged parent drug is still the major circulating component following oral administration. Presumed metabolic pathways and their resultant metabolites include amide hydrolysis (M5, M16, M17), glucuronidation (mirabegron O-glucuronide, N-glucuronide, N-carbamoylglucuronide, M12), and secondary amine oxidation or dealkylation (M8, M9, M15), amongst others. The enzymes responsible for the oxidative metabolism of mirabegron are thought to be CYP3A4 and CYP2D6, while the UDP-glucuronosyltransferases responsible for conjugation reactions have been identified as UGT2B7, UGT1A3, and UGT1A8. Other enzymes that may be involved in the metabolism of mirabegron include butylcholinesterase and possibly alcohol dehydrogenase. •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): Of a 160mg radiolabeled dose administered to healthy volunteers, approximately 55% of the radioactivity was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in the urine while 0% was recovered in the feces. Renal elimination is achieved primarily via active tubular secretion with some contribution by glomerular filtration. •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 mirabegron in adults being treated for overactive bladder is approximately 50 hours. In pediatric patients receiving the granule formulation for the treatment of neurogenic detrusor overactivity, the mean terminal elimination half-life is approximately 26-31 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total plasma clearance following intravenous administration is approximately 57 L/h, with renal clearance accounting for roughly 25% at approximately 13 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): At doses of up to 400mg in healthy volunteers (~8x the recommended maximum), reported symptoms of overdose included palpitations and increased heart rate. Symptoms of chronic overdosage are similar in presentation and may also include a rise in systolic blood pressure. In cases of overdosage, employ standard symptomatic and supportive measures in addition to ECG monitoring. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Myrbetriq •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): Mirabegron is a beta-3 adrenergic agonist used to treat overactive bladder and neurogenic detrusor overactivity. 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 Mirtazapine interact?

•Drug A: Buserelin •Drug B: Mirtazapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Mirtazapine 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): This drug is indicated for the treatment of major depressive disorder and its associated symptoms. Mirtazapine has been used off-label for a variety of conditions including panic disorder, generalized anxiety disorder, dysthymia, tension headaches, hot flushes, post-traumatic stress disorder (PTSD), sleep disorders, substance abuse disorders, and sexual disorders, among others. •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 a note on suicidality Mirtazapine is effective in treating moderate to severe depression and treats many symptoms normally associated with this condition. These symptoms may include disturbed sleep, lack of appetite, and anhedonia, in addition to anxiety.. It is important to note that suicidal ideation and behavior may emerge or increase during treatment with mirtazapine, as with any other antidepressant. This risk is especially pronounced in younger individuals. Patients, medical professionals, and families should monitor for suicidal thoughts, worsening depression, anxiety, agitation, sleep changes, irritable behavior, aggression, impulsivity, restlessness, and other unusual behavior when this drug is taken or the dose is adjusted. Do not administer mirtazapine to children. When deciding to prescribe this drug, carefully consider the increased risk of suicidal thoughts and behavior, especially in young adults. Effects on appetite and weight gain In addition to the above effects, mirtazapine exerts stimulating effects on appetite, and has been used for increasing appetite and decreasing nausea in cancer patients. Some studies and case reports have shown that this drug improves eating habits and weight gain in patients suffering from anorexia nervosa when administered in conjunction with psychotherapy and/or other psychotropic drugs. In a clinical trial, women with depression experienced a clinically significant mean increase in body weight, fat mass, and concentrations of leptin when treated with mirtazapine for a 6-week period, with a lack of effect on glucose homeostasis. Effects on sleep The use of mirtazapine to treat disordered sleep has been leveraged from its tendency to cause somnolence, which is a frequently experienced adverse effect by patients taking this drug. Mirtazapine has been shown to exert beneficial effects on sleep latency, duration, and quality due to its sedating properties. Insomnia is a common occurrence in patients with depression, and mirtazapine has been found to be efficacious in treating this condition. •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): Summary The mechanism of action of mirtazapine is not fully understood but may be explained by its effects on central adrenergic and serotonergic activity. This drug exhibits a fast onset of action, a high level of response, a manageable side-effect profile, and dual noradrenergic and serotonergic effects that are unique from the effects of other antidepressants. Effects on various receptors It has been shown that both noradrenergic and serotonergic activity increase following mirtazapine administration. The results of these studies demonstrate mirtazapine exerts antagonist activity at presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors in the central nervous system. This is thought to lead to enhanced noradrenergic and serotonergic activity, which are known to improve the symptoms of depression and form the basis of antidepressant therapy. Mirtazapine is a strong antagonist of serotonin 5-HT2 and 5-HT3 receptors. It has not been found to bind significantly to the serotonin 5-HT1A and 5-HT1B receptors but indirectly increases 5-HT1A transmission. In addition to the above effects, mirtazapine is a peripheral α1-adrenergic antagonist. This action may explain episodes of orthostatic hypotension that have been reported after mirtazapine use. Mirtazapine is a potent histamine (H1) receptor antagonist, which may contribute to its powerful sedating effects. The pain-relieving effects of mirtazapine may be explained by its effects on opioid 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 absorption of this drug is rapid and complete. Due to first pass metabolism in the liver and metabolism in the gut wall, absolute bioavailability is about 50%. Peak blood concentrations are attained within about 2 hours after an oral dose. Food has little effect on the absorption of mirtazapine, and no dose adjustment is required if it is taken with food. Steady-state levels are achieved by about 5 days after the initial dose. Mirtazapine pharmacokinetics vary across gender and age range. Females and the elderly population have been shown to have higher blood concentrations in comparison to males and younger adults. •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 after an oral steady-state dose was measured to be 107 ± 42L in a pharmacokinetic study. •Protein binding (Drug A): 15% •Protein binding (Drug B): Mirtazapine is about 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): Mirtazapine is heavily metabolized in humans. Demethylation and hydroxylation and subsequent glucuronide conjugation are the major pathways by which mirtazapine is metabolized. Data from in vitro studies on human liver microsomes show that cytochrome 2D6 and 1A2 lead to the formation of the 8-hydroxy metabolite of mirtazapine. The CYP3A enzyme metabolizes this drug into its N-desmethyl and N-oxide metabolites. There are various other unconjugated metabolites of this drug that are pharmacologically active, but are measured in the blood at limited concentrations. •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): This drug is mainly excreted by the kidney. It is 75% eliminated in the urine and 15% eliminated 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): 20-40 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Total body clearance in males was found to be 31 L/h in a clinical pharmacokinetics study after intravenous administration. Clearance in elderly patients Mirtazapine clearance is slower in the elderly than in younger subjects. Exercise caution when this drug is given to elderly patients. In a clinical trial, elderly males showed a marked decrease in mirtazapine clearance when compared to young males taking the same dose. This difference was less significant when clearance was compared between elderly females and younger females taking mirtazapine. Clearance in hepatic and renal impairment Patients with hepatic and renal impairment have decreased rates of clearance and dosage adjustments may be necessary for these patients. Moderate renal impairment and hepatic impairment cause about a 30% decrease in mirtazapine clearance. Severe renal impairment leads to a 50% decrease in mirtazapine 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): LD50 Oral LD50 was 830 mg/kg in male Swiss mice 24 hours after being administered mirtazapine. Overdose information Activated charcoal should be administered during an overdose to absorb excess mirtazapine. General supportive therapy should be employed, including maintenance of an adequate airway, oxygen therapy, and ventilation therapy. Vital signs and cardiac rhythm must be monitored. It is not advisable to induce vomiting. Gastric lavage with a large-bore orogastric tube with proper protection of the airway is recommended. There is no antidote for mirtazapine available currently. Consider the possibility of mirtazapine combined with other drugs in an overdose and ensure to contact the local poison control center for guidance on management. Carcinogenesis At higher than normal doses, mirtazapine increased the incidence of hepatocellular adenomas and carcinomas in male mice. The highest doses administered to the mice were about 20 and 12 times the maximum recommended human dose (MRHD). Hepatocellular tumors and thyroid follicular adenoma/cystadenomas in male rats occurred at an increased rate at a higher mirtazapine dose (60 mg/kg/day). In female rats, both the medium (20 mg/kg/day) and higher (60 mg/kg/day) doses of mirtazapine increased the rate of hepatocellular adenomas. The relevance of these findings in humans is not known at this time. Impairment of Fertility Mirtazapine was administered to rats at doses reaching 100 mg/kg (equivalent to 20 times the maximum recommended human dose) in a fertility study. There was no impact on mating and conception, however, there was a disturbance of reproductive (estrous) cycling at higher doses. These doses were measured to be at least 3 times the maximum recommended human dose. Loss of fetus before implantation in the uterus occurred when doses equivalent to 20 times the maximum recommended dose were administered. Use in pregnancy This drug is categorized as a pregnancy category C drug. No adequate studies in pregnant women have been conducted. In rats, an increased rate of post-implantation demise occurred with mirtazapine administration. Additionally, an increase in deaths of rat pups during the first 3 days of lactation with a decrease in pup birth weight was noted. Studies on animals are not always relevant to human response. Mirtazapine should be used during pregnancy only if the clinical need outweighs the possible risks to the fetus. Use in nursing Whether this drug is excreted in human milk is unknown. Many drugs are found excreted in human breast milk, therefore caution is advised if this drug is used during nursing. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Remeron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-Azamianserin Mepirzapine Mirtazapin Mirtazapina Mirtazapine Mirtazapinum •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): Mirtazapine is a tetracyclic antidepressant used in the treatment of major depression and is used off-label as a drug for insomnia and to increase appetite.

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 Mirtazapine interact? Information: •Drug A: Buserelin •Drug B: Mirtazapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Mirtazapine 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): This drug is indicated for the treatment of major depressive disorder and its associated symptoms. Mirtazapine has been used off-label for a variety of conditions including panic disorder, generalized anxiety disorder, dysthymia, tension headaches, hot flushes, post-traumatic stress disorder (PTSD), sleep disorders, substance abuse disorders, and sexual disorders, among others. •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 a note on suicidality Mirtazapine is effective in treating moderate to severe depression and treats many symptoms normally associated with this condition. These symptoms may include disturbed sleep, lack of appetite, and anhedonia, in addition to anxiety.. It is important to note that suicidal ideation and behavior may emerge or increase during treatment with mirtazapine, as with any other antidepressant. This risk is especially pronounced in younger individuals. Patients, medical professionals, and families should monitor for suicidal thoughts, worsening depression, anxiety, agitation, sleep changes, irritable behavior, aggression, impulsivity, restlessness, and other unusual behavior when this drug is taken or the dose is adjusted. Do not administer mirtazapine to children. When deciding to prescribe this drug, carefully consider the increased risk of suicidal thoughts and behavior, especially in young adults. Effects on appetite and weight gain In addition to the above effects, mirtazapine exerts stimulating effects on appetite, and has been used for increasing appetite and decreasing nausea in cancer patients. Some studies and case reports have shown that this drug improves eating habits and weight gain in patients suffering from anorexia nervosa when administered in conjunction with psychotherapy and/or other psychotropic drugs. In a clinical trial, women with depression experienced a clinically significant mean increase in body weight, fat mass, and concentrations of leptin when treated with mirtazapine for a 6-week period, with a lack of effect on glucose homeostasis. Effects on sleep The use of mirtazapine to treat disordered sleep has been leveraged from its tendency to cause somnolence, which is a frequently experienced adverse effect by patients taking this drug. Mirtazapine has been shown to exert beneficial effects on sleep latency, duration, and quality due to its sedating properties. Insomnia is a common occurrence in patients with depression, and mirtazapine has been found to be efficacious in treating this condition. •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): Summary The mechanism of action of mirtazapine is not fully understood but may be explained by its effects on central adrenergic and serotonergic activity. This drug exhibits a fast onset of action, a high level of response, a manageable side-effect profile, and dual noradrenergic and serotonergic effects that are unique from the effects of other antidepressants. Effects on various receptors It has been shown that both noradrenergic and serotonergic activity increase following mirtazapine administration. The results of these studies demonstrate mirtazapine exerts antagonist activity at presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors in the central nervous system. This is thought to lead to enhanced noradrenergic and serotonergic activity, which are known to improve the symptoms of depression and form the basis of antidepressant therapy. Mirtazapine is a strong antagonist of serotonin 5-HT2 and 5-HT3 receptors. It has not been found to bind significantly to the serotonin 5-HT1A and 5-HT1B receptors but indirectly increases 5-HT1A transmission. In addition to the above effects, mirtazapine is a peripheral α1-adrenergic antagonist. This action may explain episodes of orthostatic hypotension that have been reported after mirtazapine use. Mirtazapine is a potent histamine (H1) receptor antagonist, which may contribute to its powerful sedating effects. The pain-relieving effects of mirtazapine may be explained by its effects on opioid 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 absorption of this drug is rapid and complete. Due to first pass metabolism in the liver and metabolism in the gut wall, absolute bioavailability is about 50%. Peak blood concentrations are attained within about 2 hours after an oral dose. Food has little effect on the absorption of mirtazapine, and no dose adjustment is required if it is taken with food. Steady-state levels are achieved by about 5 days after the initial dose. Mirtazapine pharmacokinetics vary across gender and age range. Females and the elderly population have been shown to have higher blood concentrations in comparison to males and younger adults. •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 after an oral steady-state dose was measured to be 107 ± 42L in a pharmacokinetic study. •Protein binding (Drug A): 15% •Protein binding (Drug B): Mirtazapine is about 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): Mirtazapine is heavily metabolized in humans. Demethylation and hydroxylation and subsequent glucuronide conjugation are the major pathways by which mirtazapine is metabolized. Data from in vitro studies on human liver microsomes show that cytochrome 2D6 and 1A2 lead to the formation of the 8-hydroxy metabolite of mirtazapine. The CYP3A enzyme metabolizes this drug into its N-desmethyl and N-oxide metabolites. There are various other unconjugated metabolites of this drug that are pharmacologically active, but are measured in the blood at limited concentrations. •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): This drug is mainly excreted by the kidney. It is 75% eliminated in the urine and 15% eliminated 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): 20-40 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Total body clearance in males was found to be 31 L/h in a clinical pharmacokinetics study after intravenous administration. Clearance in elderly patients Mirtazapine clearance is slower in the elderly than in younger subjects. Exercise caution when this drug is given to elderly patients. In a clinical trial, elderly males showed a marked decrease in mirtazapine clearance when compared to young males taking the same dose. This difference was less significant when clearance was compared between elderly females and younger females taking mirtazapine. Clearance in hepatic and renal impairment Patients with hepatic and renal impairment have decreased rates of clearance and dosage adjustments may be necessary for these patients. Moderate renal impairment and hepatic impairment cause about a 30% decrease in mirtazapine clearance. Severe renal impairment leads to a 50% decrease in mirtazapine 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): LD50 Oral LD50 was 830 mg/kg in male Swiss mice 24 hours after being administered mirtazapine. Overdose information Activated charcoal should be administered during an overdose to absorb excess mirtazapine. General supportive therapy should be employed, including maintenance of an adequate airway, oxygen therapy, and ventilation therapy. Vital signs and cardiac rhythm must be monitored. It is not advisable to induce vomiting. Gastric lavage with a large-bore orogastric tube with proper protection of the airway is recommended. There is no antidote for mirtazapine available currently. Consider the possibility of mirtazapine combined with other drugs in an overdose and ensure to contact the local poison control center for guidance on management. Carcinogenesis At higher than normal doses, mirtazapine increased the incidence of hepatocellular adenomas and carcinomas in male mice. The highest doses administered to the mice were about 20 and 12 times the maximum recommended human dose (MRHD). Hepatocellular tumors and thyroid follicular adenoma/cystadenomas in male rats occurred at an increased rate at a higher mirtazapine dose (60 mg/kg/day). In female rats, both the medium (20 mg/kg/day) and higher (60 mg/kg/day) doses of mirtazapine increased the rate of hepatocellular adenomas. The relevance of these findings in humans is not known at this time. Impairment of Fertility Mirtazapine was administered to rats at doses reaching 100 mg/kg (equivalent to 20 times the maximum recommended human dose) in a fertility study. There was no impact on mating and conception, however, there was a disturbance of reproductive (estrous) cycling at higher doses. These doses were measured to be at least 3 times the maximum recommended human dose. Loss of fetus before implantation in the uterus occurred when doses equivalent to 20 times the maximum recommended dose were administered. Use in pregnancy This drug is categorized as a pregnancy category C drug. No adequate studies in pregnant women have been conducted. In rats, an increased rate of post-implantation demise occurred with mirtazapine administration. Additionally, an increase in deaths of rat pups during the first 3 days of lactation with a decrease in pup birth weight was noted. Studies on animals are not always relevant to human response. Mirtazapine should be used during pregnancy only if the clinical need outweighs the possible risks to the fetus. Use in nursing Whether this drug is excreted in human milk is unknown. Many drugs are found excreted in human breast milk, therefore caution is advised if this drug is used during nursing. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Remeron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-Azamianserin Mepirzapine Mirtazapin Mirtazapina Mirtazapine Mirtazapinum •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): Mirtazapine is a tetracyclic antidepressant used in the treatment of major depression and is used off-label as a drug for insomnia and to increase appetite. 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 Mizolastine interact?

•Drug A: Buserelin •Drug B: Mizolastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Mizolastine. •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): 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): 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): Mizolastine is a second-generation non-sedating antihistamine used to treat symptoms of allergic rhinoconjunctivitis 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 Mizolastine interact? Information: •Drug A: Buserelin •Drug B: Mizolastine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Mizolastine. •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): 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): 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): Mizolastine is a second-generation non-sedating antihistamine used to treat symptoms of allergic rhinoconjunctivitis 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 Mobocertinib interact?

•Drug A: Buserelin •Drug B: Mobocertinib •Severity: MAJOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Mobocertinib. •Extended Description: Mobocertinib can cause prolongation of the QTc interval, which can lead to life-threatening complications such as Torsades de Pointes. Its concomitant use with other QTc-prolonging medications may further increase the risk of QTc prolongation and its associated adverse effects. •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): Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based 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): Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants. It is available as an oral capsule taken with or without food once daily. Mobocertinib can cause a concentration-dependent increase in QTc interval which may lead to life-threatening complications such as Torsades de Pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus the risk of QTc-prolongation. •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 epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation. Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of EGFR mutations associated with NSCLC involve the EGFR L858R point mutation or exon 19 deletions (referred to as "classical" EGFR mutations), less common EGFR exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins. •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 mean absolute bioavailability of mobocertinib is 37% and the median T max is approximately 4 hours. Following a single oral dose of 160mg of mobocertinib to fasted patients, the mean C max and AUC 0-inf were 45.8 ng/mL and 862 ng•h/mL, 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): The mean apparent volume of distribution of mobocertinib was approximately 3,509 L at steady-state. •Protein binding (Drug A): 15% •Protein binding (Drug B): Mobocertinib and its metabolites are extensively protein-bound in plasma, although the specific proteins to which they bind have not been elucidated. Following oral administration, mobocertinib is 99.3% protein-bound, AP32960 is 99.5% protein-bound, and AP32914 is 98.6% 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): Mobocertinib is metabolized primarily by CYP3A enzymes to two active metabolites, AP32960 and AP32914, which are equipotent to mobocertinib and account for 36% and 4% of its combined molar AUC, 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): Following oral administration of mobocertinib, approximately 76% of the administered dose was recovered in the feces (6% as unchanged parent drug) with only 4% recovered in the urine (1% as unchanged parent drug). The metabolite AP32960 comprised 12% and 1% of the recovered dose found in the feces and urine, respectively, while the metabolite AP32914 was below the detection limit in both. •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): At steady-state, the mean elimination half-life of mobocertinib and its two active metabolites, AP32960 and AP32914, was 18 hours, 24 hours, and 18 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): At steady-state, the mean apparent oral clearance of mobocertinib and its two active metabolites, AP32960 and AP32914, was 138 L/hr, 149 L/hr, and 159 L/hr, 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): No data are available regarding overdosage with mobocertinib. Symptoms of overdosage are likely to be consistent with mobocertinib's adverse effects and may therefore include significant gastrointestinal symptoms, pain, fatigue, and rash. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Exkivity •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): Mobocertinib is an oral kinase inhibitor targeted against EGFR and used in the treatment of NSCLC with EGFR exon 20 insertion mutations.

Mobocertinib can cause prolongation of the QTc interval, which can lead to life-threatening complications such as Torsades de Pointes. Its concomitant use with other QTc-prolonging medications may further increase the risk of QTc prolongation and its associated adverse effects. The severity of the interaction is major.

Question: Does Buserelin and Mobocertinib interact? Information: •Drug A: Buserelin •Drug B: Mobocertinib •Severity: MAJOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Mobocertinib. •Extended Description: Mobocertinib can cause prolongation of the QTc interval, which can lead to life-threatening complications such as Torsades de Pointes. Its concomitant use with other QTc-prolonging medications may further increase the risk of QTc prolongation and its associated adverse effects. •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): Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based 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): Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants. It is available as an oral capsule taken with or without food once daily. Mobocertinib can cause a concentration-dependent increase in QTc interval which may lead to life-threatening complications such as Torsades de Pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus the risk of QTc-prolongation. •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 epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation. Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of EGFR mutations associated with NSCLC involve the EGFR L858R point mutation or exon 19 deletions (referred to as "classical" EGFR mutations), less common EGFR exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins. •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 mean absolute bioavailability of mobocertinib is 37% and the median T max is approximately 4 hours. Following a single oral dose of 160mg of mobocertinib to fasted patients, the mean C max and AUC 0-inf were 45.8 ng/mL and 862 ng•h/mL, 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): The mean apparent volume of distribution of mobocertinib was approximately 3,509 L at steady-state. •Protein binding (Drug A): 15% •Protein binding (Drug B): Mobocertinib and its metabolites are extensively protein-bound in plasma, although the specific proteins to which they bind have not been elucidated. Following oral administration, mobocertinib is 99.3% protein-bound, AP32960 is 99.5% protein-bound, and AP32914 is 98.6% 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): Mobocertinib is metabolized primarily by CYP3A enzymes to two active metabolites, AP32960 and AP32914, which are equipotent to mobocertinib and account for 36% and 4% of its combined molar AUC, 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): Following oral administration of mobocertinib, approximately 76% of the administered dose was recovered in the feces (6% as unchanged parent drug) with only 4% recovered in the urine (1% as unchanged parent drug). The metabolite AP32960 comprised 12% and 1% of the recovered dose found in the feces and urine, respectively, while the metabolite AP32914 was below the detection limit in both. •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): At steady-state, the mean elimination half-life of mobocertinib and its two active metabolites, AP32960 and AP32914, was 18 hours, 24 hours, and 18 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): At steady-state, the mean apparent oral clearance of mobocertinib and its two active metabolites, AP32960 and AP32914, was 138 L/hr, 149 L/hr, and 159 L/hr, 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): No data are available regarding overdosage with mobocertinib. Symptoms of overdosage are likely to be consistent with mobocertinib's adverse effects and may therefore include significant gastrointestinal symptoms, pain, fatigue, and rash. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Exkivity •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): Mobocertinib is an oral kinase inhibitor targeted against EGFR and used in the treatment of NSCLC with EGFR exon 20 insertion mutations. Output: Mobocertinib can cause prolongation of the QTc interval, which can lead to life-threatening complications such as Torsades de Pointes. Its concomitant use with other QTc-prolonging medications may further increase the risk of QTc prolongation and its associated adverse effects. The severity of the interaction is major.

Does Buserelin and Moexipril interact?

•Drug A: Buserelin •Drug B: Moexipril •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Moexipril 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 hypertension. •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): Moexipril is a non-sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor moexiprilat. It is used to treat high blood pressure (hypertension). It works by relaxing blood vessels, causing them to widen. Lowering high blood pressure helps prevent strokes, heart attacks and kidney problems. •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): Moexipril is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone). Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. •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): Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13% compared to intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food, which reduces C max and AUC by about 70% and 40%, respectively, after the ingestion of a low-fat breakfast or by 80% and 50%, respectively, after the ingestion of a high-fat breakfast. •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): 183 L •Protein binding (Drug A): 15% •Protein binding (Drug B): Moexiprilat is approxomately 50% 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): Rapidly converted to moexiprilat, the active metabolite. Conversion to the active metabolite is thought to require carboxyesterases and is likely to occur in organs or tissues, other than the gastrointestinal tract, in which carboxyesterases occur. The liver is thought to be one site of conversion, but not the primary site. •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): Moexiprilat undergoes renal 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): Moexipril elimination half-life is approximately 1 hour. Moexiprilat elimination half-life is 2 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 441 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): Human overdoses of moexipril have not been reported. In case reports of overdoses with other ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of 2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 3 g/kg. Common adverse effects include cough, dizziness, diarrhea, flu syndrome, fatigue, pharyngitis, flushing, rash, and myalgia •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Univasc •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): Moexipril is an angiotensin converting enzyme inhibitor prodrug used to treat hypertension.

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 Moexipril interact? Information: •Drug A: Buserelin •Drug B: Moexipril •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Moexipril 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 hypertension. •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): Moexipril is a non-sulfhydryl containing precursor of the active angiotensin-converting enzyme (ACE) inhibitor moexiprilat. It is used to treat high blood pressure (hypertension). It works by relaxing blood vessels, causing them to widen. Lowering high blood pressure helps prevent strokes, heart attacks and kidney problems. •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): Moexipril is a prodrug for moexiprilat, which inhibits ACE in humans and animals. The mechanism through which moexiprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex and provides negative feedback on renin secretion. ACE is identical to kininase II, an enzyme that degrades bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000 times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of ACE results in decreased angiotensin II formation, leading to decreased vasoconstriction, increased plasma renin activity, and decreased aldosterone secretion. The latter results in diuresis and natriuresis and a small increase in serum potassium concentration (mean increases of about 0.25 mEq/L were seen when moexipril was used alone). Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of moexipril remains to be elucidated. Although the principal mechanism of moexipril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood pressure even in apparent low-renin hypertension. •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): Moexipril is incompletely absorbed, with bioavailability as moexiprilat of about 13% compared to intravenous (I.V.) moexipril (both measuring the metabolite moexiprilat), and is markedly affected by food, which reduces C max and AUC by about 70% and 40%, respectively, after the ingestion of a low-fat breakfast or by 80% and 50%, respectively, after the ingestion of a high-fat breakfast. •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): 183 L •Protein binding (Drug A): 15% •Protein binding (Drug B): Moexiprilat is approxomately 50% 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): Rapidly converted to moexiprilat, the active metabolite. Conversion to the active metabolite is thought to require carboxyesterases and is likely to occur in organs or tissues, other than the gastrointestinal tract, in which carboxyesterases occur. The liver is thought to be one site of conversion, but not the primary site. •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): Moexiprilat undergoes renal 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): Moexipril elimination half-life is approximately 1 hour. Moexiprilat elimination half-life is 2 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 441 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): Human overdoses of moexipril have not been reported. In case reports of overdoses with other ACE inhibitors, hypotension has been the principal adverse effect noted. Single oral doses of 2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 3 g/kg. Common adverse effects include cough, dizziness, diarrhea, flu syndrome, fatigue, pharyngitis, flushing, rash, and myalgia •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Univasc •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): Moexipril is an angiotensin converting enzyme inhibitor prodrug used to treat hypertension. 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 Moxifloxacin interact?

•Drug A: Buserelin •Drug B: Moxifloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Moxifloxacin. •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 sinus and lung infections such as sinusitis, pneumonia, and secondary infections in chronic bronchitis. Also for the treatment of bacterial conjunctivitis (pinkeye). •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): Moxifloxacin is a quinolone/fluoroquinolone antibiotic. Moxifloxacin can be used to treat infections caused by the following bacteria: Aerobic Gram-positive microorganisms: Corynebacterium species, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus warneri, Streptococcus pneumoniae, and Streptococcus viridans group. Aerobic Gram-negative microorganisms: Acinetobacter lwoffii, Haemophilus influenzae, and Haemophilus parainfluenzae. Other microorganisms: Chlamydia trachomatis. Moxifloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Moxifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. •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 bactericidal action of moxifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. •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 gastrointestinal tract. Absolute oral bioavailability is approximately 90%. Food has little effect on 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): 1.7 to 2.7 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 50% bound to serum 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): Approximately 52% or oral or intravenous dose is metabolized via glucuronide and sulphate conjugation. The cytochrome P450 system is not involved in metabolism. The sulphate conjugate accounts for 38% of the dose, and the glucuronide conjugate accounts for 14% of the dose. •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 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% 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): 11.5-15.6 hours (single dose, oral) •Clearance (Drug A): No clearance available •Clearance (Drug B): 12 +/- 2 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): Symptoms of overdose include CNS and gastrointestinal effects such as decreased activity, somnolence, tremor, convulsions, vomiting, and diarrhea. The minimal lethal intravenous dose in mice and rats is 100 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Avelox, Moxeza, Vigamox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Moxifloxacin Moxifloxacino •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): Moxifloxacin is a fluoroquinolone antibiotic used to treat various 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 Moxifloxacin interact? Information: •Drug A: Buserelin •Drug B: Moxifloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Moxifloxacin. •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 sinus and lung infections such as sinusitis, pneumonia, and secondary infections in chronic bronchitis. Also for the treatment of bacterial conjunctivitis (pinkeye). •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): Moxifloxacin is a quinolone/fluoroquinolone antibiotic. Moxifloxacin can be used to treat infections caused by the following bacteria: Aerobic Gram-positive microorganisms: Corynebacterium species, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus warneri, Streptococcus pneumoniae, and Streptococcus viridans group. Aerobic Gram-negative microorganisms: Acinetobacter lwoffii, Haemophilus influenzae, and Haemophilus parainfluenzae. Other microorganisms: Chlamydia trachomatis. Moxifloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Moxifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. •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 bactericidal action of moxifloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. •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 gastrointestinal tract. Absolute oral bioavailability is approximately 90%. Food has little effect on 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): 1.7 to 2.7 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 50% bound to serum 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): Approximately 52% or oral or intravenous dose is metabolized via glucuronide and sulphate conjugation. The cytochrome P450 system is not involved in metabolism. The sulphate conjugate accounts for 38% of the dose, and the glucuronide conjugate accounts for 14% of the dose. •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 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% 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): 11.5-15.6 hours (single dose, oral) •Clearance (Drug A): No clearance available •Clearance (Drug B): 12 +/- 2 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): Symptoms of overdose include CNS and gastrointestinal effects such as decreased activity, somnolence, tremor, convulsions, vomiting, and diarrhea. The minimal lethal intravenous dose in mice and rats is 100 mg/kg. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Avelox, Moxeza, Vigamox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Moxifloxacin Moxifloxacino •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): Moxifloxacin is a fluoroquinolone antibiotic used to treat various 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 Nalidixic acid interact?

•Drug A: Buserelin •Drug B: Nalidixic acid •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nalidixic acid. •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 urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species. •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): Nalidixic acid is a quinolone antibacterial agent for oral administration. Nalidixic acid has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug. Nalidixic acid is bactericidal and is effective over the entire urinary pH range. Conventional chromosomal resistance to nalidixic acid taken in full dosage has been reported to emerge in approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to nalidixic acid has not been shown to be transferable via R factor. •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): Evidence exists for Nalidixic acid that its active metabolite, hydroxynalidixic acid, binds strongly, but reversibly, to DNA, interfering with synthesis of RNA and, consequently, with protein synthesis. •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, nalidixic acid is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 96%. Absorption may be delayed if taken with antacids. •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): Nalidixic acid is 93% bound to protein in the blood, and the active metabolite, hydroxynalidixic acid is 63% 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. 30% of administered dose is metabolized to the active metabolite, hydroxynalidixic acid. Rapid conjugation of parent drug and active metabolite to inactive metabolites. Metabolism may vary widely among individuals. In the urine, hydroxynalidixic acid represents 80 to 85% of the antibacterial 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): Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Approximately four percent of NegGram is excreted 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): 1.1 to 2.5 hours in healthy adult patients, and up to 21 hours in patients with impaired renal function. •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 ): Acute: 1160 mg/kg [Rat]. 572 mg/kg [Mouse]. Toxic psychosis, convulsions, increased intracranial pressure, or metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting, nausea, and lethargy may also occur following overdosage. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide nalidixique Acido nalidixico Acidum nalidixicum Nalidixic acid Nalidixinsäure •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): Nalidixic acid is a quinolone antibiotic used to treat urinary tract 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 Nalidixic acid interact? Information: •Drug A: Buserelin •Drug B: Nalidixic acid •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nalidixic acid. •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 urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species. •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): Nalidixic acid is a quinolone antibacterial agent for oral administration. Nalidixic acid has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug. Nalidixic acid is bactericidal and is effective over the entire urinary pH range. Conventional chromosomal resistance to nalidixic acid taken in full dosage has been reported to emerge in approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to nalidixic acid has not been shown to be transferable via R factor. •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): Evidence exists for Nalidixic acid that its active metabolite, hydroxynalidixic acid, binds strongly, but reversibly, to DNA, interfering with synthesis of RNA and, consequently, with protein synthesis. •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, nalidixic acid is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 96%. Absorption may be delayed if taken with antacids. •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): Nalidixic acid is 93% bound to protein in the blood, and the active metabolite, hydroxynalidixic acid is 63% 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. 30% of administered dose is metabolized to the active metabolite, hydroxynalidixic acid. Rapid conjugation of parent drug and active metabolite to inactive metabolites. Metabolism may vary widely among individuals. In the urine, hydroxynalidixic acid represents 80 to 85% of the antibacterial 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): Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Approximately four percent of NegGram is excreted 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): 1.1 to 2.5 hours in healthy adult patients, and up to 21 hours in patients with impaired renal function. •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 ): Acute: 1160 mg/kg [Rat]. 572 mg/kg [Mouse]. Toxic psychosis, convulsions, increased intracranial pressure, or metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting, nausea, and lethargy may also occur following overdosage. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide nalidixique Acido nalidixico Acidum nalidixicum Nalidixic acid Nalidixinsäure •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): Nalidixic acid is a quinolone antibiotic used to treat urinary tract 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 Nateglinide interact?

•Drug A: Buserelin •Drug B: Nateglinide •Severity: MODERATE •Description: The therapeutic efficacy of Nateglinide 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 non-insulin dependent-diabetes mellitus 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): Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Nateglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-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): Nateglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, nateglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, nateglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of nateglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Nateglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue. •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 prior to a meal, absolute bioavailability is estimated to be approximately 73%. Peak plasma concentrations generally occur within 1 hour of oral administration. Onset of action is <20 minutes and the duration of action is approximately 4 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): 10 liters in healthy subjects •Protein binding (Drug A): 15% •Protein binding (Drug B): 98% bound to serum proteins, primarily serum albumin and to a lesser extent α1 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): Hepatic, via cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). Metabolism is via hydroxylation followed by glucuronidation. The major metabolites have less antidiabetic activity than nateglinide, but the isoprene minor metabolite has antidiabetic activity comparable to that of nateglinide. •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 (83%) and feces (10%) •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): 1.5 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): An overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. •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): Nateglinide is a meglitinide used to treat 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 Nateglinide interact? Information: •Drug A: Buserelin •Drug B: Nateglinide •Severity: MODERATE •Description: The therapeutic efficacy of Nateglinide 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 non-insulin dependent-diabetes mellitus 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): Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Nateglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-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): Nateglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, nateglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, nateglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of nateglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Nateglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue. •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 prior to a meal, absolute bioavailability is estimated to be approximately 73%. Peak plasma concentrations generally occur within 1 hour of oral administration. Onset of action is <20 minutes and the duration of action is approximately 4 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): 10 liters in healthy subjects •Protein binding (Drug A): 15% •Protein binding (Drug B): 98% bound to serum proteins, primarily serum albumin and to a lesser extent α1 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): Hepatic, via cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). Metabolism is via hydroxylation followed by glucuronidation. The major metabolites have less antidiabetic activity than nateglinide, but the isoprene minor metabolite has antidiabetic activity comparable to that of nateglinide. •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 (83%) and feces (10%) •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): 1.5 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): An overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. •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): Nateglinide is a meglitinide used to treat 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 Nelfinavir interact?

•Drug A: Buserelin •Drug B: Nelfinavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nelfinavir 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 in combination with other antiviral drugs in the treatment of HIV in both adults and children. •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): Nelfinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. 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. Nelfinavir 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. •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): HIV viral protease is an important enzyme for HIV maturation and pathogenicity since HIV produces its structural and key proteins in the form of a polyprotein that needs to be cleaved by a protease. HIV protease is synthesized as part of the Gag-pol polyprotein, where Gag encodes for the capsid and matrix protein to form the outer protein shell, and Pol encodes for the reverse transcriptase and integrase protein to synthesize and incorporate its genome into host cells. The Gag-pol polyprotein undergoes proteolytic cleavage by HIV protease to produce 66 molecular species which will assume conformational changes to become fully active. Inhibition of protease, therefore, prevents HIV virion from fully maturing and becoming infective. Nelfinavir is a competitive inhibitor of the HIV protease by reversibly binding to the active site of the enzyme, preventing it from interacting with its substrate to produce mature and infectious viral particles. •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 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): The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Nelfinavir in serum is extensively protein-bound (>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): Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for the metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to 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): The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1–2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component. •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 plasma was typically 3.5 to 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral clearance estimates after single doses (24-33 L/h) and multiple doses (26-61 L/h) indicate that nelfinavir is a drug with medium to high hepatic bioavailability. •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 in mice and rats were conducted with nelfinavir at oral doses up to 1000 mg/kg/day. No evidence of a tumorigenic effect was noted in mice at systemic exposures (Cmax) up to 9-fold those measured in humans at the recommended therapeutic dose (750 mg TID or 1250 mg BID). In rats, thyroid follicular cell adenomas and carcinomas were increased in males at 300 mg/kg/day and higher and in females at 1000 mg/kg/day. Systemic exposures (Cmax) at 300 and 1000 mg/kg/day were 1- to 3-fold, respectively, those measured in humans at the recommended therapeutic dose. Repeated administration of nelfinavir to rats produced effects consistent with hepatic microsomal enzyme induction and increased thyroid hormone deposition; these effects predispose rats, but not humans, to thyroid follicular cell neoplasms. Nelfinavir showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo genetic toxicology assays. These studies included bacterial mutation assays in S. typhimurium and E. coli, a mouse lymphoma tyrosine kinase assay, a chromosomal aberration assay in human lymphocytes, and an in vivo mouse bone marrow micronucleus assay. Nelfinavir produced no effects on either male or female mating and fertility or embryo survival in rats at systemic exposures comparable to the human therapeutic exposure. Human experience of acute overdose with nelfinavir is limited. There is no specific antidote for overdose with VIRACEPT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid the removal of unabsorbed drug. Since nelfinavir is highly protein-bound, dialysis is unlikely to significantly remove the drug from blood. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Viracept •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): Nelfinavir is a viral protease inhibitor used in the treatment of HIV infection.

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 Nelfinavir interact? Information: •Drug A: Buserelin •Drug B: Nelfinavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nelfinavir 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 in combination with other antiviral drugs in the treatment of HIV in both adults and children. •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): Nelfinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. 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. Nelfinavir 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. •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): HIV viral protease is an important enzyme for HIV maturation and pathogenicity since HIV produces its structural and key proteins in the form of a polyprotein that needs to be cleaved by a protease. HIV protease is synthesized as part of the Gag-pol polyprotein, where Gag encodes for the capsid and matrix protein to form the outer protein shell, and Pol encodes for the reverse transcriptase and integrase protein to synthesize and incorporate its genome into host cells. The Gag-pol polyprotein undergoes proteolytic cleavage by HIV protease to produce 66 molecular species which will assume conformational changes to become fully active. Inhibition of protease, therefore, prevents HIV virion from fully maturing and becoming infective. Nelfinavir is a competitive inhibitor of the HIV protease by reversibly binding to the active site of the enzyme, preventing it from interacting with its substrate to produce mature and infectious viral particles. •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 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): The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Nelfinavir in serum is extensively protein-bound (>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): Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for the metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to 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): The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1–2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component. •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 plasma was typically 3.5 to 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral clearance estimates after single doses (24-33 L/h) and multiple doses (26-61 L/h) indicate that nelfinavir is a drug with medium to high hepatic bioavailability. •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 in mice and rats were conducted with nelfinavir at oral doses up to 1000 mg/kg/day. No evidence of a tumorigenic effect was noted in mice at systemic exposures (Cmax) up to 9-fold those measured in humans at the recommended therapeutic dose (750 mg TID or 1250 mg BID). In rats, thyroid follicular cell adenomas and carcinomas were increased in males at 300 mg/kg/day and higher and in females at 1000 mg/kg/day. Systemic exposures (Cmax) at 300 and 1000 mg/kg/day were 1- to 3-fold, respectively, those measured in humans at the recommended therapeutic dose. Repeated administration of nelfinavir to rats produced effects consistent with hepatic microsomal enzyme induction and increased thyroid hormone deposition; these effects predispose rats, but not humans, to thyroid follicular cell neoplasms. Nelfinavir showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo genetic toxicology assays. These studies included bacterial mutation assays in S. typhimurium and E. coli, a mouse lymphoma tyrosine kinase assay, a chromosomal aberration assay in human lymphocytes, and an in vivo mouse bone marrow micronucleus assay. Nelfinavir produced no effects on either male or female mating and fertility or embryo survival in rats at systemic exposures comparable to the human therapeutic exposure. Human experience of acute overdose with nelfinavir is limited. There is no specific antidote for overdose with VIRACEPT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid the removal of unabsorbed drug. Since nelfinavir is highly protein-bound, dialysis is unlikely to significantly remove the drug from blood. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Viracept •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): Nelfinavir is a viral protease inhibitor used in the treatment of HIV infection. 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 Nicardipine interact?

•Drug A: Buserelin •Drug B: Nicardipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nicardipine 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 for the management of patients with chronic stable angina and for the treatment of hypertension. •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): Nicardipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nicardipine is similar to other peripheral vasodilators. Nicardipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. 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. •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): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, nicardipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes 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. •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): While nicardipine is completely absorbed, it is subject to saturable first pass metabolism and the systemic bioavailability is about 35% following a 30 mg oral dose at steady 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): 8.3 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): >95% •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): Nicardipine HCl is metabolized extensively 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): Nicardipine has been shown to be rapidly and extensively metabolized by the liver. •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): 8.6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.4 L/hr∙kg [Following infusion] •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 Rat = 184 mg/kg, Oral LD 50 Mouse = 322 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cardene •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): Nicardipine is a calcium channel blocker used for the short-term treatment of hypertension and chronic stable angina.

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 Nicardipine interact? Information: •Drug A: Buserelin •Drug B: Nicardipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nicardipine 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 for the management of patients with chronic stable angina and for the treatment of hypertension. •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): Nicardipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nicardipine is similar to other peripheral vasodilators. Nicardipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. 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. •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): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, nicardipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes 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. •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): While nicardipine is completely absorbed, it is subject to saturable first pass metabolism and the systemic bioavailability is about 35% following a 30 mg oral dose at steady 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): 8.3 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): >95% •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): Nicardipine HCl is metabolized extensively 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): Nicardipine has been shown to be rapidly and extensively metabolized by the liver. •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): 8.6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.4 L/hr∙kg [Following infusion] •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 Rat = 184 mg/kg, Oral LD 50 Mouse = 322 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Cardene •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): Nicardipine is a calcium channel blocker used for the short-term treatment of hypertension and chronic stable angina. 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 Nifedipine interact?

•Drug A: Buserelin •Drug B: Nifedipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nifedipine. •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): Nifedipine capsules are indicated to treat vasospastic angina and chronic stable angina. Extended release tablets are indicated to treat vasospastic angina, chronic stable angina, and hypertension. •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): Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart. Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction. •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): Nifedipine blocks voltage gated L-type calcium channels in vascular smooth muscle and myocardial cells. This blockage prevents the entry of calcium ions into cells during depolarization, reducing peripheral arterial vascular resistance and dilating coronary arteries. These actions reduce blood pressure and increase the supply of oxygen to the heart, alleviating 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): Sublingual dosing leads to a C max of 10ng/mL, with a T max of 50min, and an AUC of 25ng*h/mL. Oral dosing leads to a C max of 82ng/mL, with a T max of 28min, and an AUC of 152ng*h/mL. Nifedipine is a Biopharmaceutics Classification System Class II drug, meaning it has low solubility and high intestinal permeability. It is almost completely absorbed in the gastrointestinal tract but has a bioavilability of 45-68%, partly due to first pass metabolism. •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 nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Nifedipine is 92-98% protein bound in serum. Nifedipine is 97±12% bound in a 40g/L solution of pure albumin. Nifedipine is 51.4±5.9% protein bound in a 50mg/100mL solution of alpha-1-acid glycoprotein, and 75.5±3.5% protein bound in a 150mg/mL solution. •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): Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is predominantly metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, and then further metabolized to 2-hydroxymethyl-pyridine carboxylic acid. Nifedipine is also minorly metabolized to dehydronifedipine. •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): Nifedipine is 60-80% recovered in the urine as inactive water soluble metabolites, and the rest is eliminated in the feces 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 elimination half life of nifedipine is approximately 2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance of nifedipine is 450-700mL/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): The oral LD 50 in rats is 1022mg/kg and in mice is 202mg/kg. Patients experiencing an overdose may present with hypotension, sinus node dysfunction, atrioventricular node dysfunction, and reflex tachycardia. Overdose may be managed by monitoring cardiovascular and respiratory function; elevating extremities; and administering vasopressors, fluids, and calcium infusions. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Adalat, Afeditab CR, Nifediac, Nifedical, Procardia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Nifedipine Nifedipino Nifedipinum •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): Nifedipine is a dihydropyridine calcium channel blocker indicated for the management of several subtypes of angina pectoris, and hypertension.

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 Nifedipine interact? Information: •Drug A: Buserelin •Drug B: Nifedipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nifedipine. •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): Nifedipine capsules are indicated to treat vasospastic angina and chronic stable angina. Extended release tablets are indicated to treat vasospastic angina, chronic stable angina, and hypertension. •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): Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart. Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction. •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): Nifedipine blocks voltage gated L-type calcium channels in vascular smooth muscle and myocardial cells. This blockage prevents the entry of calcium ions into cells during depolarization, reducing peripheral arterial vascular resistance and dilating coronary arteries. These actions reduce blood pressure and increase the supply of oxygen to the heart, alleviating 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): Sublingual dosing leads to a C max of 10ng/mL, with a T max of 50min, and an AUC of 25ng*h/mL. Oral dosing leads to a C max of 82ng/mL, with a T max of 28min, and an AUC of 152ng*h/mL. Nifedipine is a Biopharmaceutics Classification System Class II drug, meaning it has low solubility and high intestinal permeability. It is almost completely absorbed in the gastrointestinal tract but has a bioavilability of 45-68%, partly due to first pass metabolism. •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 nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Nifedipine is 92-98% protein bound in serum. Nifedipine is 97±12% bound in a 40g/L solution of pure albumin. Nifedipine is 51.4±5.9% protein bound in a 50mg/100mL solution of alpha-1-acid glycoprotein, and 75.5±3.5% protein bound in a 150mg/mL solution. •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): Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is predominantly metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, and then further metabolized to 2-hydroxymethyl-pyridine carboxylic acid. Nifedipine is also minorly metabolized to dehydronifedipine. •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): Nifedipine is 60-80% recovered in the urine as inactive water soluble metabolites, and the rest is eliminated in the feces 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 elimination half life of nifedipine is approximately 2 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance of nifedipine is 450-700mL/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): The oral LD 50 in rats is 1022mg/kg and in mice is 202mg/kg. Patients experiencing an overdose may present with hypotension, sinus node dysfunction, atrioventricular node dysfunction, and reflex tachycardia. Overdose may be managed by monitoring cardiovascular and respiratory function; elevating extremities; and administering vasopressors, fluids, and calcium infusions. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Adalat, Afeditab CR, Nifediac, Nifedical, Procardia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Nifedipine Nifedipino Nifedipinum •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): Nifedipine is a dihydropyridine calcium channel blocker indicated for the management of several subtypes of angina pectoris, and hypertension. 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 Nilotinib interact?

•Drug A: Buserelin •Drug B: Nilotinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nilotinib. •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 potential treatment of various leukemias, including chronic myeloid leukemia (CML). •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): Nilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML). •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): Chronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006). •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 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): 15 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): Tasigna •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): Nilotinib is a kinase inhibitor used for the chronic phase treatment of Chronic Myeloid Leukemia (CML) that is Philadelphia chromosome positive and for the treatment of CML that is resistant to therapy containing imatinib.

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 Nilotinib interact? Information: •Drug A: Buserelin •Drug B: Nilotinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nilotinib. •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 potential treatment of various leukemias, including chronic myeloid leukemia (CML). •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): Nilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML). •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): Chronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006). •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 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): 15 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): Tasigna •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): Nilotinib is a kinase inhibitor used for the chronic phase treatment of Chronic Myeloid Leukemia (CML) that is Philadelphia chromosome positive and for the treatment of CML that is resistant to therapy containing imatinib. 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 Nilvadipine interact?

•Drug A: Buserelin •Drug B: Nilvadipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nilvadipine. •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 management of vasospastic angina, chronic stable angina and hypertension. •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): Nilvadipine is similar to other dihydropyridines including amlodipine, felodipine, isradipine, and nicardipine. Nilvadipine is used to treat Prinzmetal's angina, hypertension, and other vascular disorders such as Raynaud's phenomenon. By blocking the calcium channels, Nifedipine inhibits the spasm of the coronary artery and dilates the systemic arteries, results in a increase of myocardial oxygen supply and a decrease in systemic blood pressure. •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): Nilvadipine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of 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. •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): 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): Nilvadipine is a calcium channel blocker used to manage arterial hypertension.

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 Nilvadipine interact? Information: •Drug A: Buserelin •Drug B: Nilvadipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nilvadipine. •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 management of vasospastic angina, chronic stable angina and hypertension. •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): Nilvadipine is similar to other dihydropyridines including amlodipine, felodipine, isradipine, and nicardipine. Nilvadipine is used to treat Prinzmetal's angina, hypertension, and other vascular disorders such as Raynaud's phenomenon. By blocking the calcium channels, Nifedipine inhibits the spasm of the coronary artery and dilates the systemic arteries, results in a increase of myocardial oxygen supply and a decrease in systemic blood pressure. •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): Nilvadipine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of 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. •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): 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): Nilvadipine is a calcium channel blocker used to manage arterial hypertension. 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 Nimodipine interact?

•Drug A: Buserelin •Drug B: Nimodipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nimodipine. •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 use as an adjunct to improve neurologic outcome following subarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysms by reducing the incidence and severity of ischemic deficits. •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): Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured congenital aneurysms who are in good neurological condition post-ictus (e.g., Hunt and Hess Grades I-III). The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood brain barrier. •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 of action is not known, nimodipine blocks intracellular influx of calcium through voltage-dependent and receptor-operated slow calcium channels across the membranes of myocardial, vascular smooth muscle, and neuronal cells. By specifically binding to L-type voltage-gated calcium channels, nimodipine inhibits the calcium ion transfer, resulting in the inhibition of vascular smooth muscle contraction. Evidence suggests that the dilation of small cerebral resistance vessels, with a resultant increase in collateral circulation, and/or a direct effect involving the prevention of calcium overload in neurons may be responsible for nimodipine's clinical effect in patients with subarachnoid hemorrhage. •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, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. Bioavailability is 100% following intravenous administration and 3-30% following oral administration due to extensive first-pass metabolism. •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% 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): Hepatic metabolism via CYP 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): Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. •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): 1.7-9 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 would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nimotop, Nymalize •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Nimodipine Nimodipino Nimodipinum •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): Nimodipine is a calcium channel blocker used to improve neurological outcomes in patients with subarachnoid hemorrhage due to a ruptured intracranial aneurysm.

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 Nimodipine interact? Information: •Drug A: Buserelin •Drug B: Nimodipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Nimodipine. •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 use as an adjunct to improve neurologic outcome following subarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysms by reducing the incidence and severity of ischemic deficits. •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): Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured congenital aneurysms who are in good neurological condition post-ictus (e.g., Hunt and Hess Grades I-III). The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood brain barrier. •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 of action is not known, nimodipine blocks intracellular influx of calcium through voltage-dependent and receptor-operated slow calcium channels across the membranes of myocardial, vascular smooth muscle, and neuronal cells. By specifically binding to L-type voltage-gated calcium channels, nimodipine inhibits the calcium ion transfer, resulting in the inhibition of vascular smooth muscle contraction. Evidence suggests that the dilation of small cerebral resistance vessels, with a resultant increase in collateral circulation, and/or a direct effect involving the prevention of calcium overload in neurons may be responsible for nimodipine's clinical effect in patients with subarachnoid hemorrhage. •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, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. Bioavailability is 100% following intravenous administration and 3-30% following oral administration due to extensive first-pass metabolism. •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% 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): Hepatic metabolism via CYP 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): Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. •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): 1.7-9 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 would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nimotop, Nymalize •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Nimodipine Nimodipino Nimodipinum •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): Nimodipine is a calcium channel blocker used to improve neurological outcomes in patients with subarachnoid hemorrhage due to a ruptured intracranial aneurysm. 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 Nitrendipine interact?

•Drug A: Buserelin •Drug B: Nitrendipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nitrendipine 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 mild to moderate hypertension •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): Nitrendipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nitrendipine is similar to other peripheral vasodilators. Nitrendipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. 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. •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): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nitrendipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes 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. •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): > 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): 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): Nitrendipine Nitrendipino Nitrendipinum •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): Nitrendipine is a dihydropyridine calcium channel blocker indicated in the treatment of arterial hypertension.

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 Nitrendipine interact? Information: •Drug A: Buserelin •Drug B: Nitrendipine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nitrendipine 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 mild to moderate hypertension •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): Nitrendipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nitrendipine is similar to other peripheral vasodilators. Nitrendipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. 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. •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): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nitrendipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes 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. •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): > 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): 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): Nitrendipine Nitrendipino Nitrendipinum •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): Nitrendipine is a dihydropyridine calcium channel blocker indicated in the treatment of arterial hypertension. 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 Norfloxacin interact?

•Drug A: Buserelin •Drug B: Norfloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Norfloxacin 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 urinary tract infection •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): Norfloxacin is a quinolone/fluoroquinolone antibiotic. Norfloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. •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 bactericidal action of Norfloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. Norfloxacin is a broad-spectrum antibiotic agent that is shown to be effective against various Gram-positive and Gram-negative bacterial species. The fluorine atom at the 6 position increases potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for anti-pseudomonal 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): Rapid •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): 10 and 15% (Serum 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): Via liver and kidney •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): Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. It is expected to undergo both glomerular filtration and tubular secretion during renal excretion, as shown by its high renal clearance rate of approximately 275 mL/min. •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): 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): NFLX Norfloxacin Norfloxacine Norfloxacino Norfloxacinum •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): Norfloxacin is a broad-spectrum fluoroquinolone antibiotic with variable activity against gram-positive and gram-negative bacteria. Typically reserved for the treatment of UTIs due to accumulation in the urine.

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 Norfloxacin interact? Information: •Drug A: Buserelin •Drug B: Norfloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Norfloxacin 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 urinary tract infection •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): Norfloxacin is a quinolone/fluoroquinolone antibiotic. Norfloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. •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 bactericidal action of Norfloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. Norfloxacin is a broad-spectrum antibiotic agent that is shown to be effective against various Gram-positive and Gram-negative bacterial species. The fluorine atom at the 6 position increases potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for anti-pseudomonal 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): Rapid •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): 10 and 15% (Serum 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): Via liver and kidney •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): Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. It is expected to undergo both glomerular filtration and tubular secretion during renal excretion, as shown by its high renal clearance rate of approximately 275 mL/min. •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): 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): NFLX Norfloxacin Norfloxacine Norfloxacino Norfloxacinum •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): Norfloxacin is a broad-spectrum fluoroquinolone antibiotic with variable activity against gram-positive and gram-negative bacteria. Typically reserved for the treatment of UTIs due to accumulation in the urine. 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 Nortriptyline interact?

•Drug A: Buserelin •Drug B: Nortriptyline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nortriptyline 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): Nortriptyline is indicated for the relief of the symptoms of major depressive disorder (MDD). Some off-label uses for this drug include treatment of chronic pain, myofascial pain, neuralgia, and irritable bowel 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): Nortriptyline exerts antidepressant effects likely by inhibiting the reuptake of serotonin and norepinephrine at neuronal cell membranes. It also exerts antimuscarinic effects through its actions on the acetylcholine receptor. •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): Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other 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): Nortriptyline is readily absorbed in the gastrointestinal tract with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%. •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 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of nortriptyline is approximately 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): Nortriptyline is metabolized via demethylation and hydroxylation in the liver followed by glucuronic acid conjugation. CYP2D6 plays a large role in nortriptyline metabolism, with contributions from CYP1A2, CYP2C19 and CYP3A4. The main active metabolite is 10-hydroxynortriptyline exists in both cis and a trans form, with the trans form is higher in potency. 10-hydroxynortriptyline is the most frequently found in the plasma. Most of the other metabolites are conjugated, and are less potent. •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): Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine 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 average plasma half-life of nortriptyline in healthy volunteers is about 26 hours, but is said to range from 16 to 38 hours. One study mentions a mean half-life of about 39 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour. •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 nortriptyline in the rat is 405 mg/kg. Symptoms of overdose with nortriptyline include cardiac arrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, coma, and CNS depression. Changes in the electrocardiogram, particularly in QRS segment, may be indicative of tricyclic antidepressant toxicity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aventyl, Pamelor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Demethylamitriptyline Desmethylamitriptyline Nortriptylina Nortriptyline Nortriptylinum •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): Nortriptyline 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 Nortriptyline interact? Information: •Drug A: Buserelin •Drug B: Nortriptyline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Nortriptyline 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): Nortriptyline is indicated for the relief of the symptoms of major depressive disorder (MDD). Some off-label uses for this drug include treatment of chronic pain, myofascial pain, neuralgia, and irritable bowel 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): Nortriptyline exerts antidepressant effects likely by inhibiting the reuptake of serotonin and norepinephrine at neuronal cell membranes. It also exerts antimuscarinic effects through its actions on the acetylcholine receptor. •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): Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other 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): Nortriptyline is readily absorbed in the gastrointestinal tract with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%. •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 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of nortriptyline is approximately 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): Nortriptyline is metabolized via demethylation and hydroxylation in the liver followed by glucuronic acid conjugation. CYP2D6 plays a large role in nortriptyline metabolism, with contributions from CYP1A2, CYP2C19 and CYP3A4. The main active metabolite is 10-hydroxynortriptyline exists in both cis and a trans form, with the trans form is higher in potency. 10-hydroxynortriptyline is the most frequently found in the plasma. Most of the other metabolites are conjugated, and are less potent. •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): Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine 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 average plasma half-life of nortriptyline in healthy volunteers is about 26 hours, but is said to range from 16 to 38 hours. One study mentions a mean half-life of about 39 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour. •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 nortriptyline in the rat is 405 mg/kg. Symptoms of overdose with nortriptyline include cardiac arrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, coma, and CNS depression. Changes in the electrocardiogram, particularly in QRS segment, may be indicative of tricyclic antidepressant toxicity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aventyl, Pamelor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Demethylamitriptyline Desmethylamitriptyline Nortriptylina Nortriptyline Nortriptylinum •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): Nortriptyline 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 Octreotide interact?

•Drug A: Buserelin •Drug B: Octreotide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Octreotide 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): Octreotide by injection is used for the treatment of acromegaly and the reduction of flushing and diarrhea symptoms related to carcinoid tumors and/or vasoactive intestinal peptide (VIPoma) tumors. The delayed-release oral formulation is used for the long-term treatment of acromegaly in patients who tolerate and respond adequately to injectable octreotide and lanreotide. •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): Octreotide mimics the naturally occurring hormone known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea. Product labeling warns that octreotide may reduce gallbladder contractility, bile secretion, and the release of thyroid-stimulating hormone (TSH) in healthy volunteers. In addition, reports of decreased vitamin B12 in patients treated with octreotide have been made. Ensure to monitor vitamin B12 levels in patients taking octreotide. •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): Octreotide binds to somatostatin receptors coupled to phospholipase C through G proteins and leads to smooth muscle contraction in the blood vessels. Downstream effects that stimulate phospholipase C, the production of 1, 4,5-inositol triphosphate, and action on the L-type calcium channels lead to the inhibition of growth hormone, treating the various growth-hormone and metabolic effects of acromegaly. Octreotide's suppression of luteinizing hormone (LH), reduction in splanchnic blood flow, and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide provide relief for the gastrointestinal and flushing symptoms of carcinoid and/or VIPoma tumors. •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 a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1.67–2.5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2.5 mg/nL versus 5.30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route. •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, the volume of distribution was 13.6 L in healthy volunteers. One pharmacokinetic study revealed a volume of distribution ranging from 18.1-30.4L after intravenous administration in healthy volunteers. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 65% of the dose is bound in the plasma to lipoproteins and 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): Octreotide has been reported to be heavily metabolized in 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): About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces.. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered 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): After a subcutaneous dose, the plasma half-life is estimated to be 0.2 hours. The average elimination half-lives for subcutaneous and oral administration ranged from 2.3 - 2.7 hours and did not differ significantly. One pharmacokinetic study revealed a plasma half-life ranging from 72-113 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance of octreotide is 7-10 L/h. One pharmacokinetic study revealed a total body clearance of 11.4 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 limited information regarding cases of octreotide overdose aside from case reports of an overdose with injectable octreotide. The dose ranged from 2.4 mg/day to 6 mg/day administered by continuous infusion or subcutaneous administration of 1.5 mg three times daily. Effects of an overdose with octreotide may include hypotension, brain hypoxia, arrhythmia, cardiac arrest, lactic acidosis, pancreatitis, hepatomegaly, diarrhea, flushing, lethargy, and weakness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bynfezia, Mycapssa, Sandostatin •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): Octreotide is a peptide drug used to treat acromegaly as well as diarrhea associated with metastatic carcinoid tumors and vasoactive intestinal peptide secreting tumors.

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 Octreotide interact? Information: •Drug A: Buserelin •Drug B: Octreotide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Octreotide 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): Octreotide by injection is used for the treatment of acromegaly and the reduction of flushing and diarrhea symptoms related to carcinoid tumors and/or vasoactive intestinal peptide (VIPoma) tumors. The delayed-release oral formulation is used for the long-term treatment of acromegaly in patients who tolerate and respond adequately to injectable octreotide and lanreotide. •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): Octreotide mimics the naturally occurring hormone known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea. Product labeling warns that octreotide may reduce gallbladder contractility, bile secretion, and the release of thyroid-stimulating hormone (TSH) in healthy volunteers. In addition, reports of decreased vitamin B12 in patients treated with octreotide have been made. Ensure to monitor vitamin B12 levels in patients taking octreotide. •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): Octreotide binds to somatostatin receptors coupled to phospholipase C through G proteins and leads to smooth muscle contraction in the blood vessels. Downstream effects that stimulate phospholipase C, the production of 1, 4,5-inositol triphosphate, and action on the L-type calcium channels lead to the inhibition of growth hormone, treating the various growth-hormone and metabolic effects of acromegaly. Octreotide's suppression of luteinizing hormone (LH), reduction in splanchnic blood flow, and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide provide relief for the gastrointestinal and flushing symptoms of carcinoid and/or VIPoma tumors. •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 a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1.67–2.5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2.5 mg/nL versus 5.30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route. •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, the volume of distribution was 13.6 L in healthy volunteers. One pharmacokinetic study revealed a volume of distribution ranging from 18.1-30.4L after intravenous administration in healthy volunteers. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 65% of the dose is bound in the plasma to lipoproteins and 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): Octreotide has been reported to be heavily metabolized in 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): About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces.. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered 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): After a subcutaneous dose, the plasma half-life is estimated to be 0.2 hours. The average elimination half-lives for subcutaneous and oral administration ranged from 2.3 - 2.7 hours and did not differ significantly. One pharmacokinetic study revealed a plasma half-life ranging from 72-113 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance of octreotide is 7-10 L/h. One pharmacokinetic study revealed a total body clearance of 11.4 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 limited information regarding cases of octreotide overdose aside from case reports of an overdose with injectable octreotide. The dose ranged from 2.4 mg/day to 6 mg/day administered by continuous infusion or subcutaneous administration of 1.5 mg three times daily. Effects of an overdose with octreotide may include hypotension, brain hypoxia, arrhythmia, cardiac arrest, lactic acidosis, pancreatitis, hepatomegaly, diarrhea, flushing, lethargy, and weakness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Bynfezia, Mycapssa, Sandostatin •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): Octreotide is a peptide drug used to treat acromegaly as well as diarrhea associated with metastatic carcinoid tumors and vasoactive intestinal peptide secreting tumors. 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 Ofloxacin interact?

•Drug A: Buserelin •Drug B: Ofloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ofloxacin. •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 infections (respiratory tract, kidney, skin, soft tissue, UTI), urethral and cervical gonorrhoea. •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): Ofloxacin is a quinolone/fluoroquinolone antibiotic. Ofloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Ofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. •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): Ofloxacin acts on DNA gyrase and toposiomerase IV, enzymes which, like human topoisomerase, prevents the excessive supercoiling of DNA during replication or transcription. By inhibiting their function, the drug thereby inhibits normal cell division. •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 ofloxacin in the tablet formulation is approximately 98% •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): 32% •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): Ofloxacin is mainly eliminated by renal excretion, where between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via urine within 48 hours of dosing. About 4-8% of an ofloxacin dose is excreted in the feces and the drug is minimally subject to biliary 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): 9 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): LD 50 =5450 mg/kg (orally in mice) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ocuflox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ofloxacin Ofloxacine Ofloxacino Ofloxacinum OFLX •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): Ofloxacin is an antibacterial agent used for the treatment of bacterial infections in many parts of the body, including the respiratory tract, kidney, skin, soft tissue, and urinary tract.

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 Ofloxacin interact? Information: •Drug A: Buserelin •Drug B: Ofloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ofloxacin. •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 infections (respiratory tract, kidney, skin, soft tissue, UTI), urethral and cervical gonorrhoea. •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): Ofloxacin is a quinolone/fluoroquinolone antibiotic. Ofloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Ofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. •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): Ofloxacin acts on DNA gyrase and toposiomerase IV, enzymes which, like human topoisomerase, prevents the excessive supercoiling of DNA during replication or transcription. By inhibiting their function, the drug thereby inhibits normal cell division. •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 ofloxacin in the tablet formulation is approximately 98% •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): 32% •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): Ofloxacin is mainly eliminated by renal excretion, where between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via urine within 48 hours of dosing. About 4-8% of an ofloxacin dose is excreted in the feces and the drug is minimally subject to biliary 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): 9 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): LD 50 =5450 mg/kg (orally in mice) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ocuflox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ofloxacin Ofloxacine Ofloxacino Ofloxacinum OFLX •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): Ofloxacin is an antibacterial agent used for the treatment of bacterial infections in many parts of the body, including the respiratory tract, kidney, skin, soft tissue, and urinary tract. 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 Olanzapine interact?

•Drug A: Buserelin •Drug B: Olanzapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Olanzapine 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): Olanzapine was initially used orally and intramuscularly for the chronic treatment of schizophrenia in patients over 13 years old and other psychiatric disorders such as bipolar I disorder including mixed or manic episodes. Olanzapine is also indicated, in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in adults. As well, olanzapine is indicated, in combination with fluoxetine for the treatment of episodes of depression associated with bipolar disorder type 1 and treatment-resistant depression in patients over 10 years old. Olanzapine is also approved for the management of psychomotor agitation associated with schizophrenia and bipolar I mania. Schizophrenia is a complex biochemical brain disorder that affects the person's ability to differentiate reality. It is usually observed as the presence of delusions, hallucinations, social withdrawal and disturbed thinking. Bipolar disorder is a mental health condition defined by periods of extreme mood disturbances. It is categorized in different types from which type 1 is known to involve episodes of severe mania and often depression while type 2 presents less severe forms of mania. Olanzapine is also indicated in combination with samidorphan for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia 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): The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention. Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects. Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents. The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase. •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 activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor D1, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor, the histamine receptor H1 and multiple muscarinic receptors. As abovementioned, olanzapine presents a wide profile of targets, however, its antagonistic effect towards the dopamine D2 receptor in the mesolimbic pathway is key as it blocks dopamine from having a potential action at the post-synaptic receptor. The binding of olanzapine to the dopamine D2 receptors is easily dissociable and hence, it allows for a certain degree of dopamine neurotransmission. On the other hand, olanzapine acts in the serotonin 5HT2A receptors in the frontal cortex in a similar manner than the reported on dopamine D2 receptors. This determined effect allows for a decrease in 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): Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week. Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours 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): The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body. •Protein binding (Drug A): 15% •Protein binding (Drug B): Olanzapine is largely bound to plasma proteins and hence, about 93% of the administered dose is bound. The main proteins for binding are 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): Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system. From the CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6. As part of the phase I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2. On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine. On the phase II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine. •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): Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form. It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 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): Olanzapine presents a half-life ranging between 21 to 54 hours with an average half-life of 30 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 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 toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects. The overdosage effects in children are generally associated with more significant side effects. The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech. However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness. One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine. In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended. In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas. On fertility studies, there was solely found impairment in male mating performance and delays in ovulation. There is no evidence of mutagenic, genotoxic potential not adverse events on fertility. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lybalvi, Olazax, Symbyax, Zalasta, Zypadhera, Zyprexa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Olanzapin Olanzapina Olanzapine Olanzapinum •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): Olanzapine is an antipsychotic drug used in the management of schizophrenia, bipolar 1 disorder, and agitation associated with these disorders.

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 Olanzapine interact? Information: •Drug A: Buserelin •Drug B: Olanzapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Olanzapine 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): Olanzapine was initially used orally and intramuscularly for the chronic treatment of schizophrenia in patients over 13 years old and other psychiatric disorders such as bipolar I disorder including mixed or manic episodes. Olanzapine is also indicated, in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in adults. As well, olanzapine is indicated, in combination with fluoxetine for the treatment of episodes of depression associated with bipolar disorder type 1 and treatment-resistant depression in patients over 10 years old. Olanzapine is also approved for the management of psychomotor agitation associated with schizophrenia and bipolar I mania. Schizophrenia is a complex biochemical brain disorder that affects the person's ability to differentiate reality. It is usually observed as the presence of delusions, hallucinations, social withdrawal and disturbed thinking. Bipolar disorder is a mental health condition defined by periods of extreme mood disturbances. It is categorized in different types from which type 1 is known to involve episodes of severe mania and often depression while type 2 presents less severe forms of mania. Olanzapine is also indicated in combination with samidorphan for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia 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): The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention. Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects. Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents. The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase. •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 activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor D1, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor, the histamine receptor H1 and multiple muscarinic receptors. As abovementioned, olanzapine presents a wide profile of targets, however, its antagonistic effect towards the dopamine D2 receptor in the mesolimbic pathway is key as it blocks dopamine from having a potential action at the post-synaptic receptor. The binding of olanzapine to the dopamine D2 receptors is easily dissociable and hence, it allows for a certain degree of dopamine neurotransmission. On the other hand, olanzapine acts in the serotonin 5HT2A receptors in the frontal cortex in a similar manner than the reported on dopamine D2 receptors. This determined effect allows for a decrease in 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): Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week. Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours 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): The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body. •Protein binding (Drug A): 15% •Protein binding (Drug B): Olanzapine is largely bound to plasma proteins and hence, about 93% of the administered dose is bound. The main proteins for binding are 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): Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system. From the CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6. As part of the phase I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2. On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine. On the phase II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine. •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): Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form. It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 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): Olanzapine presents a half-life ranging between 21 to 54 hours with an average half-life of 30 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 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 toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects. The overdosage effects in children are generally associated with more significant side effects. The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech. However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness. One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine. In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended. In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas. On fertility studies, there was solely found impairment in male mating performance and delays in ovulation. There is no evidence of mutagenic, genotoxic potential not adverse events on fertility. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lybalvi, Olazax, Symbyax, Zalasta, Zypadhera, Zyprexa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Olanzapin Olanzapina Olanzapine Olanzapinum •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): Olanzapine is an antipsychotic drug used in the management of schizophrenia, bipolar 1 disorder, and agitation associated with these disorders. 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 Olodaterol interact?

•Drug A: Buserelin •Drug B: Olodaterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Olodaterol. •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): Olodaterol is indicated for use in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. It is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma. •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): Olodaterol is a potent agonist of the human beta2-adrenergic receptor in vitro, and is highly selective for this receptor, with much lower levels of activity at the b1- and b3-adrenergic receptors that are commonly expressed on cardiac smooth muscle and adipose tissue, respectively. Binding to the receptor causes smooth muscle relaxation in the lungs and bronchodilation. It has also been shown to potently reverse active bronchoconstriction. •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): Olodaterol is a long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. •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): Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic 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): The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro binding of olodaterol to human plasma proteins is independent of concentration and is approximately 60%. •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): Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides. •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 of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). •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 following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 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): Adverse drug reactions that occurred at a frequency greater than 2% include nasopharyngitis (11.3%), upper respiratory tract infection (8.2%), bronchitis (4.7%), urinary tract infection (2.5%), cough (4.2%), dizziness (2.3%), rash (2.2%), diarrhea (2.9%), back pain (3.5%), and arthralgia (2.1%). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Inspiolto Respimat, Stiolto, Striverdi Respimat •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): Olodaterol is a long-acting beta2-adrenergic agonist used in the management of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or 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 Olodaterol interact? Information: •Drug A: Buserelin •Drug B: Olodaterol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Olodaterol. •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): Olodaterol is indicated for use in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. It is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma. •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): Olodaterol is a potent agonist of the human beta2-adrenergic receptor in vitro, and is highly selective for this receptor, with much lower levels of activity at the b1- and b3-adrenergic receptors that are commonly expressed on cardiac smooth muscle and adipose tissue, respectively. Binding to the receptor causes smooth muscle relaxation in the lungs and bronchodilation. It has also been shown to potently reverse active bronchoconstriction. •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): Olodaterol is a long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. •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): Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic 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): The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro binding of olodaterol to human plasma proteins is independent of concentration and is approximately 60%. •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): Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides. •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 of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). •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 following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 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): Adverse drug reactions that occurred at a frequency greater than 2% include nasopharyngitis (11.3%), upper respiratory tract infection (8.2%), bronchitis (4.7%), urinary tract infection (2.5%), cough (4.2%), dizziness (2.3%), rash (2.2%), diarrhea (2.9%), back pain (3.5%), and arthralgia (2.1%). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Inspiolto Respimat, Stiolto, Striverdi Respimat •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): Olodaterol is a long-acting beta2-adrenergic agonist used in the management of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or 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 Ondansetron interact?

•Drug A: Buserelin •Drug B: Ondansetron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ondansetron. •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): In the adult patient population: i) orally administered ondansetron tablets and orally disintegrating tablets (ODT) are indicated for: - the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including high dose (ie. greater than or equal to 50 mg/m2) cisplatin therapy, and radiotherapy, and - the prevention and treatment of postoperative nausea and vomiting ii) intravenously administered ondansetron injection formulations are indicated for: - the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including high dose (ie. greater than or equal to 50 mg/m2) cisplatin therapy, and - the prevention and treatment of postoperative nausea and vomiting In the pediatric (4-18 years of age) patient population: i) ondansetron was effective and well tolerated when given to children 4-12 years of age for the treatment of post-chemotherapy induced nausea and vomiting, ii) ondansetron tablets, ondansetron ODT, ondansetron injection are not indicated for the treatment of children 3 years of age or younger, iii) ondansetron tablets, ondansetron ODT, ondansetron injection are not indicated for use in any age group of the pediatric population for the treatment of post-radiotherapy induced nausea and vomiting, and iV) ondansetron tablets, ondansetron ODT, ondansetron injection are not indicated for use in any age group of the pediatric population for the treatment of postoperative nausea and vomiting In the geriatric (>65 years of age) patient population: i) efficacy and tolerance of ondansetron were similar to that observed in younger adults for the treatment of post-chemotherapy and radiotherapy-induced nausea and vomiting, and ii) clinical experience in the use of ondansetron in the prevention and treatment of postoperative nausea and vomiting is limited and is not indicated for use in the geriatric patient population •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): Ondansetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors,. The serotonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema,. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract,. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting,. Moreover, the effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, prolongation of the Fridericia-corrected QTc interval (QT/RR0.33=QTcF) was observed from 15 min to 4 h after the start of the 15 min infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 (21.5) msec at 20 min. At the lower tested dose of 8 mg, QTc prolongation was observed from 15 min to 1 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min. The magnitude of QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes. The 32 mg intravenous dose of ondansetron must not be administered. No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 or 32 mg dose. An ECG assessment study has not been performed for orally administered ondansetron. On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron is predicted to cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at steady-state, assuming a mean maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0). The magnitude of QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modeling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations. In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma prolactin concentrations. •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): Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both. Although the mechanisms of action of ondansetron in treating postoperative nausea and vomiting and cytotoxic induced nausea and vomiting may share similar pathways, the role of ondansetron in opiate-induced emesis has not yet been formally established. •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): Ondansetron is absorbed from the gastrointestinal tract and undergoes some limited first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, was recorded as being approximately 56% to 60%. Bioavailability is also slightly enhanced by the presence of food. Ondansetron systemic exposure does not increase proportionately to dose. The AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. •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 ondansetron has been recorded as being approximately 160L. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding associated with ondansetron was documented as approximately 73%. •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 metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes, including CYP1A2, CYP2D6 and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g. CYP2D6 enzyme deficiency) will be compensated by others and may result in little change in overall rates of ondansetron clearance. Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces. In humans, less than 10% of the dose is excreted unchanged in the urine. The major urinary metabolites are glucuronide conjugates (45%), sulphate conjugates (20%) and hydroxylation products (10%). The primary metabolic pathway is subsequently hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. •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 or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces. •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 ondansetron after either an 8 mg oral dose or intravenous dose was approximately 3-4 hours and could be extended to 6-8 hours in the elderly. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance values determined for ondansetron in various patient age groups were recorded as approximately 0.38 L/h/kg in normal adult volunteers aged 19-40 yrs, 0.32 L/h/kg in normal adult volunteers aged 61-74 yrs, 0.26 L/h/kg in normal adult volunteers aged >=75 yrs. •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): At present, there is little information concerning overdosage with ondansetron. Nevertheless, there have been certain cases of somewhat idiosyncratic adverse effects associated with particular dosages of ondansetron used. “Sudden blindness” (amaurosis) of 2 to 3 minutes duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. Neuromuscular abnormalities, autonomic instability, somnolence, and a brief generalized tonic-clonic seizure (which resolved after a dose of benzodiazepine) were observed in a 12-month-old infant who ingested seven or eight 8-mg ondansetron tablets (approximately forty times the recommended 0.1-0.15 mg/kg dose for a pediatric patient). In all instances, however, the events resolved completely. The safety of ondansetron for use in human pregnancy has not been established. Ondansetron is not teratogenic in animals. However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended. Ondansetron is excreted in the milk of lactating rats. It is not known if it is excreted in human milk, however, nursing is not recommended during treatment with ondansetron. Insufficient information is available to provide dosage recommendations for children 3 years of age or younger. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zofran, Zuplenz •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): Ondansetron is a serotonin 5-HT3 receptor antagonist used to prevent nausea and vomiting in cancer chemotherapy and postoperatively.

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 Ondansetron interact? Information: •Drug A: Buserelin •Drug B: Ondansetron •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ondansetron. •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): In the adult patient population: i) orally administered ondansetron tablets and orally disintegrating tablets (ODT) are indicated for: - the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including high dose (ie. greater than or equal to 50 mg/m2) cisplatin therapy, and radiotherapy, and - the prevention and treatment of postoperative nausea and vomiting ii) intravenously administered ondansetron injection formulations are indicated for: - the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, including high dose (ie. greater than or equal to 50 mg/m2) cisplatin therapy, and - the prevention and treatment of postoperative nausea and vomiting In the pediatric (4-18 years of age) patient population: i) ondansetron was effective and well tolerated when given to children 4-12 years of age for the treatment of post-chemotherapy induced nausea and vomiting, ii) ondansetron tablets, ondansetron ODT, ondansetron injection are not indicated for the treatment of children 3 years of age or younger, iii) ondansetron tablets, ondansetron ODT, ondansetron injection are not indicated for use in any age group of the pediatric population for the treatment of post-radiotherapy induced nausea and vomiting, and iV) ondansetron tablets, ondansetron ODT, ondansetron injection are not indicated for use in any age group of the pediatric population for the treatment of postoperative nausea and vomiting In the geriatric (>65 years of age) patient population: i) efficacy and tolerance of ondansetron were similar to that observed in younger adults for the treatment of post-chemotherapy and radiotherapy-induced nausea and vomiting, and ii) clinical experience in the use of ondansetron in the prevention and treatment of postoperative nausea and vomiting is limited and is not indicated for use in the geriatric patient population •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): Ondansetron is a highly specific and selective serotonin 5-HT 3 receptor antagonist, not shown to have activity at other known serotonin receptors and with low affinity for dopamine receptors,. The serotonin 5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema,. The temporal relationship between the emetogenic action of emetogenic drugs and the release of serotonin, as well as the efficacy of antiemetic agents, suggest that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract,. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT 3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting,. Moreover, the effect of ondansetron on the QTc interval was evaluated in a double-blind, randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron was tested at single doses of 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, prolongation of the Fridericia-corrected QTc interval (QT/RR0.33=QTcF) was observed from 15 min to 4 h after the start of the 15 min infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 19.6 (21.5) msec at 20 min. At the lower tested dose of 8 mg, QTc prolongation was observed from 15 min to 1 h after the start of the 15-minute infusion, with a maximum mean (upper limit of 90% CI) difference in QTcF from placebo after baseline-correction of 5.8 (7.8) msec at 15 min. The magnitude of QTc prolongation with ondansetron is expected to be greater if the infusion rate is faster than 15 minutes. The 32 mg intravenous dose of ondansetron must not be administered. No treatment-related effects on the QRS duration or the PR interval were observed at either the 8 or 32 mg dose. An ECG assessment study has not been performed for orally administered ondansetron. On the basis of pharmacokinetic-pharmacodynamic modelling, an 8 mg oral dose of ondansetron is predicted to cause a mean QTcF increase of 0.7 ms (90% CI -2.1, 3.3) at steady-state, assuming a mean maximal plasma concentration of 24.7 ng/mL (95% CI 21.1, 29.0). The magnitude of QTc prolongation at the recommended 5 mg/m2 dose in pediatrics has not been studied, but pharmacokinetic-pharmacodynamic modeling predicts a mean increase of 6.6 ms (90% CI 2.8, 10.7) at maximal plasma concentrations. In healthy subjects, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of ondansetron has been shown to slow colonic transit in healthy subjects. Ondansetron has no effect on plasma prolactin concentrations. •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): Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3. Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents. Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle. Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both. Although the mechanisms of action of ondansetron in treating postoperative nausea and vomiting and cytotoxic induced nausea and vomiting may share similar pathways, the role of ondansetron in opiate-induced emesis has not yet been formally established. •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): Ondansetron is absorbed from the gastrointestinal tract and undergoes some limited first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, was recorded as being approximately 56% to 60%. Bioavailability is also slightly enhanced by the presence of food. Ondansetron systemic exposure does not increase proportionately to dose. The AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses. •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 ondansetron has been recorded as being approximately 160L. •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding associated with ondansetron was documented as approximately 73%. •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 metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes, including CYP1A2, CYP2D6 and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g. CYP2D6 enzyme deficiency) will be compensated by others and may result in little change in overall rates of ondansetron clearance. Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces. In humans, less than 10% of the dose is excreted unchanged in the urine. The major urinary metabolites are glucuronide conjugates (45%), sulphate conjugates (20%) and hydroxylation products (10%). The primary metabolic pathway is subsequently hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. •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 or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces. •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 ondansetron after either an 8 mg oral dose or intravenous dose was approximately 3-4 hours and could be extended to 6-8 hours in the elderly. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance values determined for ondansetron in various patient age groups were recorded as approximately 0.38 L/h/kg in normal adult volunteers aged 19-40 yrs, 0.32 L/h/kg in normal adult volunteers aged 61-74 yrs, 0.26 L/h/kg in normal adult volunteers aged >=75 yrs. •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): At present, there is little information concerning overdosage with ondansetron. Nevertheless, there have been certain cases of somewhat idiosyncratic adverse effects associated with particular dosages of ondansetron used. “Sudden blindness” (amaurosis) of 2 to 3 minutes duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. Neuromuscular abnormalities, autonomic instability, somnolence, and a brief generalized tonic-clonic seizure (which resolved after a dose of benzodiazepine) were observed in a 12-month-old infant who ingested seven or eight 8-mg ondansetron tablets (approximately forty times the recommended 0.1-0.15 mg/kg dose for a pediatric patient). In all instances, however, the events resolved completely. The safety of ondansetron for use in human pregnancy has not been established. Ondansetron is not teratogenic in animals. However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended. Ondansetron is excreted in the milk of lactating rats. It is not known if it is excreted in human milk, however, nursing is not recommended during treatment with ondansetron. Insufficient information is available to provide dosage recommendations for children 3 years of age or younger. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Zofran, Zuplenz •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): Ondansetron is a serotonin 5-HT3 receptor antagonist used to prevent nausea and vomiting in cancer chemotherapy and postoperatively. 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 Orphenadrine interact?

•Drug A: Buserelin •Drug B: Orphenadrine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Orphenadrine 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 as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculo skeletal conditions. •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): Orphenadrine is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Orphenadrine is an anticholinergic with a predominantly central effect and only a weak peripheral effect. In addition, it has mild antihistaminic and local anaesthetic properties. Parkinson's syndrome is the consequence of a disturbed balance between cholinergic and dopaminergic neurotransmission in the basal ganglia caused by a decrease in dopamine. Orphenadrine restores the physiological equilibrium and has a favourable effect on the rigidity and tremor of Parkinson's disease and Parkinsonian syndromes. The effect is somewhat less on bradykinesia. •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): Orphenadrine binds and inhibits both histamine H1 receptors and NMDA receptors. It restores the motor disturbances induced by neuroleptics, in particular the hyperkinesia. The dopamine deficiency in the striatum increases the stimulating effects of the cholinergic system. This stimulation is counteracted by the anticholinergic effect of orphenadrine. It may have a relaxing effect on skeletal muscle spasms and it has a mood elevating effect. •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): Orphenadrine is almost completely 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): 95% •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): Biotransformation occurs mainly in the liver. Pharmacologically active metabolites are N-demethyl orphenadrine and N,N-didemethyl orphenadrine. •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): 13-20 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): Oral, mouse LD 50 = 100 mg/kg; oral, rat LD 50 = 255 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Norgesic, Norgesic Forte, Orfenace, Orphengesic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Orfenadrina Orphenadrine Orphenadrinum •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): Orphenadrine is a muscarinic antagonist used as an adjunct for the symptomatic relief of musculoskeletal pain and discomfort.

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 Orphenadrine interact? Information: •Drug A: Buserelin •Drug B: Orphenadrine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Orphenadrine 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 as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculo skeletal conditions. •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): Orphenadrine is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Orphenadrine is an anticholinergic with a predominantly central effect and only a weak peripheral effect. In addition, it has mild antihistaminic and local anaesthetic properties. Parkinson's syndrome is the consequence of a disturbed balance between cholinergic and dopaminergic neurotransmission in the basal ganglia caused by a decrease in dopamine. Orphenadrine restores the physiological equilibrium and has a favourable effect on the rigidity and tremor of Parkinson's disease and Parkinsonian syndromes. The effect is somewhat less on bradykinesia. •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): Orphenadrine binds and inhibits both histamine H1 receptors and NMDA receptors. It restores the motor disturbances induced by neuroleptics, in particular the hyperkinesia. The dopamine deficiency in the striatum increases the stimulating effects of the cholinergic system. This stimulation is counteracted by the anticholinergic effect of orphenadrine. It may have a relaxing effect on skeletal muscle spasms and it has a mood elevating effect. •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): Orphenadrine is almost completely 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): 95% •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): Biotransformation occurs mainly in the liver. Pharmacologically active metabolites are N-demethyl orphenadrine and N,N-didemethyl orphenadrine. •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): 13-20 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): Oral, mouse LD 50 = 100 mg/kg; oral, rat LD 50 = 255 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Norgesic, Norgesic Forte, Orfenace, Orphengesic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Orfenadrina Orphenadrine Orphenadrinum •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): Orphenadrine is a muscarinic antagonist used as an adjunct for the symptomatic relief of musculoskeletal pain and discomfort. 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 Oxaliplatin interact?

•Drug A: Buserelin •Drug B: Oxaliplatin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Buserelin. •Extended Description: Since oxaliplatin can cause ventricular arrhythmias and QT interval prolongation, the co-administration of oxaliplatin with QT-prolonging agents can increase the risk of 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): Oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for the treatment of advanced colorectal cancer and adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. •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 vivo studies have shown antitumor activities of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models (HT29 [colon], GR [mammary], and L1210 [leukemia]). •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): Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. •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 reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. After a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m, pharmacokinetic parameters expressed as ultrafiltrable platinum was C max of 0.814 mcg/mL. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC 0-48hr ) assessed over 3 cycles was 23% and 6%, 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): After a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m, the volume of distribution is 440 L.At the end of a 2-hour infusion, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. •Protein binding (Drug A): 15% •Protein binding (Drug B): In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m every two weeks. •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): Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species. •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 major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. •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 decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic with two distribution phases: t1/2α; 0.43 hours and t1/2β; 16.8 hours. This is followed by a long terminal elimination phase that lasts 391 hours (t1/2γ). •Clearance (Drug A): No clearance available •Clearance (Drug B): Platinum was cleared from plasma at a rate (10-17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). The renal clearance of ultrafiltrable platinum is significantly correlated with GFR. •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 dose of oxaliplatin that has been administered in a single infusion is 825 mg. Several cases of overdoses have been reported with oxaliplatin. Adverse reactions observed following an overdosage were grade 4 thrombocytopenia (less than 25,000/mm3) without bleeding, anemia, sensory neuropathy (including paresthesia, dysesthesia, laryngospasm, and facial muscle spasms), gastrointestinal disorders (including nausea, vomiting, stomatitis, flatulence, abdomen enlarged and grade 4 intestinal obstruction), grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia, and death. Closely monitor patients suspected of receiving an overdose, including for the adverse reactions described above, and administer appropriate supportive treatment. Based on its direct interaction with DNA, ELOXATIN can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriages related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise a pregnant woman of the potential risk to a fetus. In the adjuvant treatment trial, 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving ELOXATIN experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years. The AUC of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment. No dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment, calculated by Cockcroft-Gault equation. Reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay). In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect the pregnancy rate but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births), and delayed growth (decreased fetal weight). Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on a body surface area basis) × 5 days every 28 days for three cycles. A no-effect level was not identified. •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): Oxaliplatin is a platinum based chemotherapy agent used to treat carcinoma of the colon or rectum or stage III colon cancer.

Since oxaliplatin can cause ventricular arrhythmias and QT interval prolongation, the co-administration of oxaliplatin with QT-prolonging agents can increase the risk of QT prolongation. The severity of the interaction is moderate.

Question: Does Buserelin and Oxaliplatin interact? Information: •Drug A: Buserelin •Drug B: Oxaliplatin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Buserelin. •Extended Description: Since oxaliplatin can cause ventricular arrhythmias and QT interval prolongation, the co-administration of oxaliplatin with QT-prolonging agents can increase the risk of 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): Oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for the treatment of advanced colorectal cancer and adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. •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 vivo studies have shown antitumor activities of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models (HT29 [colon], GR [mammary], and L1210 [leukemia]). •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): Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. •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 reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. After a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m, pharmacokinetic parameters expressed as ultrafiltrable platinum was C max of 0.814 mcg/mL. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC 0-48hr ) assessed over 3 cycles was 23% and 6%, 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): After a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m, the volume of distribution is 440 L.At the end of a 2-hour infusion, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. •Protein binding (Drug A): 15% •Protein binding (Drug B): In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m every two weeks. •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): Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species. •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 major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. •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 decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic with two distribution phases: t1/2α; 0.43 hours and t1/2β; 16.8 hours. This is followed by a long terminal elimination phase that lasts 391 hours (t1/2γ). •Clearance (Drug A): No clearance available •Clearance (Drug B): Platinum was cleared from plasma at a rate (10-17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). The renal clearance of ultrafiltrable platinum is significantly correlated with GFR. •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 dose of oxaliplatin that has been administered in a single infusion is 825 mg. Several cases of overdoses have been reported with oxaliplatin. Adverse reactions observed following an overdosage were grade 4 thrombocytopenia (less than 25,000/mm3) without bleeding, anemia, sensory neuropathy (including paresthesia, dysesthesia, laryngospasm, and facial muscle spasms), gastrointestinal disorders (including nausea, vomiting, stomatitis, flatulence, abdomen enlarged and grade 4 intestinal obstruction), grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia, and death. Closely monitor patients suspected of receiving an overdose, including for the adverse reactions described above, and administer appropriate supportive treatment. Based on its direct interaction with DNA, ELOXATIN can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriages related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise a pregnant woman of the potential risk to a fetus. In the adjuvant treatment trial, 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving ELOXATIN experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years. The AUC of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment. No dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment, calculated by Cockcroft-Gault equation. Reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay). In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect the pregnancy rate but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births), and delayed growth (decreased fetal weight). Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on a body surface area basis) × 5 days every 28 days for three cycles. A no-effect level was not identified. •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): Oxaliplatin is a platinum based chemotherapy agent used to treat carcinoma of the colon or rectum or stage III colon cancer. Output: Since oxaliplatin can cause ventricular arrhythmias and QT interval prolongation, the co-administration of oxaliplatin with QT-prolonging agents can increase the risk of QT prolongation. The severity of the interaction is moderate.

Does Buserelin and Oxatomide interact?

•Drug A: Buserelin •Drug B: Oxatomide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Oxatomide. •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): 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): 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): Oxatomide is an antihistamine indicated in the treatment and prevention of allergic symptoms.

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 Oxatomide interact? Information: •Drug A: Buserelin •Drug B: Oxatomide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Oxatomide. •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): 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): 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): Oxatomide is an antihistamine indicated in the treatment and prevention of allergic symptoms. 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 Oxybuprocaine interact?

•Drug A: Buserelin •Drug B: Oxybuprocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Oxybuprocaine. •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): Used to temporarily numb the front surface of the eye so that the eye pressure can be measured or a foreign body removed. •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): Oxybuprocaine is a local anaesthetic. It may be less irritating than tetracaine, and the onset and duration of action are similar to tetracaine. •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): Oxybuprocaine binds to sodium channel and reversibly stabilizes the neuronal membrane which decreases its permeability to sodium ions. Depolarization of the neuronal membrane is inhibited thereby blocking the initiation and conduction of 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): 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): Altafluor, Fluress •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benoxinate Oxibuprocaina Oxybucaine Oxybuprocaine Oxybuprocainum Oxyriprocaine •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): Oxybuprocaine is a local anesthetic used in ophthalmology.

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 Oxybuprocaine interact? Information: •Drug A: Buserelin •Drug B: Oxybuprocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Oxybuprocaine. •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): Used to temporarily numb the front surface of the eye so that the eye pressure can be measured or a foreign body removed. •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): Oxybuprocaine is a local anaesthetic. It may be less irritating than tetracaine, and the onset and duration of action are similar to tetracaine. •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): Oxybuprocaine binds to sodium channel and reversibly stabilizes the neuronal membrane which decreases its permeability to sodium ions. Depolarization of the neuronal membrane is inhibited thereby blocking the initiation and conduction of 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): 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): Altafluor, Fluress •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benoxinate Oxibuprocaina Oxybucaine Oxybuprocaine Oxybuprocainum Oxyriprocaine •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): Oxybuprocaine is a local anesthetic used in ophthalmology. 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 Oxytocin interact?

•Drug A: Buserelin •Drug B: Oxytocin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Oxytocin 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): Administration of exogenous oxytocin is indicated in the antepartum period to initiate or improve uterine contractions for vaginal delivery in situations where there is fetal or maternal concern. For example, It may be used to induce labor in cases of Rh sensitization, maternal diabetes, preeclampsia at or near term, and when delivery is indicated due to prematurely ruptured membranes. Importantly, oxytocin is not approved or indicated for elective induction of labor. Oxytocin may be used to reinforce labor in select cases of uterine inertia and as adjunctive therapy in the management of incomplete or inevitable abortion. In the postpartum period, oxytocin may be used to induced contractions in the 3rd stage of labor and to control postpartum bleeding or hemorrhage. •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): Oxytocin is a nonapeptide, pleiotropic hormone that exerts important physiological effects. It is most well known to stimulate parturition and lactation, but also has important physiological influences on metabolic and cardiovascular functions, sexual and maternal behaviour, pair bonding, social cognition, and fear conditioning. It is worth noting that oxytocin receptors are not limited to the reproductive system but can be found in many peripheral tissues and in central nervous system structures including the brain stem and amygdala. •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): Oxytocin plays a vital role in labour and delivery. The hormone is produced in the hypothalamus and is secreted from the paraventricular nucleus to the posterior pituitary where it is stored. It is then released in pulses during childbirth to induce uterine contractions. The concentration of oxytocin receptors on the myometrium increases significantly during pregnancy and reaches a peak in early labor. Activation of oxytocin receptors on the myometrium triggers a downstream cascade that leads to increased intracellular calcium in uterine myofibrils which strengthens and increases the frequency of uterine contractions. In humans, most hormones are regulated by negative feedback; however, oxytocin is one of the few that is regulated by positive feedback. The head of the fetus pushing on the cervix signals the release of oxytocin from the posterior pituitary of the mother. Oxytocin then travels to the uterus where it stimulates uterine contractions. The elicited uterine contractions will then stimulate the release of increasing amounts of oxytocin. This positive feedback loop will continue until parturition. Since exogenously administered and endogenously secreted oxytocin result in the same effects on the female reproductive system, synthetic oxytocin may be used in specific instances during the antepartum and postpartum period to induce or improve uterine contractions. •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): Oxytocin is administered parenterally and is fully bioavailable. It takes approximately 40 minutes for oxytocin to reach steady-state concentrations in the plasma after parenteral 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): Oxytocin is rapidly removed from the plasma by the liver and kidney. The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy and only a small percentage of the neurohormone is excreted in the urine unchanged. Oxytocinase activity increases throughout pregnancy and peaks in the plasma, placenta and uterus near term. The placenta is a key source of oxytocinase during gestation and produces increasing amounts of the enzyme in response to increasing levels of oxytocin produced by the mother. Oxytocinase activity is also expressed in mammary glands, heart, kidney, and the small intestine. Lower levels of activity can be found in the brain, spleen, liver, skeletal muscle, testes, and colon. The level of oxytocin degradation is negligible in non-pregnant women, men, and cord blood. •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 enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy; only a small percentage of the neurohormone is excreted in the urine 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 plasma half-life of oxytocin ranges from 1-6 minutes. The half-life is decreased in late pregnancy and during lactation. •Clearance (Drug A): No clearance available •Clearance (Drug B): In a study that observed 10 women who were given oxytocin to induce labor, the mean metabolic clearance rate was 7.87 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): Administration of supratherapeutic doses of exogenous oxytocin can lead to myocardial ischemia, tachycardia, and arrhythmias. High doses can also lead to uterine spasms, hypertonicity, or rupture. Oxytocin has antidiuretic properties, thus, high daily doses (as a single dose or administered slowly over 24 hours) may lead to extreme water intoxication resulting in maternal seizures, coma, and even death. The risk of antidiuresis and water intoxication in the mother appears to be greater when fluids are given orally. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Pitocin •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): Oxytocin is a recombinant hormone used to induce or strengthen uterine contractions in pregnant women to aid in labor and delivery or to control postpartum bleeding.

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 Oxytocin interact? Information: •Drug A: Buserelin •Drug B: Oxytocin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Oxytocin 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): Administration of exogenous oxytocin is indicated in the antepartum period to initiate or improve uterine contractions for vaginal delivery in situations where there is fetal or maternal concern. For example, It may be used to induce labor in cases of Rh sensitization, maternal diabetes, preeclampsia at or near term, and when delivery is indicated due to prematurely ruptured membranes. Importantly, oxytocin is not approved or indicated for elective induction of labor. Oxytocin may be used to reinforce labor in select cases of uterine inertia and as adjunctive therapy in the management of incomplete or inevitable abortion. In the postpartum period, oxytocin may be used to induced contractions in the 3rd stage of labor and to control postpartum bleeding or hemorrhage. •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): Oxytocin is a nonapeptide, pleiotropic hormone that exerts important physiological effects. It is most well known to stimulate parturition and lactation, but also has important physiological influences on metabolic and cardiovascular functions, sexual and maternal behaviour, pair bonding, social cognition, and fear conditioning. It is worth noting that oxytocin receptors are not limited to the reproductive system but can be found in many peripheral tissues and in central nervous system structures including the brain stem and amygdala. •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): Oxytocin plays a vital role in labour and delivery. The hormone is produced in the hypothalamus and is secreted from the paraventricular nucleus to the posterior pituitary where it is stored. It is then released in pulses during childbirth to induce uterine contractions. The concentration of oxytocin receptors on the myometrium increases significantly during pregnancy and reaches a peak in early labor. Activation of oxytocin receptors on the myometrium triggers a downstream cascade that leads to increased intracellular calcium in uterine myofibrils which strengthens and increases the frequency of uterine contractions. In humans, most hormones are regulated by negative feedback; however, oxytocin is one of the few that is regulated by positive feedback. The head of the fetus pushing on the cervix signals the release of oxytocin from the posterior pituitary of the mother. Oxytocin then travels to the uterus where it stimulates uterine contractions. The elicited uterine contractions will then stimulate the release of increasing amounts of oxytocin. This positive feedback loop will continue until parturition. Since exogenously administered and endogenously secreted oxytocin result in the same effects on the female reproductive system, synthetic oxytocin may be used in specific instances during the antepartum and postpartum period to induce or improve uterine contractions. •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): Oxytocin is administered parenterally and is fully bioavailable. It takes approximately 40 minutes for oxytocin to reach steady-state concentrations in the plasma after parenteral 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): Oxytocin is rapidly removed from the plasma by the liver and kidney. The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy and only a small percentage of the neurohormone is excreted in the urine unchanged. Oxytocinase activity increases throughout pregnancy and peaks in the plasma, placenta and uterus near term. The placenta is a key source of oxytocinase during gestation and produces increasing amounts of the enzyme in response to increasing levels of oxytocin produced by the mother. Oxytocinase activity is also expressed in mammary glands, heart, kidney, and the small intestine. Lower levels of activity can be found in the brain, spleen, liver, skeletal muscle, testes, and colon. The level of oxytocin degradation is negligible in non-pregnant women, men, and cord blood. •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 enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy; only a small percentage of the neurohormone is excreted in the urine 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 plasma half-life of oxytocin ranges from 1-6 minutes. The half-life is decreased in late pregnancy and during lactation. •Clearance (Drug A): No clearance available •Clearance (Drug B): In a study that observed 10 women who were given oxytocin to induce labor, the mean metabolic clearance rate was 7.87 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): Administration of supratherapeutic doses of exogenous oxytocin can lead to myocardial ischemia, tachycardia, and arrhythmias. High doses can also lead to uterine spasms, hypertonicity, or rupture. Oxytocin has antidiuretic properties, thus, high daily doses (as a single dose or administered slowly over 24 hours) may lead to extreme water intoxication resulting in maternal seizures, coma, and even death. The risk of antidiuresis and water intoxication in the mother appears to be greater when fluids are given orally. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Pitocin •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): Oxytocin is a recombinant hormone used to induce or strengthen uterine contractions in pregnant women to aid in labor and delivery or to control postpartum bleeding. 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 Pacritinib interact?

•Drug A: Buserelin •Drug B: Pacritinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pacritinib. •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): Pacritinib is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 10 /L. This indication is approved under accelerated approval based on spleen volume reduction. Continued approval 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): Pacritinib is administered orally twice daily, with or without food. It should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment, nor in patients with significant renal impairment (eGFR <30 mL/min). Patients taking pacritinib may experience a prolonged QTc interval - while no cases of torsades de pointes have been reported in clinical trials, QTc prolongations to >500 msec and/or increases in baseline QTc by >60 msec were observed in some patients during clinical trials. A baseline QTc interval should be obtained prior to initiating therapy and regular monitoring (including for risk factors, e.g. hypokalemia) should continue throughout 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): While the pathogenesis of myelofibrosis (MF) is still poorly understood, both primary and secondary (i.e. post-polycythemia vera or post-essential thrombocythemia) myelofibrosis have been associated with mutations of JAK2. Signaling pathways initiated by JAK2 generate a number of cytokines and growth factors responsible for hematopoiesis and immune functioning, and its dysregulation is thought to be a driver of MF pathogenesis. Pacritinib is thought to exert its pharmacologic activity via inhibition of wild-type JAK2, mutant JAK2, and FMS-like tyrosine kinase 3 (FLT3). It has a greater inhibitory potency towards JAK2 than related proteins (e.g. JAK3, TYK2), and does not inhibit JAK1 at clinically relevant concentrations. Pacritinib also exhibits some inhibitory activity against other cellular kinases (e.g. CSF1R and IRAK1), although the clinical significance of this activity 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): Following oral administration of 200mg pacritinib twice daily, the mean C max and AUC 0-12 at steady-state were 8.4 mg/L and 95.6 mg*h/L, respectively. The T max is approximately 4-5 hours post-dose. Co-administration with food does not significantly impact the pharmacokinetics of pacritinib. •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 apparent volume of distribution of pacritinib at steady-state is 229 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pacritinib is 98.8% 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): Pacritinib metabolism is mediated primarily by CYP3A4. While it undergoes extensive metabolism to at least four identified metabolites - M1, M2, M3, and M4 - parent drug is the major circulating component in plasma and is responsible for the pharmacologic activity. The two major metabolites, M1 and M2, represent 9.6% and 10.5% of parent drug exposure, 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): Following oral administration of radiolabeled pacritinib, approximately 87% of the radioactivity was recovered in feces and 6% was recovered in urine. Unchanged parent drug was not present in the feces and accounted for only 0.12% of the radioactivity 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): The mean effective half-life of pacritinib is 27.7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance of pacritinib is 2.09 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): Overdosage with pacritinib may lead to gastrointestinal toxicity, myelosuppression, blurred vision, dizziness, worsening performance status, and sepsis. There is no known antidote for pacritinib overdose, and hemodialysis is not expected to enhance its elimination. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Vonjo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pacritinib •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): Pacritinib is a kinase inhibitor used for the treatment of primary and secondary myelofibrosis in adult patients with significantly reduced platelet counts.

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 Pacritinib interact? Information: •Drug A: Buserelin •Drug B: Pacritinib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pacritinib. •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): Pacritinib is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 10 /L. This indication is approved under accelerated approval based on spleen volume reduction. Continued approval 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): Pacritinib is administered orally twice daily, with or without food. It should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment, nor in patients with significant renal impairment (eGFR <30 mL/min). Patients taking pacritinib may experience a prolonged QTc interval - while no cases of torsades de pointes have been reported in clinical trials, QTc prolongations to >500 msec and/or increases in baseline QTc by >60 msec were observed in some patients during clinical trials. A baseline QTc interval should be obtained prior to initiating therapy and regular monitoring (including for risk factors, e.g. hypokalemia) should continue throughout 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): While the pathogenesis of myelofibrosis (MF) is still poorly understood, both primary and secondary (i.e. post-polycythemia vera or post-essential thrombocythemia) myelofibrosis have been associated with mutations of JAK2. Signaling pathways initiated by JAK2 generate a number of cytokines and growth factors responsible for hematopoiesis and immune functioning, and its dysregulation is thought to be a driver of MF pathogenesis. Pacritinib is thought to exert its pharmacologic activity via inhibition of wild-type JAK2, mutant JAK2, and FMS-like tyrosine kinase 3 (FLT3). It has a greater inhibitory potency towards JAK2 than related proteins (e.g. JAK3, TYK2), and does not inhibit JAK1 at clinically relevant concentrations. Pacritinib also exhibits some inhibitory activity against other cellular kinases (e.g. CSF1R and IRAK1), although the clinical significance of this activity 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): Following oral administration of 200mg pacritinib twice daily, the mean C max and AUC 0-12 at steady-state were 8.4 mg/L and 95.6 mg*h/L, respectively. The T max is approximately 4-5 hours post-dose. Co-administration with food does not significantly impact the pharmacokinetics of pacritinib. •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 apparent volume of distribution of pacritinib at steady-state is 229 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pacritinib is 98.8% 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): Pacritinib metabolism is mediated primarily by CYP3A4. While it undergoes extensive metabolism to at least four identified metabolites - M1, M2, M3, and M4 - parent drug is the major circulating component in plasma and is responsible for the pharmacologic activity. The two major metabolites, M1 and M2, represent 9.6% and 10.5% of parent drug exposure, 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): Following oral administration of radiolabeled pacritinib, approximately 87% of the radioactivity was recovered in feces and 6% was recovered in urine. Unchanged parent drug was not present in the feces and accounted for only 0.12% of the radioactivity 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): The mean effective half-life of pacritinib is 27.7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean apparent clearance of pacritinib is 2.09 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): Overdosage with pacritinib may lead to gastrointestinal toxicity, myelosuppression, blurred vision, dizziness, worsening performance status, and sepsis. There is no known antidote for pacritinib overdose, and hemodialysis is not expected to enhance its elimination. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Vonjo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pacritinib •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): Pacritinib is a kinase inhibitor used for the treatment of primary and secondary myelofibrosis in adult patients with significantly reduced platelet counts. 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 Paliperidone interact?

•Drug A: Buserelin •Drug B: Paliperidone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Paliperidone. •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): As an oral extended-release tablet and a once-monthly extended-release suspension for intramuscular injection, paliperidone is indicated for the treatment of adults and adolescents with schizophrenia and in the treatment of schizoaffective disorder in combination with antidepressants or mood stabilizers. Paliperidone is also available in both an every-three-month and twice-yearly extended-release suspension for intramuscular injection for the treatment of schizophrenia. •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): Paliperidone is an atypical antipsychotic developed by Janssen Pharmaceutica. Chemically, paliperidone is primary active metabolite of the older antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone). The mechanism of action is unknown but it is likely to act via a similar pathway to risperidone. •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): Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. •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 absolute oral bioavailability of paliperidone following paliperidone administration is 28%. •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): 487 L •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of racemic paliperidone is 74%. •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): Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone. Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Paliperidone does not undergo extensive metabolism and a significant portion of its metabolism occurs in the kidneys. •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): One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone to 5 healthy volunteers, 59% (range 51% – 67%) of the dose was excreted unchanged into urine, 32% (26% – 41%) of the dose was recovered as metabolites, and 6% – 12% of the dose was not recovered. •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 paliperidone is approximately 23 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 possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Invega, Invega Hafyera, Xeplion •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): Paliperidone is an atypical antipsychotic used in the treatment of schizophrenia and other schizoaffective or delusional disorders.

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 Paliperidone interact? Information: •Drug A: Buserelin •Drug B: Paliperidone •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Paliperidone. •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): As an oral extended-release tablet and a once-monthly extended-release suspension for intramuscular injection, paliperidone is indicated for the treatment of adults and adolescents with schizophrenia and in the treatment of schizoaffective disorder in combination with antidepressants or mood stabilizers. Paliperidone is also available in both an every-three-month and twice-yearly extended-release suspension for intramuscular injection for the treatment of schizophrenia. •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): Paliperidone is an atypical antipsychotic developed by Janssen Pharmaceutica. Chemically, paliperidone is primary active metabolite of the older antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone). The mechanism of action is unknown but it is likely to act via a similar pathway to risperidone. •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): Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. •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 absolute oral bioavailability of paliperidone following paliperidone administration is 28%. •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): 487 L •Protein binding (Drug A): 15% •Protein binding (Drug B): The plasma protein binding of racemic paliperidone is 74%. •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): Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone. Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Paliperidone does not undergo extensive metabolism and a significant portion of its metabolism occurs in the kidneys. •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): One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone to 5 healthy volunteers, 59% (range 51% – 67%) of the dose was excreted unchanged into urine, 32% (26% – 41%) of the dose was recovered as metabolites, and 6% – 12% of the dose was not recovered. •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 paliperidone is approximately 23 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 possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Invega, Invega Hafyera, Xeplion •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): Paliperidone is an atypical antipsychotic used in the treatment of schizophrenia and other schizoaffective or delusional disorders. 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 Panobinostat interact?

•Drug A: Buserelin •Drug B: Panobinostat •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Panobinostat. •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): Panobinostat is indicated in the treatment of multiple myeloma in combination with dexamethasone and bortezomib in patients who have received 2 previous treatment regimens including bortezomib and an immunomodulatory agent. This indication is approved by accelerated approval based on progression free survival as of February 23, 2015. •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): Panobinostat is a deacetylase (DAC) inhibitor. DACs, also known as histone DACs (HDAC), are responsible for regulating the acetylation of about 1750 proteins in the body; their functions are involved in many biological processes including DNA replication and repair, chromatin remodelling, transcription of genes, progression of the cell-cycle, protein degradation and cytoskeletal reorganization. In multiple myeloma, there is an overexpression of DAC proteins. Panobinostat inhibits class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC 11) proteins. Panobinostat's antitumor activity is believed to be attributed to epigenetic modulation of gene expression and inhibition of protein metabolism. Panobinostat also exhibits cytotoxic synergy with bortezomib, a proteasome inhibitor concurrently used in treatment of multiple myeloma. •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 a 20 mg dose, panobinostat was quickly absorbed with a time to maximum absorption of 2 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): 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): Panobinostat was extensively metabolized to 77 metabolites. Unchanged panobinostat recovered in urine and feces was 2% and 3%, respectively. Primary metabolic pathways of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. CYP and non-CYP enzymes were found to play significant role in metabolism, CYP2D6 and CYP2C19 playing minor roles. •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): 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): Farydak carries a Boxed Warning alerting patients and health care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving Farydak. Because of these risks, Farydak is being approved with a Risk Evaluation and Mitigation Strategy (REMS) consisting of a communication plan to inform health care professionals of these risks and how to minimize them. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Farydak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-PROPENAMIDE, N-HYDROXY-3-(4-(((2-(2-METHYL-1H-INDOL-3-YL)ETHYL)AMINO)METHYL)PHENYL)-, (2E)- hydroxypropyl-B-cyclodextrin-panobinostat complex Panobinostat Panobinostatum •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): Panobinostat is a non-selective histone deacetylase inhibitor used to treat multiple myeloma in combination with other antineoplastic agents.

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 Panobinostat interact? Information: •Drug A: Buserelin •Drug B: Panobinostat •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Panobinostat. •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): Panobinostat is indicated in the treatment of multiple myeloma in combination with dexamethasone and bortezomib in patients who have received 2 previous treatment regimens including bortezomib and an immunomodulatory agent. This indication is approved by accelerated approval based on progression free survival as of February 23, 2015. •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): Panobinostat is a deacetylase (DAC) inhibitor. DACs, also known as histone DACs (HDAC), are responsible for regulating the acetylation of about 1750 proteins in the body; their functions are involved in many biological processes including DNA replication and repair, chromatin remodelling, transcription of genes, progression of the cell-cycle, protein degradation and cytoskeletal reorganization. In multiple myeloma, there is an overexpression of DAC proteins. Panobinostat inhibits class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC 11) proteins. Panobinostat's antitumor activity is believed to be attributed to epigenetic modulation of gene expression and inhibition of protein metabolism. Panobinostat also exhibits cytotoxic synergy with bortezomib, a proteasome inhibitor concurrently used in treatment of multiple myeloma. •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 a 20 mg dose, panobinostat was quickly absorbed with a time to maximum absorption of 2 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): 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): Panobinostat was extensively metabolized to 77 metabolites. Unchanged panobinostat recovered in urine and feces was 2% and 3%, respectively. Primary metabolic pathways of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. CYP and non-CYP enzymes were found to play significant role in metabolism, CYP2D6 and CYP2C19 playing minor roles. •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): 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): Farydak carries a Boxed Warning alerting patients and health care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving Farydak. Because of these risks, Farydak is being approved with a Risk Evaluation and Mitigation Strategy (REMS) consisting of a communication plan to inform health care professionals of these risks and how to minimize them. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Farydak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-PROPENAMIDE, N-HYDROXY-3-(4-(((2-(2-METHYL-1H-INDOL-3-YL)ETHYL)AMINO)METHYL)PHENYL)-, (2E)- hydroxypropyl-B-cyclodextrin-panobinostat complex Panobinostat Panobinostatum •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): Panobinostat is a non-selective histone deacetylase inhibitor used to treat multiple myeloma in combination with other antineoplastic agents. 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 Papaverine interact?

•Drug A: Buserelin •Drug B: Papaverine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Papaverine. •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 impotence and vasospasms. •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): Papaverine is a nonxanthine phosphodiesterase inhibitor for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias. The main actions of Papaverine are exerted on cardiac and smooth muscle. Like qathidine, Papaverine acts directly on the heart muscle to depress conduction and prolong the refractory period. Papaverine relaxes various smooth muscles. This relaxation may be prominent if spasm exists. The muscle cell is not paralyzed by Papaverine and still responds to drugs and other stimuli causing contraction. The antispasmodic effect is a direct one, and unrelated to muscle innervation. Papaverine is practically devoid of effects on the central nervous system. Papaverine relaxes the smooth musculature of the larger blood vessels, especially coronary, systemic peripheral, and pulmonary arteries. •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): Perhaps by its direct vasodilating action on cerebral blood vessels, Papaverine increases cerebral blood flow and decreases cerebral vascular resistance in normal subjects; oxygen consumption is unaltered. These effects may explain the benefit reported from the drug in cerebral vascular encephalopathy. •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): ~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): 0.5-2 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): 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): Papaverine is an alkaloid used to treat many types of smooth muscle spasms such as "vascular spasms" associated with acute myocardial infarction and angina pectoris, as well as "visceral spasms".

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 Papaverine interact? Information: •Drug A: Buserelin •Drug B: Papaverine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Papaverine. •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 impotence and vasospasms. •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): Papaverine is a nonxanthine phosphodiesterase inhibitor for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias. The main actions of Papaverine are exerted on cardiac and smooth muscle. Like qathidine, Papaverine acts directly on the heart muscle to depress conduction and prolong the refractory period. Papaverine relaxes various smooth muscles. This relaxation may be prominent if spasm exists. The muscle cell is not paralyzed by Papaverine and still responds to drugs and other stimuli causing contraction. The antispasmodic effect is a direct one, and unrelated to muscle innervation. Papaverine is practically devoid of effects on the central nervous system. Papaverine relaxes the smooth musculature of the larger blood vessels, especially coronary, systemic peripheral, and pulmonary arteries. •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): Perhaps by its direct vasodilating action on cerebral blood vessels, Papaverine increases cerebral blood flow and decreases cerebral vascular resistance in normal subjects; oxygen consumption is unaltered. These effects may explain the benefit reported from the drug in cerebral vascular encephalopathy. •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): ~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): 0.5-2 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): 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): Papaverine is an alkaloid used to treat many types of smooth muscle spasms such as "vascular spasms" associated with acute myocardial infarction and angina pectoris, as well as "visceral spasms". 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 Pasireotide interact?

•Drug A: Buserelin •Drug B: Pasireotide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pasireotide 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 Cushing’s disease, specifically for those patients whom pituitary surgery has not been curative or is not an option. •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): Signifor® is an analogue of somatostatin that promotes reduced levels of cortisol secretion in Cushing's disease 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): Pasireotide activates a broad spectrum of somatostatin receptors, exhbiting a much higher binding affinity for somatostatin receptors 1, 3, and 5 than octreotide in vitro, as well as a comparable binding affinity for somatostatin receptor 2. The binding and activation of the somatostatin receptors causes inhibition of ACTH secretion and results in reduced cortisol secretion in Cushing's disease patients. Also this agent is more potent than somatostatin in inhibiting the release of human growth hormone (HGH), glucagon, and 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): The peak plasma concentration of pasireotide occurs in 0.25-0.5 hours. After administration of single and multiple doses, there is dose-proportionoal increases in Cmax and 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): Pasireotide is widely distributed and has a volume of distribution of >100L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding is 88%. •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): Metabolism is minimal. •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): Pasireotide is eliminated mostly by hepatic clearance (biliary excretion)(about 48%) with some minor renal clearance (about 7.63%). •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 is 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance in healthy patient is ~7.6 L/h and in Cushing’s disease patients is ~3.8 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 toxic effects observed are hyperglycemia, cholelithiasis, diarrhea, nausea, headache, abdominal pain, fatigue, and diabetes mellitus. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Signifor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pasireotida Pasiréotide Pasireotide Pasireotidum •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): Pasireotide is a somatostatin analog used in the treatment of Cushing’s disease, specifically for those patients whom pituitary surgery is not appropriate.

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 Pasireotide interact? Information: •Drug A: Buserelin •Drug B: Pasireotide •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pasireotide 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 Cushing’s disease, specifically for those patients whom pituitary surgery has not been curative or is not an option. •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): Signifor® is an analogue of somatostatin that promotes reduced levels of cortisol secretion in Cushing's disease 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): Pasireotide activates a broad spectrum of somatostatin receptors, exhbiting a much higher binding affinity for somatostatin receptors 1, 3, and 5 than octreotide in vitro, as well as a comparable binding affinity for somatostatin receptor 2. The binding and activation of the somatostatin receptors causes inhibition of ACTH secretion and results in reduced cortisol secretion in Cushing's disease patients. Also this agent is more potent than somatostatin in inhibiting the release of human growth hormone (HGH), glucagon, and 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): The peak plasma concentration of pasireotide occurs in 0.25-0.5 hours. After administration of single and multiple doses, there is dose-proportionoal increases in Cmax and 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): Pasireotide is widely distributed and has a volume of distribution of >100L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Plasma protein binding is 88%. •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): Metabolism is minimal. •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): Pasireotide is eliminated mostly by hepatic clearance (biliary excretion)(about 48%) with some minor renal clearance (about 7.63%). •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 is 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance in healthy patient is ~7.6 L/h and in Cushing’s disease patients is ~3.8 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 toxic effects observed are hyperglycemia, cholelithiasis, diarrhea, nausea, headache, abdominal pain, fatigue, and diabetes mellitus. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Signifor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pasireotida Pasiréotide Pasireotide Pasireotidum •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): Pasireotide is a somatostatin analog used in the treatment of Cushing’s disease, specifically for those patients whom pituitary surgery is not appropriate. 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 Pazopanib interact?

•Drug A: Buserelin •Drug B: Pazopanib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pazopanib. •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): Treatment of advanced renal cell cancer and advanced soft tissue sarcoma (in patients previously treated 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): Pazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01 - 0.084 μmol/L). A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving 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): Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumour blood vessel for tumour survival and growth. •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 pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · 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): Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4) •Protein binding (Drug A): 15% •Protein binding (Drug B): >99% protein bound, independent of concentrations over a range of 10-100 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): Metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Metabolites are less active than pazopanib (10 to 20-fold less active). Three of its metabolites can be observed in the systemic and account for <10% of plasma 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): Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via 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): 35 hours. Oral absorption is not the rate limiting step of elimination from the plasma. •Clearance (Drug A): No clearance available •Clearance (Drug B): CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism. •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): Votrient •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): Pazopanib is an antineoplastic agent used in the treatment of advanced renal cell cancer and advanced soft tissue sarcoma in patients with prior chemotherapy.

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 Pazopanib interact? Information: •Drug A: Buserelin •Drug B: Pazopanib •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pazopanib. •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): Treatment of advanced renal cell cancer and advanced soft tissue sarcoma (in patients previously treated 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): Pazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01 - 0.084 μmol/L). A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving 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): Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumour blood vessel for tumour survival and growth. •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 pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · 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): Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4) •Protein binding (Drug A): 15% •Protein binding (Drug B): >99% protein bound, independent of concentrations over a range of 10-100 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): Metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Metabolites are less active than pazopanib (10 to 20-fold less active). Three of its metabolites can be observed in the systemic and account for <10% of plasma 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): Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via 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): 35 hours. Oral absorption is not the rate limiting step of elimination from the plasma. •Clearance (Drug A): No clearance available •Clearance (Drug B): CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism. •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): Votrient •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): Pazopanib is an antineoplastic agent used in the treatment of advanced renal cell cancer and advanced soft tissue sarcoma in patients with prior chemotherapy. 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 Pefloxacin interact?

•Drug A: Buserelin •Drug B: Pefloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pefloxacin 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 uncomplicated gonococcal urethritis in males and for gram-negative-bacterial infections in the gastrointestinal system and the genitourinary tract. •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): Pefloxacin is a fluoroquinolone antibiotic. Flouroquinolones such as pefloxacin possess excellent activity against gram-negative aerobic bacteria such as E.coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also posses effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. •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 bactericidal action of pefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited. •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 by the oral route. •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): 20-30% •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): Hepatic. Primary metabolites are pefloxacin N-oxide and norfloxacin. •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): 8.6 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): Adverse reactions include peripheral neuropathy, nervousness, agitation, anxiety, and phototoxic events (rash, itching, burning) due to sunlight exposure. •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): Pefloxacin is an antibiotic used to treat a variety of bacterial 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 Pefloxacin interact? Information: •Drug A: Buserelin •Drug B: Pefloxacin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pefloxacin 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 uncomplicated gonococcal urethritis in males and for gram-negative-bacterial infections in the gastrointestinal system and the genitourinary tract. •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): Pefloxacin is a fluoroquinolone antibiotic. Flouroquinolones such as pefloxacin possess excellent activity against gram-negative aerobic bacteria such as E.coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also posses effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. •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 bactericidal action of pefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited. •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 by the oral route. •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): 20-30% •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): Hepatic. Primary metabolites are pefloxacin N-oxide and norfloxacin. •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): 8.6 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): Adverse reactions include peripheral neuropathy, nervousness, agitation, anxiety, and phototoxic events (rash, itching, burning) due to sunlight exposure. •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): Pefloxacin is an antibiotic used to treat a variety of bacterial 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 Pentamidine interact?

•Drug A: Buserelin •Drug B: Pentamidine •Severity: MODERATE •Description: The therapeutic efficacy of Pentamidine 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 pneumonia due to Pneumocystis carinii. •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): Pentamidine is an antiprotozoal agent. It is an aromatic diamidine, and is known to have activity against Pneumocystis carinii. The exact nature of its antiprotozoal action is unknown. in vitro studies with mammalian tissues and the protozoan Crithidia oncopelti indicate that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids and proteins. Little is known about the drug's pharmacokinetics. The medication is also useful in Leishmaniasis and in prophylaxis against sleeping sickness caused by Trypanosoma brucei gambiense. Hydration before treatment lessens the incidence and severity of side effects, which include liver or kidney dysfunction, hypertension, hypotension, hypoglycemia, hypocalemia, leukopenia, thrombcytopenia, anemia, and allergic reaction. It is generally well-tolerated. •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 mode of action of pentamidine is not fully understood. It is thought that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins. •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): Absorbed poorly through the gastrointestinal tract and is usually administered parenterally. •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): 69% •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): 9.1-13.2 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): Symptoms of overdose include pain, nausea, anorexia, hypotension, fever, rash, bad taste in mouth, confusion/hallucinations, dizziness, and diarrhea. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nebupent, Pentam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pentamidin Pentamidina Pentamidine Pentamidinum •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): Pentamidine is an antifungal agent used to treat Pneumocystis pneumonia in patients infected with HIV.

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 Pentamidine interact? Information: •Drug A: Buserelin •Drug B: Pentamidine •Severity: MODERATE •Description: The therapeutic efficacy of Pentamidine 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 pneumonia due to Pneumocystis carinii. •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): Pentamidine is an antiprotozoal agent. It is an aromatic diamidine, and is known to have activity against Pneumocystis carinii. The exact nature of its antiprotozoal action is unknown. in vitro studies with mammalian tissues and the protozoan Crithidia oncopelti indicate that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids and proteins. Little is known about the drug's pharmacokinetics. The medication is also useful in Leishmaniasis and in prophylaxis against sleeping sickness caused by Trypanosoma brucei gambiense. Hydration before treatment lessens the incidence and severity of side effects, which include liver or kidney dysfunction, hypertension, hypotension, hypoglycemia, hypocalemia, leukopenia, thrombcytopenia, anemia, and allergic reaction. It is generally well-tolerated. •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 mode of action of pentamidine is not fully understood. It is thought that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins. •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): Absorbed poorly through the gastrointestinal tract and is usually administered parenterally. •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): 69% •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): 9.1-13.2 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): Symptoms of overdose include pain, nausea, anorexia, hypotension, fever, rash, bad taste in mouth, confusion/hallucinations, dizziness, and diarrhea. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nebupent, Pentam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pentamidin Pentamidina Pentamidine Pentamidinum •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): Pentamidine is an antifungal agent used to treat Pneumocystis pneumonia in patients infected with HIV. 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 Perflutren interact?

•Drug A: Buserelin •Drug B: Perflutren •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Perflutren. •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): Used as an ultrasound contrast imaging in cardiology and radiology. •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): Perflutren, a diagnostic drug that is intended to be used for contrast enhancement during the indicated echocardiographic procedures, comprised of lipid-coated microspheres filled with octafluoropropane(OFP) gas. It provide contrast enhancement of the endocardial borders during echocardiography. The perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. •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): Perflutren is comprised of gas-filled microspheres that are injected or infused into the body. When exposed to ultrasound waves, the microspheres resonate and "echo" strong signals back to the ultrasound machine. The difference in density between the gas-filled bubbles and the blood around them creates an increased level of contrast visible in the resulting ultrasound image. During echocardiography, activated Perflutren enhances images of the inner edges or borders of the heart, producing an improved image that may enable physicians to better diagnose 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): 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): OFP is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids. •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 mean half-life of OFP in blood 1.9 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): There is new temporal evidence that perflutren may be associated with new-onset seizure activity following perflutren microbubble contrast injection during dobutamine-atropine stress echocardiography. [PMID: 23432576] •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Definity, Luminity, Optison •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Freon 218 Octafluoropropane Octafluorpropan Oktafluorpropan Perfluoropropane Perflutren Perflutreno •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): Perflutren is a diagnostic medication to improve contrast during echocardiograms.

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 Perflutren interact? Information: •Drug A: Buserelin •Drug B: Perflutren •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Perflutren. •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): Used as an ultrasound contrast imaging in cardiology and radiology. •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): Perflutren, a diagnostic drug that is intended to be used for contrast enhancement during the indicated echocardiographic procedures, comprised of lipid-coated microspheres filled with octafluoropropane(OFP) gas. It provide contrast enhancement of the endocardial borders during echocardiography. The perflutren lipid microspheres exhibit lower acoustic impedance than blood and enhance the intrinsic backscatter of blood. •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): Perflutren is comprised of gas-filled microspheres that are injected or infused into the body. When exposed to ultrasound waves, the microspheres resonate and "echo" strong signals back to the ultrasound machine. The difference in density between the gas-filled bubbles and the blood around them creates an increased level of contrast visible in the resulting ultrasound image. During echocardiography, activated Perflutren enhances images of the inner edges or borders of the heart, producing an improved image that may enable physicians to better diagnose 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): 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): OFP is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids. •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 mean half-life of OFP in blood 1.9 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): There is new temporal evidence that perflutren may be associated with new-onset seizure activity following perflutren microbubble contrast injection during dobutamine-atropine stress echocardiography. [PMID: 23432576] •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Definity, Luminity, Optison •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Freon 218 Octafluoropropane Octafluorpropan Oktafluorpropan Perfluoropropane Perflutren Perflutreno •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): Perflutren is a diagnostic medication to improve contrast during echocardiograms. 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 Pheniramine interact?

•Drug A: Buserelin •Drug B: Pheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pheniramine 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): Pheniramine is commonly used in over-the-counter products to treat seasonal allergies or cold and flu symptoms. •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): Pheniramine acts as an antagonist to allergic symptoms stemming from inappropriate histamine release to reduce edema, itching, and redness. The same antihistamine effect also produces sedation by acting in the central nervous 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): Pheniramine competes with histamine for the histamine H1 receptor, acting as an inverse agonist once bound. The reduction in H1 receptor activity is responsible for reduced itching as well as reduced vasodilation and capillary leakage leading to less redness and edema. This can be seen in the suppression of the histamine-induced wheal (swelling) and flare (vasodilation) response. Inverse agonism of the H1 receptor in the CNS is also responsible for the sedation produced by first-generation antihistamines like pheniramine. The binding of pheniramine to H4 receptors, and subsequent inverse agonism, may also contribute to reduced itching by antagonizing inflammation. •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 administration of 30.5 mg of free base pheniramine resulted in a Cmax of 173-294 ng/L with a Tmax of 1-2.5 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): 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): Pheniramine undergoes N-dealkylation to N-didesmethylpheniramine and N-desmethylpheniramine. •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): Pheniramine is eliminated by metabolism and via renal excretion. 24.3% of pheniramine is present in the urine 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 terminal half-life of pheniramine administered via IV is 8-17 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): Case reports involving pheniramine overdosage mention the rare possibility of arrythmias, cutaneous eruptions, and rhabdomyolysis with acute kidney injury. The administration of activated charcoal effectively prevents the absorption of pheniramine as it largely adsorbs to the charcoal, therefore this may be of benefit in cases of overdose if provided early after ingestion. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Naphcon A, Opcon-A, Visine-A •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): Pheniramine is an antihistamine used to treat allergic rhinitis and pruritus.

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 Pheniramine interact? Information: •Drug A: Buserelin •Drug B: Pheniramine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pheniramine 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): Pheniramine is commonly used in over-the-counter products to treat seasonal allergies or cold and flu symptoms. •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): Pheniramine acts as an antagonist to allergic symptoms stemming from inappropriate histamine release to reduce edema, itching, and redness. The same antihistamine effect also produces sedation by acting in the central nervous 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): Pheniramine competes with histamine for the histamine H1 receptor, acting as an inverse agonist once bound. The reduction in H1 receptor activity is responsible for reduced itching as well as reduced vasodilation and capillary leakage leading to less redness and edema. This can be seen in the suppression of the histamine-induced wheal (swelling) and flare (vasodilation) response. Inverse agonism of the H1 receptor in the CNS is also responsible for the sedation produced by first-generation antihistamines like pheniramine. The binding of pheniramine to H4 receptors, and subsequent inverse agonism, may also contribute to reduced itching by antagonizing inflammation. •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 administration of 30.5 mg of free base pheniramine resulted in a Cmax of 173-294 ng/L with a Tmax of 1-2.5 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): 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): Pheniramine undergoes N-dealkylation to N-didesmethylpheniramine and N-desmethylpheniramine. •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): Pheniramine is eliminated by metabolism and via renal excretion. 24.3% of pheniramine is present in the urine 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 terminal half-life of pheniramine administered via IV is 8-17 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): Case reports involving pheniramine overdosage mention the rare possibility of arrythmias, cutaneous eruptions, and rhabdomyolysis with acute kidney injury. The administration of activated charcoal effectively prevents the absorption of pheniramine as it largely adsorbs to the charcoal, therefore this may be of benefit in cases of overdose if provided early after ingestion. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Naphcon A, Opcon-A, Visine-A •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): Pheniramine is an antihistamine used to treat allergic rhinitis and pruritus. 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 Phenol interact?

•Drug A: Buserelin •Drug B: Phenol •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Phenol. •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): Phenol is primarily indicated for minor sore throat pain, sore mouth, minor mouth irritation, and pain associated with canker sores. Additionally, phenol is indicated in the treatment of focal spasticity. •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): Phenol is a potent proteolytic agent. Concentrations in the 5% to 7% range dissolve tissue on contact via proteolysis. In high concentrations when injected next to a nerve, phenol produces a chemical neurolysis which is nonselective across nerve fiber size and most prominent on its outer aspect. Local anesthetic effects occur within 5-10 minutes. •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): Phenol is rapidly absorbed through the skin and into the lungs. •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): At I5 min after exposure, the liver contained the highest level of phenol, consisting mainly of free phenol. After 82 minutes post administration, phenol is uniformly distributed in the liver, blood, kidneys, lungs, along with the heart, testes, thymus and the spleen. With the passage of time, the proportion of free to conjugated phenol changed. By 360 minutes most phenol appears in conjugated forms. •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): Phenyl sulfate, phenyl glucuronide, quinol sulfate, and quinol glucuronide were detected in human beings as phenol 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): The kidney is the primary route of elimination of phenol. •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): In rabbits, 72% is excreted in the urine, 1% in the feces, 4% in the carcass following sacrifice, and trace amounts were exhaled. •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): Mouse, Subcutaneous, LD50: 0.3-0.35 g/kg. (Duplay and Cazin, 1891; Tollens, 1905). Rat, Subcutaneous, LD50: 0.45. (Deichmann and Witherup, 1944). Rat, Oral, LD50: 0.53. (Deichmann and Witherup, 1944). Rat, Oral, LD50: 0.65. (Flickinger, 1976). Rat, Cutaneous, LD50: 0.67. (Conning and Hayes, 1970). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide carbolique Acide phénique Benzenol Carbolic acid Carbolsäure Fenol Hydroxybenzene Karbolsäure Monohydroxybenzene Oxybenzene Phenic Acid Phenol Phenyl alcohol Phenylic acid •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): Phenol is an antiseptic and disinfectant used in a variety of settings.

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 Phenol interact? Information: •Drug A: Buserelin •Drug B: Phenol •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Phenol. •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): Phenol is primarily indicated for minor sore throat pain, sore mouth, minor mouth irritation, and pain associated with canker sores. Additionally, phenol is indicated in the treatment of focal spasticity. •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): Phenol is a potent proteolytic agent. Concentrations in the 5% to 7% range dissolve tissue on contact via proteolysis. In high concentrations when injected next to a nerve, phenol produces a chemical neurolysis which is nonselective across nerve fiber size and most prominent on its outer aspect. Local anesthetic effects occur within 5-10 minutes. •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): Phenol is rapidly absorbed through the skin and into the lungs. •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): At I5 min after exposure, the liver contained the highest level of phenol, consisting mainly of free phenol. After 82 minutes post administration, phenol is uniformly distributed in the liver, blood, kidneys, lungs, along with the heart, testes, thymus and the spleen. With the passage of time, the proportion of free to conjugated phenol changed. By 360 minutes most phenol appears in conjugated forms. •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): Phenyl sulfate, phenyl glucuronide, quinol sulfate, and quinol glucuronide were detected in human beings as phenol 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): The kidney is the primary route of elimination of phenol. •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): In rabbits, 72% is excreted in the urine, 1% in the feces, 4% in the carcass following sacrifice, and trace amounts were exhaled. •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): Mouse, Subcutaneous, LD50: 0.3-0.35 g/kg. (Duplay and Cazin, 1891; Tollens, 1905). Rat, Subcutaneous, LD50: 0.45. (Deichmann and Witherup, 1944). Rat, Oral, LD50: 0.53. (Deichmann and Witherup, 1944). Rat, Oral, LD50: 0.65. (Flickinger, 1976). Rat, Cutaneous, LD50: 0.67. (Conning and Hayes, 1970). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide carbolique Acide phénique Benzenol Carbolic acid Carbolsäure Fenol Hydroxybenzene Karbolsäure Monohydroxybenzene Oxybenzene Phenic Acid Phenol Phenyl alcohol Phenylic acid •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): Phenol is an antiseptic and disinfectant used in a variety of settings. 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 Pimavanserin interact?

•Drug A: Buserelin •Drug B: Pimavanserin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pimavanserin. •Extended Description: QT interval prolongation has been reported with the use of pimavanserin, although the exact cause is unknown.2,1 Therefore, the concomitant use of pimavanserin with other QT-prolonging agents can further increase the risk of cardiac arrhythmias. •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): Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. •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): Pimavanserin's unique actions on serotonin receptors improve symptoms of hallucinations and delusions associated with Parkinson's disease. In clinical studies, 80.5% of individuals treated with pimavanserin reported improvement in symptoms. Pimavanserin does not worsen motor functioning in patients with Parkinson's disease psychosis. In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT 2A receptors with high binding affinity (K i value 0.087 nM) and at serotonin 5-HT 2C receptors with lower binding affinity (K i value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (K i value 120 nM) and has no appreciable affinity (K i value >300 nM), to serotonin 5-HT 2B, dopaminergic (including D 2 ), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels. The effect of pimavanserin on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. A pharmacokinetic/pharmacodynamic analysis with pimavanserin suggested a concentration-dependent QTc interval prolongation in the therapeutic range. In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of pimavanserin 34 mg. These data are consistent with the profile observed in a thorough QT study in healthy subjects. Sporadic QTcF values ≥500 msec and change from baseline values ≥60 msec were observed in subjects treated with pimavanserin 34 mg; although the incidence was generally similar for pimavanserin and placebo groups. There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of pimavanserin, including those patients with hallucinations and delusions associated with Parkinson’s disease psychosis. •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): Parkinson's disease psychosis (PDP) is an imbalance of serotonin and dopamine from disruption of the normal balance between the serotonergic and dopaminergic receptors and neurotransmitters in the brain. The mechanism by which pimavanserin treats hallucinations and delusions associated with Parkinson’s disease psychosis is not fully established. It is possible that pimavanserin acts via inverse agonist and antagonist activity at serotonin 5-HT 2A receptors with limited effects on serotonin 5-HT 2C receptors. Pimavanserin is an inverse agonist and antagonist of serotonin 5-HT 2A receptors with high binding affinity, demonstrating low binding affinity to serotonin 5-HT 2C receptors. In addition, this drug exhibits low affinity binding to sigma 1 receptors. Pimavanserin lacks activity at muscarinic, dopaminergic, adrenergic, and histaminergic receptors, preventing various undesirable effects typically associated with antipsychotics. •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 T max of pimavanserin in clinical studies was 6 hours, regardless of the dose. The bioavailability of an oral tablet of pimavanserin and a solution were almost identical. Ingestion of a high-fat meal had no significant effect on the rate (C max ) and extent (AUC) of pimavanserin exposure. C max decreased by about 9% while AUC increased by about 8% with a high-fat meal. The major active circulating N-desmethylated metabolite, AC-279, has a median T max of 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): Following administration of a single dose of 34 mg, the average apparent volume of distribution was 2173 L in clinical studies. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pimavanserin is highly protein-bound (~95%) in human plasma. Protein binding appeared to be dose-independent and did not change significantly over dosing time from Day 1 to Day 14. •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): Pimavanserin is mainly metabolized CYP3A4 and CYP3A5 hepatic cytochrome enzymes, and to a lesser extent by CYP2J2, CYP2D6, and other cytochrome and flavin-containing monooxygenase enzymes. CYP3A4 metabolizes pimavanserin to its major active metabolite, AC-279. •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 0.55% of the 34 mg oral dose of C-pimavanserin was eliminated as unchanged drug in urine and 1.53% was eliminated in feces after 10 days. Less than 1% of the administered dose of pimavanserin and its active metabolite AC-279 were recovered 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): The average plasma half-lives for pimavanserin and its active metabolite (AC-279) are estimated at 57 hours and 200 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): LD50 information for pimavanserin is not readily available in the literature. Pre-marketing clinical trials involving pimavanserin in approximately 1200 subjects and patients do not report symptoms of overdose. In healthy subject studies, nausea and vomiting were reported. There are no known antidotes for an overdose with this drug. Cardiovascular monitoring should begin immediately in the case of an overdose and continuous ECG monitoring is recommended. If antiarrhythmic drugs are administered in an overdose of pimavanserin, disopyramide, procainamide, and quinidine should not be used due to their potential for QT-prolonging effects. In the case of an overdose, consider the 57 hour plasma half-life of pimavanserin and the possibility of multiple drug involvement. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nuplazid •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): Pimavanserin is a second generation atypical antipsychotic used for the treatment of hallucinations and delusions caused by Parkinson's Disease.

QT interval prolongation has been reported with the use of pimavanserin, although the exact cause is unknown.2,1 Therefore, the concomitant use of pimavanserin with other QT-prolonging agents can further increase the risk of cardiac arrhythmias. The severity of the interaction is moderate.

Question: Does Buserelin and Pimavanserin interact? Information: •Drug A: Buserelin •Drug B: Pimavanserin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pimavanserin. •Extended Description: QT interval prolongation has been reported with the use of pimavanserin, although the exact cause is unknown.2,1 Therefore, the concomitant use of pimavanserin with other QT-prolonging agents can further increase the risk of cardiac arrhythmias. •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): Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. •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): Pimavanserin's unique actions on serotonin receptors improve symptoms of hallucinations and delusions associated with Parkinson's disease. In clinical studies, 80.5% of individuals treated with pimavanserin reported improvement in symptoms. Pimavanserin does not worsen motor functioning in patients with Parkinson's disease psychosis. In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT 2A receptors with high binding affinity (K i value 0.087 nM) and at serotonin 5-HT 2C receptors with lower binding affinity (K i value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (K i value 120 nM) and has no appreciable affinity (K i value >300 nM), to serotonin 5-HT 2B, dopaminergic (including D 2 ), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels. The effect of pimavanserin on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. A pharmacokinetic/pharmacodynamic analysis with pimavanserin suggested a concentration-dependent QTc interval prolongation in the therapeutic range. In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of pimavanserin 34 mg. These data are consistent with the profile observed in a thorough QT study in healthy subjects. Sporadic QTcF values ≥500 msec and change from baseline values ≥60 msec were observed in subjects treated with pimavanserin 34 mg; although the incidence was generally similar for pimavanserin and placebo groups. There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of pimavanserin, including those patients with hallucinations and delusions associated with Parkinson’s disease psychosis. •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): Parkinson's disease psychosis (PDP) is an imbalance of serotonin and dopamine from disruption of the normal balance between the serotonergic and dopaminergic receptors and neurotransmitters in the brain. The mechanism by which pimavanserin treats hallucinations and delusions associated with Parkinson’s disease psychosis is not fully established. It is possible that pimavanserin acts via inverse agonist and antagonist activity at serotonin 5-HT 2A receptors with limited effects on serotonin 5-HT 2C receptors. Pimavanserin is an inverse agonist and antagonist of serotonin 5-HT 2A receptors with high binding affinity, demonstrating low binding affinity to serotonin 5-HT 2C receptors. In addition, this drug exhibits low affinity binding to sigma 1 receptors. Pimavanserin lacks activity at muscarinic, dopaminergic, adrenergic, and histaminergic receptors, preventing various undesirable effects typically associated with antipsychotics. •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 T max of pimavanserin in clinical studies was 6 hours, regardless of the dose. The bioavailability of an oral tablet of pimavanserin and a solution were almost identical. Ingestion of a high-fat meal had no significant effect on the rate (C max ) and extent (AUC) of pimavanserin exposure. C max decreased by about 9% while AUC increased by about 8% with a high-fat meal. The major active circulating N-desmethylated metabolite, AC-279, has a median T max of 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): Following administration of a single dose of 34 mg, the average apparent volume of distribution was 2173 L in clinical studies. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pimavanserin is highly protein-bound (~95%) in human plasma. Protein binding appeared to be dose-independent and did not change significantly over dosing time from Day 1 to Day 14. •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): Pimavanserin is mainly metabolized CYP3A4 and CYP3A5 hepatic cytochrome enzymes, and to a lesser extent by CYP2J2, CYP2D6, and other cytochrome and flavin-containing monooxygenase enzymes. CYP3A4 metabolizes pimavanserin to its major active metabolite, AC-279. •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 0.55% of the 34 mg oral dose of C-pimavanserin was eliminated as unchanged drug in urine and 1.53% was eliminated in feces after 10 days. Less than 1% of the administered dose of pimavanserin and its active metabolite AC-279 were recovered 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): The average plasma half-lives for pimavanserin and its active metabolite (AC-279) are estimated at 57 hours and 200 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): LD50 information for pimavanserin is not readily available in the literature. Pre-marketing clinical trials involving pimavanserin in approximately 1200 subjects and patients do not report symptoms of overdose. In healthy subject studies, nausea and vomiting were reported. There are no known antidotes for an overdose with this drug. Cardiovascular monitoring should begin immediately in the case of an overdose and continuous ECG monitoring is recommended. If antiarrhythmic drugs are administered in an overdose of pimavanserin, disopyramide, procainamide, and quinidine should not be used due to their potential for QT-prolonging effects. In the case of an overdose, consider the 57 hour plasma half-life of pimavanserin and the possibility of multiple drug involvement. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nuplazid •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): Pimavanserin is a second generation atypical antipsychotic used for the treatment of hallucinations and delusions caused by Parkinson's Disease. Output: QT interval prolongation has been reported with the use of pimavanserin, although the exact cause is unknown.2,1 Therefore, the concomitant use of pimavanserin with other QT-prolonging agents can further increase the risk of cardiac arrhythmias. The severity of the interaction is moderate.

Does Buserelin and Pimozide interact?

•Drug A: Buserelin •Drug B: Pimozide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pimozide. •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 the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard 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): Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol). •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 ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS. •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): Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion. •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): Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined. •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): 29 ± 10 hours (single-dose study of healthy volunteers). •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 = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Orap •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): Pimozide is an antipsychotic used to manage debilitating motor and phonic tics in patients with Tourette's Disorder.

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 Pimozide interact? Information: •Drug A: Buserelin •Drug B: Pimozide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pimozide. •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 the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard 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): Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol). •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 ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS. •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): Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion. •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): Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined. •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): 29 ± 10 hours (single-dose study of healthy volunteers). •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 = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Orap •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): Pimozide is an antipsychotic used to manage debilitating motor and phonic tics in patients with Tourette's Disorder. 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 Pinaverium interact?

•Drug A: Buserelin •Drug B: Pinaverium •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pinaverium. •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): Pinaverium is indicated for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract. •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): Pinaverium is a selective and specific voltage-dependent calcium channel blocker located on intestinal smooth muscle cells to inhibit calcium influx. It mediates various effects on the GI tract: it causes oesophageal, gastric and duodenal relaxation, relaxes the colon and intestines, inhibits colonic motility in response to food, hormonal or pharmacological stimuli, accelerates gastric emptying, and reduces contractions of the gallbladder and phasic contractions of sphincter of Oddi. At higher concentrations, pinaverium also exhibits very weak anticholinergic effects but is not shown to display vasodilatory or anti-arrythmic actions. •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): Pinaverium interacts with the 1,4-dihydropyridine binding sites on voltage dependent L-type calcium channels located on GI smooth muscle cells in a competitve manner. The binding site is located in the alpha 1S subunit and pinaverium most likely antagonizes the action of calcium ions by stabilizing a non-conducting channel state. Pinaverium inhibits smooth muscle contractions of the GI tract by inhibiting inward calcium current and calcium influx. It is suggested that pinaverium may be able to bind to both closed or inactivates states of the calcium channel with similar affinity. •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, pinaverium is poorly absorbed (5-10%) followed by uptake by liver. Poor absorption is due to its highly polar quaternary ammonium group and high molecular weight, which limits extensive diffusion across all cell membranes and promotes its selectivity towards the gastrointestinal tracts []. Peak plasma concentration is reached within one hour after administration and the absolute oral bioavailability is reported to be less than 1%. •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): It is selectively distributed to the digestive tract due to poor absorption and marked hepatobiliary excretion. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pinaverium is highly bound to human plasma proteins with the ratio of 97%. •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 of pinaverium involves demethylation of one of the methoxy groups, hydroxylation of the norpinanyl ring and elimination of the benzyl group with subsequent opening of the morpholine ring. •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): Pinaverium is predominantly eliminated into 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 is approximately 1.5 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): Some minor GI-related adverse effects include epigastric pain and/or fullness, nausea, constipation, heartburn, distension, and diarrhoea. Other side effects are headache, dry mouth, drowsiness, vertigo and skin allergy. Oral LD50 in mice, rats and rabbits are 1531 mg/kg, 1145 mg/kg and 154 mg/kg, respectively. Pinaverium displays no teratogenic, mutagenic or carcinogenic potential. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Dicetel •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): Pinaverium is a spasmolytic agent used for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract.

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 Pinaverium interact? Information: •Drug A: Buserelin •Drug B: Pinaverium •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Pinaverium. •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): Pinaverium is indicated for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract. •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): Pinaverium is a selective and specific voltage-dependent calcium channel blocker located on intestinal smooth muscle cells to inhibit calcium influx. It mediates various effects on the GI tract: it causes oesophageal, gastric and duodenal relaxation, relaxes the colon and intestines, inhibits colonic motility in response to food, hormonal or pharmacological stimuli, accelerates gastric emptying, and reduces contractions of the gallbladder and phasic contractions of sphincter of Oddi. At higher concentrations, pinaverium also exhibits very weak anticholinergic effects but is not shown to display vasodilatory or anti-arrythmic actions. •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): Pinaverium interacts with the 1,4-dihydropyridine binding sites on voltage dependent L-type calcium channels located on GI smooth muscle cells in a competitve manner. The binding site is located in the alpha 1S subunit and pinaverium most likely antagonizes the action of calcium ions by stabilizing a non-conducting channel state. Pinaverium inhibits smooth muscle contractions of the GI tract by inhibiting inward calcium current and calcium influx. It is suggested that pinaverium may be able to bind to both closed or inactivates states of the calcium channel with similar affinity. •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, pinaverium is poorly absorbed (5-10%) followed by uptake by liver. Poor absorption is due to its highly polar quaternary ammonium group and high molecular weight, which limits extensive diffusion across all cell membranes and promotes its selectivity towards the gastrointestinal tracts []. Peak plasma concentration is reached within one hour after administration and the absolute oral bioavailability is reported to be less than 1%. •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): It is selectively distributed to the digestive tract due to poor absorption and marked hepatobiliary excretion. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pinaverium is highly bound to human plasma proteins with the ratio of 97%. •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 of pinaverium involves demethylation of one of the methoxy groups, hydroxylation of the norpinanyl ring and elimination of the benzyl group with subsequent opening of the morpholine ring. •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): Pinaverium is predominantly eliminated into 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 is approximately 1.5 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): Some minor GI-related adverse effects include epigastric pain and/or fullness, nausea, constipation, heartburn, distension, and diarrhoea. Other side effects are headache, dry mouth, drowsiness, vertigo and skin allergy. Oral LD50 in mice, rats and rabbits are 1531 mg/kg, 1145 mg/kg and 154 mg/kg, respectively. Pinaverium displays no teratogenic, mutagenic or carcinogenic potential. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Dicetel •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): Pinaverium is a spasmolytic agent used for the symptomatic treatment of irritable bowel syndrome (IBS) and functional disorders of the biliary tract. 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 Pioglitazone interact?

•Drug A: Buserelin •Drug B: Pioglitazone •Severity: MODERATE •Description: The therapeutic efficacy of Pioglitazone 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): Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also available in combination with metformin, glimepiride, or alogliptin for the same indication. •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): Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves impaired glucose homeostasis. In patients with type 2 diabetes mellitus, these effects result in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. Significant fluid retention leading to the development/exacerbation of congestive heart failure has been reported with pioglitazone - avoid its use in patients in heart failure or at risk of developing heart failure. There is some evidence that pioglitazone may be associated with an increased risk of developing bladder cancer. Pioglitazone should not be used in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer. •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): Pioglitazone is a selective agonist at peroxisome proliferator-activated receptor-gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose and lipid production, transport, and utilization. Through this mechanism, pioglitazone both enhances tissue sensitivity to insulin and reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta 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): Following oral administration of pioglitazone, peak serum concentrations are observed within 2 hours (T max ) - food slightly delays the time to peak serum concentration, increasing T max to approximately 3-4 hours, but does not alter the extent of absorption. Steady-state concentrations of both parent drug and its primary active metabolites are achieved after 7 days of once-daily administration of pioglitazone. C max and AUC increase proportionately to administered doses. •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 average apparent volume of distribution of pioglitazone is 0.63 ± 0.41 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pioglitazone is >99% protein-bound in human plasma - binding is primarily to albumin, although pioglitazone has been shown to bind other serum proteins with a lower affinity. The M-III and M-IV metabolites of pioglitazone are >98% protein-bound (also 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): Pioglitazone is extensively metabolized by both hydroxylation and oxidation - the resulting metabolites are also partly converted to glucuronide or sulfate conjugates. The pharmacologically active M-IV and M-III metabolites are the main metabolites found in human serum and their circulating concentrations are equal to, or greater than, those of the parent drug. The specific CYP isoenzymes involved in the metabolism of pioglitazone are CYP2C8 and, to a lesser degree, CYP3A4. There is also some evidence to suggest a contribution by extrahepatic CYP1A1. •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 15-30% of orally administered pioglitazone is recovered in the urine. The bulk of its elimination, then, is presumed to be through the excretion of unchanged drug in the bile or as metabolites 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 serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3-7 hours and 16-24 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance of orally administered pioglitazone is 5-7 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 oral TDLo observed in mice is 24 mg/kg for 4 days and for rats is 3 mg/kg for 6 days. One instance of overdose was reported during clinical trials with pioglitazone in which a patient took an oral dose of 120mg daily for four days, followed by 180mg daily for seven days - this patient did not report any adverse clinical symptoms during this time. In the event of overdosage, employ symptomatic and supportive measures according to the patient's clinical status. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actoplus Met, Actos, Duetact, Incresync, Oseni, Tandemact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pioglitazona Pioglitazone Pioglitazonum •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): Pioglitazone is a thiazolidinedione used adjunctively with diet and exercise to normalize glycemic levels in adults 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 Pioglitazone interact? Information: •Drug A: Buserelin •Drug B: Pioglitazone •Severity: MODERATE •Description: The therapeutic efficacy of Pioglitazone 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): Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also available in combination with metformin, glimepiride, or alogliptin for the same indication. •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): Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves impaired glucose homeostasis. In patients with type 2 diabetes mellitus, these effects result in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. Significant fluid retention leading to the development/exacerbation of congestive heart failure has been reported with pioglitazone - avoid its use in patients in heart failure or at risk of developing heart failure. There is some evidence that pioglitazone may be associated with an increased risk of developing bladder cancer. Pioglitazone should not be used in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer. •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): Pioglitazone is a selective agonist at peroxisome proliferator-activated receptor-gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose and lipid production, transport, and utilization. Through this mechanism, pioglitazone both enhances tissue sensitivity to insulin and reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta 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): Following oral administration of pioglitazone, peak serum concentrations are observed within 2 hours (T max ) - food slightly delays the time to peak serum concentration, increasing T max to approximately 3-4 hours, but does not alter the extent of absorption. Steady-state concentrations of both parent drug and its primary active metabolites are achieved after 7 days of once-daily administration of pioglitazone. C max and AUC increase proportionately to administered doses. •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 average apparent volume of distribution of pioglitazone is 0.63 ± 0.41 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pioglitazone is >99% protein-bound in human plasma - binding is primarily to albumin, although pioglitazone has been shown to bind other serum proteins with a lower affinity. The M-III and M-IV metabolites of pioglitazone are >98% protein-bound (also 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): Pioglitazone is extensively metabolized by both hydroxylation and oxidation - the resulting metabolites are also partly converted to glucuronide or sulfate conjugates. The pharmacologically active M-IV and M-III metabolites are the main metabolites found in human serum and their circulating concentrations are equal to, or greater than, those of the parent drug. The specific CYP isoenzymes involved in the metabolism of pioglitazone are CYP2C8 and, to a lesser degree, CYP3A4. There is also some evidence to suggest a contribution by extrahepatic CYP1A1. •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 15-30% of orally administered pioglitazone is recovered in the urine. The bulk of its elimination, then, is presumed to be through the excretion of unchanged drug in the bile or as metabolites 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 serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3-7 hours and 16-24 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent clearance of orally administered pioglitazone is 5-7 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 oral TDLo observed in mice is 24 mg/kg for 4 days and for rats is 3 mg/kg for 6 days. One instance of overdose was reported during clinical trials with pioglitazone in which a patient took an oral dose of 120mg daily for four days, followed by 180mg daily for seven days - this patient did not report any adverse clinical symptoms during this time. In the event of overdosage, employ symptomatic and supportive measures according to the patient's clinical status. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Actoplus Met, Actos, Duetact, Incresync, Oseni, Tandemact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Pioglitazona Pioglitazone Pioglitazonum •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): Pioglitazone is a thiazolidinedione used adjunctively with diet and exercise to normalize glycemic levels in adults 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 Pitolisant interact?

•Drug A: Buserelin •Drug B: Pitolisant •Severity: MODERATE •Description: Buserelin may increase the QTc-prolonging activities of Pitolisant. •Extended Description: Pitolisant was shown to cause QTc prolongation by blocking the hERG channels.1 Concomitant use of drugs that prolong the QT interval with pitolisant may lead to an additive QTc-prolonging effect and increase the risk of cardiac arrhythmia. •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): Pitolisant is indicated for the treatment of narcolepsy with or without cataplexy in adults in the US [L1471] and patients aged six years and older. In the US, it is also indicated for the treatment of excessive daytime sleepiness in narcolepsy in adult 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): Pitolisant promotes wakefulness in narcolepsy by enhancing histaminergic signalling in the central nervous system. It does not significantly bind to H1, H2, or H4 receptors. In patients with narcolepsy in presence or absence of cataplexy, treatment of pitolisant was associated with an improvement in the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) Scores) and attention (e.g. Sustained Attention to Response Task (SART)).[L1471] Pitolisant also improved the frequency and severity of narcolepsy-associated cataplexy. Pitolisant acts as a blocker at hERG channels. In two QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms).[L1471] •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): Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain [L1471] via activating orexin receptors. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by neurons located from the lateral hypothalamus. These neurons project to aminergic neurons, such as histaminergic or noradrenergic neurons, that are responsible for the effects of orexin and control of wakefulness. Histamine H3 receptors are presynaptic inhibitory autoreceptors that are located in the cerebral cortex, hypothalamus, hippocampus, and basal ganglia. H3 receptors promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of histaminergic neurons and promotes wakefulness.[L1471] Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level. Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human H3 receptor and mediates its pharmacological action at the presynaptic level. It is thought to bind to the antagonist binding site of the H3 receptor, which is located within the transmembrane core just below the extracellular loops. Piperidines form a salt bridge with Glu206 in the membrane-spanning segment, and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine. Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex, including the nucleus accumbens.[L1471] At lower nanomolar concentrations, pitolisant acts as an inverse agonist at H3 receptors and enhances the release of endogenous histamine over the basal level. •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): Pitolisant is rapidly and well absorbed following oral administration, resulting in the drug being 90% absorbed. In healthy individuals receiving an oral dose of 20 mg, the Cmax was approximately 30 ng/mL. Following oral administration of pitolisant 35.6 mg once daily, the mean steady state Cmax and AUC were 73 ng/mL and 812 ngxhr/mL, respectively. The Tmax was typically reached approximately 3 hours following administration.[L1471] Following repeated dosing, the steady-state plasma concentration is achieved after 5-6 days of administration but the inter-individual variability in the time to reach steady-state is reported to be high.[L1471] The absolute bioavailability of pitolisant has not been determined. •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 single and multiple oral dosing of pitolisant to healthy male adults at doses between 1 and 240 mg, the apparent volume of distribution (V/F) ranges from 1100 to 2825 L. Pitolisant is thought to be equally distributed between red blood cells and plasma.[L1471] Following intravenous administration of pitolisant in rats and monkeys, the apparent Vd at steady-state was approximately 10-fold greater than total body water. Pitolisant crosses the blood-brain barrier and placenta, and was found in milk in rats. •Protein binding (Drug A): 15% •Protein binding (Drug B): The serum protein binding of pitolisant is approximately 91% to 96%. Pitolisant is mainly bound to serum albumin and alpha-1 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): Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4 in the liver. The major non-conjugated metabolites are BP2.941 (piperidine N-oxide) and BP2.951 (5-aminovaleric acid).[L1471] Metabolites can further undergo conjugation with glycine or glucuronic acid, and oxidation to a minimal extent. Most metabolites of pitolisant do not retain considerable pharmacological activities. Several conjugated metabolites were also identified; the major conjugated inactive metabolite was a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.[L1471] Due to its extensive metabolism in the liver, the systemic exposure of pitolisant thus adverse events of the drug may be elevated in case of compromised liver function. The dosage adjustments for pitolisant is advised in patients with moderate hepatic impairment. •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 hepatic metabolism, about 63% of total elimination occurs via renal excretion into the urine as an inactive non-conjugated metabolite BP2.951 and a glycine conjugated metabolite.[L1471] About 25% of the total dose administered is excreted through expired air as metabolites, and a small fraction (<3%) of drug can be recovered in faeces.[L1471] •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): Pitolisant has a plasma half-life of 10-12 hours.[L1471] After administration of a single dose of 35.6 mg, the median half-life of pitolisant was approximately 20 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent oral clearance (CL/F) of pitolisant was 43.9 L/hr following a single dose of 35.6 mg. The clearance rate is expected to be lower with increasing age. •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 pitolisant overdose may include headache, insomnia, irritability, nausea and abdominal pain. In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.[L1471] After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively.[L1471] Pitolisant was not found to be genotoxic in Ames test nor carcinogenic in mouse and rat carcinogenicity studies. In rabbit and rat teratogenicity studies, maternally high toxic doses of pitolisant sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats. It also decreased the percentage of live conceptuses and increased post-implantation loss in female rats. A delay in post-natal development was observed.[L1471] •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Wakix •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): Pitolisant is an antagonist and inverse agonist at the histamine H3 receptor that is used to treat narcolepsy in adults.

Pitolisant was shown to cause QTc prolongation by blocking the hERG channels.1 Concomitant use of drugs that prolong the QT interval with pitolisant may lead to an additive QTc-prolonging effect and increase the risk of cardiac arrhythmia. The severity of the interaction is moderate.

Question: Does Buserelin and Pitolisant interact? Information: •Drug A: Buserelin •Drug B: Pitolisant •Severity: MODERATE •Description: Buserelin may increase the QTc-prolonging activities of Pitolisant. •Extended Description: Pitolisant was shown to cause QTc prolongation by blocking the hERG channels.1 Concomitant use of drugs that prolong the QT interval with pitolisant may lead to an additive QTc-prolonging effect and increase the risk of cardiac arrhythmia. •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): Pitolisant is indicated for the treatment of narcolepsy with or without cataplexy in adults in the US [L1471] and patients aged six years and older. In the US, it is also indicated for the treatment of excessive daytime sleepiness in narcolepsy in adult 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): Pitolisant promotes wakefulness in narcolepsy by enhancing histaminergic signalling in the central nervous system. It does not significantly bind to H1, H2, or H4 receptors. In patients with narcolepsy in presence or absence of cataplexy, treatment of pitolisant was associated with an improvement in the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) Scores) and attention (e.g. Sustained Attention to Response Task (SART)).[L1471] Pitolisant also improved the frequency and severity of narcolepsy-associated cataplexy. Pitolisant acts as a blocker at hERG channels. In two QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms).[L1471] •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): Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain [L1471] via activating orexin receptors. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by neurons located from the lateral hypothalamus. These neurons project to aminergic neurons, such as histaminergic or noradrenergic neurons, that are responsible for the effects of orexin and control of wakefulness. Histamine H3 receptors are presynaptic inhibitory autoreceptors that are located in the cerebral cortex, hypothalamus, hippocampus, and basal ganglia. H3 receptors promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of histaminergic neurons and promotes wakefulness.[L1471] Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level. Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human H3 receptor and mediates its pharmacological action at the presynaptic level. It is thought to bind to the antagonist binding site of the H3 receptor, which is located within the transmembrane core just below the extracellular loops. Piperidines form a salt bridge with Glu206 in the membrane-spanning segment, and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine. Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex, including the nucleus accumbens.[L1471] At lower nanomolar concentrations, pitolisant acts as an inverse agonist at H3 receptors and enhances the release of endogenous histamine over the basal level. •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): Pitolisant is rapidly and well absorbed following oral administration, resulting in the drug being 90% absorbed. In healthy individuals receiving an oral dose of 20 mg, the Cmax was approximately 30 ng/mL. Following oral administration of pitolisant 35.6 mg once daily, the mean steady state Cmax and AUC were 73 ng/mL and 812 ngxhr/mL, respectively. The Tmax was typically reached approximately 3 hours following administration.[L1471] Following repeated dosing, the steady-state plasma concentration is achieved after 5-6 days of administration but the inter-individual variability in the time to reach steady-state is reported to be high.[L1471] The absolute bioavailability of pitolisant has not been determined. •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 single and multiple oral dosing of pitolisant to healthy male adults at doses between 1 and 240 mg, the apparent volume of distribution (V/F) ranges from 1100 to 2825 L. Pitolisant is thought to be equally distributed between red blood cells and plasma.[L1471] Following intravenous administration of pitolisant in rats and monkeys, the apparent Vd at steady-state was approximately 10-fold greater than total body water. Pitolisant crosses the blood-brain barrier and placenta, and was found in milk in rats. •Protein binding (Drug A): 15% •Protein binding (Drug B): The serum protein binding of pitolisant is approximately 91% to 96%. Pitolisant is mainly bound to serum albumin and alpha-1 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): Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4 in the liver. The major non-conjugated metabolites are BP2.941 (piperidine N-oxide) and BP2.951 (5-aminovaleric acid).[L1471] Metabolites can further undergo conjugation with glycine or glucuronic acid, and oxidation to a minimal extent. Most metabolites of pitolisant do not retain considerable pharmacological activities. Several conjugated metabolites were also identified; the major conjugated inactive metabolite was a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.[L1471] Due to its extensive metabolism in the liver, the systemic exposure of pitolisant thus adverse events of the drug may be elevated in case of compromised liver function. The dosage adjustments for pitolisant is advised in patients with moderate hepatic impairment. •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 hepatic metabolism, about 63% of total elimination occurs via renal excretion into the urine as an inactive non-conjugated metabolite BP2.951 and a glycine conjugated metabolite.[L1471] About 25% of the total dose administered is excreted through expired air as metabolites, and a small fraction (<3%) of drug can be recovered in faeces.[L1471] •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): Pitolisant has a plasma half-life of 10-12 hours.[L1471] After administration of a single dose of 35.6 mg, the median half-life of pitolisant was approximately 20 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent oral clearance (CL/F) of pitolisant was 43.9 L/hr following a single dose of 35.6 mg. The clearance rate is expected to be lower with increasing age. •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 pitolisant overdose may include headache, insomnia, irritability, nausea and abdominal pain. In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.[L1471] After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively.[L1471] Pitolisant was not found to be genotoxic in Ames test nor carcinogenic in mouse and rat carcinogenicity studies. In rabbit and rat teratogenicity studies, maternally high toxic doses of pitolisant sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats. It also decreased the percentage of live conceptuses and increased post-implantation loss in female rats. A delay in post-natal development was observed.[L1471] •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Wakix •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): Pitolisant is an antagonist and inverse agonist at the histamine H3 receptor that is used to treat narcolepsy in adults. Output: Pitolisant was shown to cause QTc prolongation by blocking the hERG channels.1 Concomitant use of drugs that prolong the QT interval with pitolisant may lead to an additive QTc-prolonging effect and increase the risk of cardiac arrhythmia. The severity of the interaction is moderate.

Does Buserelin and Ponesimod interact?

•Drug A: Buserelin •Drug B: Ponesimod •Severity: MAJOR •Description: The risk or severity of bradycardia can be increased when Ponesimod is combined with Buserelin. •Extended Description: Ponesimod may potentially have an additive effect on heart rate in patients who are also taking QTc prolonging agents.1 •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): Ponesimod is indicated to treat adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive 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): Ponesimod is a sphingosine 1-phosphate receptor 1 modulator indicated to treat adults with relapsing forms of multiple sclerosis. It has a long duration of action as it is given once daily. Patients should be counselled about the risk of infections, bradyarrhythmia, atrioventricular conduction delays, decreased respiratory function, liver injury, increased blood pressure, cutaneous malignancies, fetal harm, and macular edema. •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 sphingosine 1-phosphate receptor 1 (S1P1R) is expressed on the surface of lymphocytes and detects sphingosine 1-phosphate (S1P) at nanomolar concentrations. S1P is a metabolite of the cell membrane component, sphingomyelin. As sphingomyelin degrades, lymphocytes respond to agonism of S1P1R by concentration gradients of S1P. Lymphocytes leave the lymphoid organs in response to higher concentrations of S1P in blood and lymph. Ponesimod modulates this response by stimulating and internalizing S1P1R on lymphocytes, effectively blinding them to concentration gradients of S1P, reducing the number of lymphocytes in blood. Ponesimod is roughly 650 times more selective for S1P1R than S1P. •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 10mg oral dose of ponesimod is 84% bioavailable. Ponesimod reaches a C max of 109 ng/mL, with a T max of 4.0 hours, and an AUC of 3872 h*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): The volume of distribution of ponesimod at steady state is 160 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ponesimod is >99% protein bound in plasma. Though the proteins it binds to have not been identified in literature. •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): Ponesimod can be sulfated to the M5 metabolite, oxidized to an undefined M27 metabolite, reduced to the M6 metabolite, dealkylated to the M32 metabolite, or oxidized and hydrolyzed to the M13 metabolite. Ponesimod can also be oxidized by CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12 to the M12 metabolite. The undefined M27 metabolite can be glucuronidated by UGT1A1 and UGT 2B7 to the M38, M39, and M40 metabolites. The M12 metabolite is either dealkylated to the M32 metabolite or oxidized and hydrolyzed to M13. M13 is dealkylated to M32, which is reduced and oxidized to M48. •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): 57.3-79.6% of a radiolabelled oral dose is recovered in the feces, with 16-26% as the unmetabolized parent compound and 22% as the M12 metabolite. 10.3-18.4% of an oral dose is eliminated in the urine. 0.6-1.9% of a radiolabelled dose was recovered as expired CO 2. •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): Ponesimod has an elimination half life of 33 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of ponesimod is 3.8 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): Patients experiencing an overdose may present with bradycardia, AV conduction block, and changes in blood pressure. Patients should be monitored for pulse rate and blood pressure, as well as ECGs. Treat patients with symptomatic and supportive measures, which may include atropine for bradycardia. dialysis is not expected to remove a significant amount of drug from blood. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ponvory •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): Ponesimod is a sphingosine 1-phosphate receptor modulator indicated to treat relapsing multiple sclerosis.

Ponesimod may potentially have an additive effect on heart rate in patients who are also taking QTc prolonging agents.1 The severity of the interaction is major.

Question: Does Buserelin and Ponesimod interact? Information: •Drug A: Buserelin •Drug B: Ponesimod •Severity: MAJOR •Description: The risk or severity of bradycardia can be increased when Ponesimod is combined with Buserelin. •Extended Description: Ponesimod may potentially have an additive effect on heart rate in patients who are also taking QTc prolonging agents.1 •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): Ponesimod is indicated to treat adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive 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): Ponesimod is a sphingosine 1-phosphate receptor 1 modulator indicated to treat adults with relapsing forms of multiple sclerosis. It has a long duration of action as it is given once daily. Patients should be counselled about the risk of infections, bradyarrhythmia, atrioventricular conduction delays, decreased respiratory function, liver injury, increased blood pressure, cutaneous malignancies, fetal harm, and macular edema. •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 sphingosine 1-phosphate receptor 1 (S1P1R) is expressed on the surface of lymphocytes and detects sphingosine 1-phosphate (S1P) at nanomolar concentrations. S1P is a metabolite of the cell membrane component, sphingomyelin. As sphingomyelin degrades, lymphocytes respond to agonism of S1P1R by concentration gradients of S1P. Lymphocytes leave the lymphoid organs in response to higher concentrations of S1P in blood and lymph. Ponesimod modulates this response by stimulating and internalizing S1P1R on lymphocytes, effectively blinding them to concentration gradients of S1P, reducing the number of lymphocytes in blood. Ponesimod is roughly 650 times more selective for S1P1R than S1P. •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 10mg oral dose of ponesimod is 84% bioavailable. Ponesimod reaches a C max of 109 ng/mL, with a T max of 4.0 hours, and an AUC of 3872 h*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): The volume of distribution of ponesimod at steady state is 160 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ponesimod is >99% protein bound in plasma. Though the proteins it binds to have not been identified in literature. •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): Ponesimod can be sulfated to the M5 metabolite, oxidized to an undefined M27 metabolite, reduced to the M6 metabolite, dealkylated to the M32 metabolite, or oxidized and hydrolyzed to the M13 metabolite. Ponesimod can also be oxidized by CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12 to the M12 metabolite. The undefined M27 metabolite can be glucuronidated by UGT1A1 and UGT 2B7 to the M38, M39, and M40 metabolites. The M12 metabolite is either dealkylated to the M32 metabolite or oxidized and hydrolyzed to M13. M13 is dealkylated to M32, which is reduced and oxidized to M48. •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): 57.3-79.6% of a radiolabelled oral dose is recovered in the feces, with 16-26% as the unmetabolized parent compound and 22% as the M12 metabolite. 10.3-18.4% of an oral dose is eliminated in the urine. 0.6-1.9% of a radiolabelled dose was recovered as expired CO 2. •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): Ponesimod has an elimination half life of 33 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of ponesimod is 3.8 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): Patients experiencing an overdose may present with bradycardia, AV conduction block, and changes in blood pressure. Patients should be monitored for pulse rate and blood pressure, as well as ECGs. Treat patients with symptomatic and supportive measures, which may include atropine for bradycardia. dialysis is not expected to remove a significant amount of drug from blood. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Ponvory •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): Ponesimod is a sphingosine 1-phosphate receptor modulator indicated to treat relapsing multiple sclerosis. Output: Ponesimod may potentially have an additive effect on heart rate in patients who are also taking QTc prolonging agents.1 The severity of the interaction is major.

Does Buserelin and Posaconazole interact?

•Drug A: Buserelin •Drug B: Posaconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Posaconazole 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 prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals. •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): Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action. •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): As a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death. •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): Posaconazole is absorbed with a median Tmax of approximately 3 to 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): 1774 L •Protein binding (Drug A): 15% •Protein binding (Drug B): Posaconazole is highly protein bound (>98%), predominantly 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): Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. •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 excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. •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): Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): 32 L/hr 51 L/hr [Single-Dose Suspension Administration of 200 mg, fasted] 21 L/hr [Single-Dose Suspension Administration of 200 mg, nonfat meal] 14 L/hr [Single-Dose Suspension Administration of 200 mg, high fat meal] 91 L/hr [Single-Dose Suspension Administration of 400 mg, fasted] 43 L/hr [Single-Dose Suspension Administration of 400 mg with liquid nutritional supplement (14 g fat)] •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): During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Noxafil, Posanol •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): Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.

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 Posaconazole interact? Information: •Drug A: Buserelin •Drug B: Posaconazole •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Posaconazole 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 prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals. •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): Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action. •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): As a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death. •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): Posaconazole is absorbed with a median Tmax of approximately 3 to 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): 1774 L •Protein binding (Drug A): 15% •Protein binding (Drug B): Posaconazole is highly protein bound (>98%), predominantly 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): Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. •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 excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. •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): Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours). •Clearance (Drug A): No clearance available •Clearance (Drug B): 32 L/hr 51 L/hr [Single-Dose Suspension Administration of 200 mg, fasted] 21 L/hr [Single-Dose Suspension Administration of 200 mg, nonfat meal] 14 L/hr [Single-Dose Suspension Administration of 200 mg, high fat meal] 91 L/hr [Single-Dose Suspension Administration of 400 mg, fasted] 43 L/hr [Single-Dose Suspension Administration of 400 mg with liquid nutritional supplement (14 g fat)] •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): During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Noxafil, Posanol •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): Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients. 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 Pramlintide interact?

•Drug A: Buserelin •Drug B: Pramlintide •Severity: MODERATE •Description: The therapeutic efficacy of Pramlintide 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 type 1 and type 2 diabetes mellitus as an adjunct to preprandial insulin therapy in patients without adequate glycemic control of insulin 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): Pramlintide is a synthetic analog of amylin, a glucoregulatory hormone that is synthesized by pancreatic β-cells and released into the bloodstream, in a similar pattern as insulin, after a meal. Like insulin, amylin is deficient in individuals with diabetes. It is provided as an acetate salt. Pramlintide is a 37-amino acid polypeptide that differs structurally from human amylin by the replacement of alanine, serine, and serine at positions 25, 28, and 29 respectively with proline. •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): Pramlintide is an amlyinomimetic, a functional analog of the naturally occurring pancreatic hormone amylin. Amylin has activity in a number of gastrointestinal and glucodynamic systems, and by mimicking its activity, pramlintide acts to improve glycemic control through modulation of the rate of gastric emptying, prevention of post-prandial rise in glucagon levels, and by increasing sensations of satiety, thereby reducing caloric intake and potentiating weight loss. There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three Receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3. •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 absolute bioavailability of a single subcutaneous dose of pramlintide is approximately 30 to 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): Pramlintide does not extensively bind to blood cells or albumin (approximately 40% of the drug is unbound 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): Metabolized primarily by the kidneys. •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): Pramlintide is metabolized primarily by the kidneys. •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 48 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): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Symlin •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): Pramlintide is an amylin analog used for the management of type 1 and type 2 diabetes mellitus as an adjunct to preprandial insulin therapy in patients without adequate glycemic control of insulin therapy.

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 Pramlintide interact? Information: •Drug A: Buserelin •Drug B: Pramlintide •Severity: MODERATE •Description: The therapeutic efficacy of Pramlintide 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 type 1 and type 2 diabetes mellitus as an adjunct to preprandial insulin therapy in patients without adequate glycemic control of insulin 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): Pramlintide is a synthetic analog of amylin, a glucoregulatory hormone that is synthesized by pancreatic β-cells and released into the bloodstream, in a similar pattern as insulin, after a meal. Like insulin, amylin is deficient in individuals with diabetes. It is provided as an acetate salt. Pramlintide is a 37-amino acid polypeptide that differs structurally from human amylin by the replacement of alanine, serine, and serine at positions 25, 28, and 29 respectively with proline. •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): Pramlintide is an amlyinomimetic, a functional analog of the naturally occurring pancreatic hormone amylin. Amylin has activity in a number of gastrointestinal and glucodynamic systems, and by mimicking its activity, pramlintide acts to improve glycemic control through modulation of the rate of gastric emptying, prevention of post-prandial rise in glucagon levels, and by increasing sensations of satiety, thereby reducing caloric intake and potentiating weight loss. There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three Receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3. •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 absolute bioavailability of a single subcutaneous dose of pramlintide is approximately 30 to 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): Pramlintide does not extensively bind to blood cells or albumin (approximately 40% of the drug is unbound 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): Metabolized primarily by the kidneys. •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): Pramlintide is metabolized primarily by the kidneys. •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 48 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): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Symlin •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): Pramlintide is an amylin analog used for the management of type 1 and type 2 diabetes mellitus as an adjunct to preprandial insulin therapy in patients without adequate glycemic control of insulin therapy. 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 Pramocaine interact?

•Drug A: Buserelin •Drug B: Pramocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Pramocaine. •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): It is indicated for temporary relief of pain and pruritus from minor lip and skin irritations as well as for temporary relief from pain, burning, itching and discomfort associated with hemorrhoids and other anorectal/anogenital 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): Pramocaine temporarily relieves pain, pruritis, burning and discomfort associated with minor lip and skin irritations and hemorrhoid's by inhibiting voltage gated sodium channels on neurons. •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): Pramocaine reversibly binds and inhibits voltage gated sodium channels on neurons decreasing sodium permeability into the cell. This stabilizes the membrane and prevents ionic fluctuations needed for depolarization stopping any action potential propagation. •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): There is minimal absorption after topical administration and it is not given orally. •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): LD50 Mouse ip 300 mg/kg, LD50 Mouse sc 750 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Analpram HC, Caladryl, Caladryl Clear, Cortane-B, Epifoam, Gold Bond Maximum Relief, Itch-X, Neosporin Plus Maximum Strength, Neosporin Plus Maximum Strength Cream, Pramosone, Prax, Preparation H Cream, Procort 1.85/1.15, Proctodan-HC, Proctofoam, Proctofoam-HC, Sarna Sensitive, Triple Antibiotic, Tronolane Anesthetic •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): Pramocaine is a local anesthetic and antipruritic agent found in various topical preparations.

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 Pramocaine interact? Information: •Drug A: Buserelin •Drug B: Pramocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Pramocaine. •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): It is indicated for temporary relief of pain and pruritus from minor lip and skin irritations as well as for temporary relief from pain, burning, itching and discomfort associated with hemorrhoids and other anorectal/anogenital 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): Pramocaine temporarily relieves pain, pruritis, burning and discomfort associated with minor lip and skin irritations and hemorrhoid's by inhibiting voltage gated sodium channels on neurons. •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): Pramocaine reversibly binds and inhibits voltage gated sodium channels on neurons decreasing sodium permeability into the cell. This stabilizes the membrane and prevents ionic fluctuations needed for depolarization stopping any action potential propagation. •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): There is minimal absorption after topical administration and it is not given orally. •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): LD50 Mouse ip 300 mg/kg, LD50 Mouse sc 750 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Analpram HC, Caladryl, Caladryl Clear, Cortane-B, Epifoam, Gold Bond Maximum Relief, Itch-X, Neosporin Plus Maximum Strength, Neosporin Plus Maximum Strength Cream, Pramosone, Prax, Preparation H Cream, Procort 1.85/1.15, Proctodan-HC, Proctofoam, Proctofoam-HC, Sarna Sensitive, Triple Antibiotic, Tronolane Anesthetic •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): Pramocaine is a local anesthetic and antipruritic agent found in various topical preparations. 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 Pregabalin interact?

•Drug A: Buserelin •Drug B: Pregabalin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pregabalin 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): Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury, and as adjunctive therapy for the treatment of partial-onset seizures in patients 1 month 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): Although the structure of pregabalin is similar to gamma-aminobutyric acid (GABA), it does not bind to GABA receptors. Instead, it binds the alpha2-delta subunit of presynaptic voltage-gated calcium channels in the central nervous system. Pregabalin does not modulate dopamine receptors, serotonin receptors, opiate receptors, sodium channels or cyclooxygenase 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): Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models. By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or 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): After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional. Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin 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): After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg. Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB. In rat models, pregabalin has been shown to cross the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pregabalin is not plasma 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): Less than 2% of pregabalin is metabolized and it is excreted virtually unchanged in the 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): Pregabalin is almost exclusively eliminated in the urine. Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body. •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 pregabalin is 6.3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved. •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 a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation. The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures. Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway). Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lyrica •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Isobutyl GABA Pregabalin Pregabalina •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): Pregabalin is an anticonvulsant drug used to treat neuropathic pain conditions and fibromyalgia, and for the treatment of partial onset seizures in combination with other anticonvulsants.

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 Pregabalin interact? Information: •Drug A: Buserelin •Drug B: Pregabalin •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Pregabalin 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): Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury, and as adjunctive therapy for the treatment of partial-onset seizures in patients 1 month 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): Although the structure of pregabalin is similar to gamma-aminobutyric acid (GABA), it does not bind to GABA receptors. Instead, it binds the alpha2-delta subunit of presynaptic voltage-gated calcium channels in the central nervous system. Pregabalin does not modulate dopamine receptors, serotonin receptors, opiate receptors, sodium channels or cyclooxygenase 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): Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models. By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or 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): After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional. Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin 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): After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg. Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB. In rat models, pregabalin has been shown to cross the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): Pregabalin is not plasma 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): Less than 2% of pregabalin is metabolized and it is excreted virtually unchanged in the 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): Pregabalin is almost exclusively eliminated in the urine. Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body. •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 pregabalin is 6.3 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved. •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 a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation. The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures. Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway). Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Lyrica •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Isobutyl GABA Pregabalin Pregabalina •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): Pregabalin is an anticonvulsant drug used to treat neuropathic pain conditions and fibromyalgia, and for the treatment of partial onset seizures in combination with other anticonvulsants. 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 Prilocaine interact?

•Drug A: Buserelin •Drug B: Prilocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Prilocaine. •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): Used as a local anaesthetic and is often used in dentistry. •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): Prilocaine binds to the intracellular surface of sodium channels which blocks the subsequent influx of sodium into the cell. Action potential propagation and never function is, therefore, prevented. This block is reversible and when the drug diffuses away from the cell, sodium channel function is restored and nerve propagation returns. •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): Prilocaine acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers. •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): Prilocaine is 55% protein bound in plasma at a concentraion of 0.5-1.0 mg/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 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): Prilocaine is metabolized in both the liver and the kidney and excreted 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): 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): Agoneaze, Anodyne Lpt, Citanest, Citanest Forte, Dermacinrx Prikaan, Emla, Fortacin, Lido Bdk, Lido-prilo Caine Pack, Lidopril, Oraqix, Prilolid, Prizotral, Relador •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Prilocain Prilocaina Prilocaïne Prilocaine Prilocaine base Prilocainum Propitocaine •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): Prilocaine is a local anesthetic used in 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 Prilocaine interact? Information: •Drug A: Buserelin •Drug B: Prilocaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Prilocaine. •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): Used as a local anaesthetic and is often used in dentistry. •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): Prilocaine binds to the intracellular surface of sodium channels which blocks the subsequent influx of sodium into the cell. Action potential propagation and never function is, therefore, prevented. This block is reversible and when the drug diffuses away from the cell, sodium channel function is restored and nerve propagation returns. •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): Prilocaine acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers. •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): Prilocaine is 55% protein bound in plasma at a concentraion of 0.5-1.0 mg/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 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): Prilocaine is metabolized in both the liver and the kidney and excreted 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): 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): Agoneaze, Anodyne Lpt, Citanest, Citanest Forte, Dermacinrx Prikaan, Emla, Fortacin, Lido Bdk, Lido-prilo Caine Pack, Lidopril, Oraqix, Prilolid, Prizotral, Relador •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Prilocain Prilocaina Prilocaïne Prilocaine Prilocaine base Prilocainum Propitocaine •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): Prilocaine is a local anesthetic used in 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 Primaquine interact?

•Drug A: Buserelin •Drug B: Primaquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Primaquine. •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 malaria. •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): Primaquine is an antimalarial agent and is the essential co-drug with chloroquine in treating all cases of malaria. In the blood, malaria parasites break down a part of the red blood cells known as haemoglobin. When this happens haemoglobin is divided into two parts; haem and globin. Haem is toxic to the malaria parasite. To prevent it from being damaged, the malaria parasite produces an chemical which converts the toxic haem into a non-toxic product. Primaquine acts by interfering with a part of the parasite (mitochondria) that is responsible for supplying it with energy. Without energy the parasite dies. This stops the infection from continuing and allows the person to recover. Primaquine kills the intrahepatic form of Plasmodium vivax and Plasmodium ovale, and thereby prevents the development of the erythrocytic forms that are responsible for relapses (it also kills gametocytes). Primaquine is not used in the prevention of malaria, only in the treatment. It has insignificant activity against the asexual blood forms of the parasite and therefore it is always used in conjunction with a blood schizonticide and never as a single agent. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum. •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): Primaquine's mechanism of action is not well understood. It may be acting by generating reactive oxygen species or by interfering with the electron transport in the parasite. Also, although its mechanism of action is unclear, primaquine may bind to and alter the properties of protozoal DNA. •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): 3.7-7.4 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): 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): Primachin Primachina Primachinum Primaquin Primaquina Primaquine Primaquinum •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): Primaquine is an antimalarial indicated to prevent relapse of vivax malaria.

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 Primaquine interact? Information: •Drug A: Buserelin •Drug B: Primaquine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Primaquine. •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 malaria. •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): Primaquine is an antimalarial agent and is the essential co-drug with chloroquine in treating all cases of malaria. In the blood, malaria parasites break down a part of the red blood cells known as haemoglobin. When this happens haemoglobin is divided into two parts; haem and globin. Haem is toxic to the malaria parasite. To prevent it from being damaged, the malaria parasite produces an chemical which converts the toxic haem into a non-toxic product. Primaquine acts by interfering with a part of the parasite (mitochondria) that is responsible for supplying it with energy. Without energy the parasite dies. This stops the infection from continuing and allows the person to recover. Primaquine kills the intrahepatic form of Plasmodium vivax and Plasmodium ovale, and thereby prevents the development of the erythrocytic forms that are responsible for relapses (it also kills gametocytes). Primaquine is not used in the prevention of malaria, only in the treatment. It has insignificant activity against the asexual blood forms of the parasite and therefore it is always used in conjunction with a blood schizonticide and never as a single agent. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum. •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): Primaquine's mechanism of action is not well understood. It may be acting by generating reactive oxygen species or by interfering with the electron transport in the parasite. Also, although its mechanism of action is unclear, primaquine may bind to and alter the properties of protozoal DNA. •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): 3.7-7.4 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): 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): Primachin Primachina Primachinum Primaquin Primaquina Primaquine Primaquinum •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): Primaquine is an antimalarial indicated to prevent relapse of vivax malaria. 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 Procainamide interact?

•Drug A: Buserelin •Drug B: Procainamide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Procainamide. •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 treatment of life-threatening ventricular 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): Procainamide is an agent indicated for production of local or regional anesthesia and in the treatment of ventricular tachycardia occurring during cardiac manipulation, such as surgery or catheterization, or which may occur during acute myocardial infarction, digitalis toxicity, or other cardiac diseases. The mode of action of the antiarrhythmic effect of Procainamide appears to be similar to that of procaine and quinidine. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole. The sinoatrial node is, however, unaffected. •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): Procainamide is sodium channel blocker. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. •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): 75 to 95% •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): 2 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 15 to 20% •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): Trace amounts may be excreted in the urine as free and conjugated p-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. •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): ~2.5-4.5 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): LD 50 =95 mg/kg (rat, IV); LD 50 =312 mg/kg (mouse, oral); LD 50 =103 mg/kg (mouse, IV); LD 50 =250 mg/kg (rabbit, IV) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Procan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Procainamida Procainamide Procaïnamide Procainamidum •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): Procainamide is a medication used to treat life threatening ventricular arrhythmias.

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 Procainamide interact? Information: •Drug A: Buserelin •Drug B: Procainamide •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Procainamide. •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 treatment of life-threatening ventricular 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): Procainamide is an agent indicated for production of local or regional anesthesia and in the treatment of ventricular tachycardia occurring during cardiac manipulation, such as surgery or catheterization, or which may occur during acute myocardial infarction, digitalis toxicity, or other cardiac diseases. The mode of action of the antiarrhythmic effect of Procainamide appears to be similar to that of procaine and quinidine. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole. The sinoatrial node is, however, unaffected. •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): Procainamide is sodium channel blocker. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. •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): 75 to 95% •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): 2 L/kg •Protein binding (Drug A): 15% •Protein binding (Drug B): 15 to 20% •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): Trace amounts may be excreted in the urine as free and conjugated p-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. •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): ~2.5-4.5 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): LD 50 =95 mg/kg (rat, IV); LD 50 =312 mg/kg (mouse, oral); LD 50 =103 mg/kg (mouse, IV); LD 50 =250 mg/kg (rabbit, IV) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Procan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Procainamida Procainamide Procaïnamide Procainamidum •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): Procainamide is a medication used to treat life threatening ventricular arrhythmias. 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 Procaine interact?

•Drug A: Buserelin •Drug B: Procaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Procaine. •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): Used as a local anesthetic primarily in oral surgery •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): Procaine is an anesthetic agent indicated for production of local or regional anesthesia, particularly for oral surgery. Procaine (like cocaine) has the advantage of constricting blood vessels which reduces bleeding, unlike other local anesthetics like lidocaine. Procaine is an ester anesthetic. It is metabolized in the plasma by the enzyme pseudocholinesterase through hydrolysis into para-aminobenzoic acid (PABA), which is then excreted by the kidneys into the urine. •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): Procaine acts mainly by inhibiting sodium influx through voltage gated sodium channels in the neuronal cell membrane of peripheral nerves. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Procaine has also been shown to bind or antagonize the function of N-methyl-D-aspartate (NMDA) receptors as well as nicotinic acetylcholine receptors and the serotonin receptor-ion channel complex. •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): Hydrolysis by plasma esterases to PABA •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): With normal kidney function, the drug is excreted rapidly by tubular 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): 7.7 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): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Novocain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Novocaine Procaina Procaine Procainum Vitamin H3 •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): Procaine is a local anesthetic used for anesthesia, peripheral nerve block, and spinal nerve block.

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 Procaine interact? Information: •Drug A: Buserelin •Drug B: Procaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Procaine. •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): Used as a local anesthetic primarily in oral surgery •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): Procaine is an anesthetic agent indicated for production of local or regional anesthesia, particularly for oral surgery. Procaine (like cocaine) has the advantage of constricting blood vessels which reduces bleeding, unlike other local anesthetics like lidocaine. Procaine is an ester anesthetic. It is metabolized in the plasma by the enzyme pseudocholinesterase through hydrolysis into para-aminobenzoic acid (PABA), which is then excreted by the kidneys into the urine. •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): Procaine acts mainly by inhibiting sodium influx through voltage gated sodium channels in the neuronal cell membrane of peripheral nerves. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Procaine has also been shown to bind or antagonize the function of N-methyl-D-aspartate (NMDA) receptors as well as nicotinic acetylcholine receptors and the serotonin receptor-ion channel complex. •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): Hydrolysis by plasma esterases to PABA •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): With normal kidney function, the drug is excreted rapidly by tubular 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): 7.7 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): No toxicity available •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Novocain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Novocaine Procaina Procaine Procainum Vitamin H3 •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): Procaine is a local anesthetic used for anesthesia, peripheral nerve block, and spinal nerve block. 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 Prochlorperazine interact?

•Drug A: Buserelin •Drug B: Prochlorperazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Prochlorperazine. •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): Indicated for the symptomatic treatment of severe nausea and vomiting. Indicated for the management of manifestations of psychotic disorders, such as schizophrenia and generalized non-psychotic anxiety. The use of prochlorperazine for the management of generalized non-psychotic anxiety is typically not a first-line therapy and should be limited to doses of less than 20 mg per day or for shorter than 12 weeks. Off-label uses include use in emergency settings for adult and pediatric migraines. The American Headache Society recommends the use of prochlorperazine as the first-line medication in this setting. In pediatric migraines, a non-steroidal anti-inflammatory agent is often used in combination with dopamine antagonist. •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): Prochlorperazine is an antipsychotic agent that works to promote postsynaptic inhibition of dopaminergic neurons. It also exerts its anti-emetic actions via anti-dopaminergic effects, where it displays similar efficacy as ondansteron, a 5HT-3 receptor antagonist and anti-emetic, in preventing delayed nausea and vomiting. Prochlorperazine was shown to inhibit histaminergic, cholinergic and alpha-1 adrenergic receptors. The blockade of alpha-1 adrenergic receptors may result in sedation, muscle relaxation, and hypotension. It displays anti-anxiety effects as well. Compared to other phenothiazine derivatives, prochlorperazine is less sedating and has a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. Other than its primary action on D2 receptors, one study showed that prochlorperazine may inhibit the P2X7 receptor in human macrophages, leading to inhibition of calcium ion influx. •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 prochlorperazine has not been fully determined, but may be primarily related to its anti-dopaminergic effects. Prochlorperazine blocks the D2 dopamine receptors in the brain, which are somatodendritic autoreceptors. Inhibition of D2 receptor signaling results in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Nausea and vomiting are proposed to arise from peripheral or central stimulation of serotonin type 3 (5-HT3) and dopamine type 2 receptors, the predominant receptors expressed at the chemoreceptor trigger zone (CTZ). Prochlorperazine exerts antiemetic effects and was shown to inhibit apomorphine-induced vomiting by blocking D2 dopamine receptors in the CTZ.. •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, prochlorperazine is reported to be well absorbed from the gastrointestinal tract. The onset of pharmacological action is about 30 to 40 minutes following oral administration and 10 to 20 minutes following intramuscular administration. The duration of action for all routes is about 3 to 4 hours. Following oral administration in healthy volunteers, the mean oral bioavailability was about 12.5%. In these patients, the time to reach the peak plasma concentrations was about 5 hours. Repeated oral dosing resulted in an accumulation of prochlorperazine and its metabolite. Following multiple twice daily dosing, the steady state of prochlorperazine was reached by 7 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): In a preliminary pharmacokinetic study involving healthy volunteers, the mean apparent volume of distribution following intravenous administration of 6.25 mg and 12.5 mg prochlorperazine were approximately 1401 L and 1548 L, respectively. Prochlorperazine is reported to be distributed to most body tissues with high concentrations being distributed into liver and spleen. There is evidence that phenothiazines are excreted in the breast milk of nursing mothers. •Protein binding (Drug A): 15% •Protein binding (Drug B): There is limited data on protein binding of prochlorperazine. •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): Prochlorperazine undergoes hepatic metabolism involving oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The oxidation reaction is mediated by CYP2D6. N-desmethyl prochlorperazine was detected in the plasma, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, following oral and buccal administration. Prochlorperazine may enter the enterohepatic 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): Prochlorperazine is reported to be mainly excreted via the feces and bile. Low quantities of unchanged prochlorperazine and its metabolite were detectable 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): Following intravenous and single oral dose administration, the terminal elimination half live were 9 and 8 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean plasma clearance (CL) of prochlorperazine following intravenous administration in healthy volunteers was approximately 0.98L/h x kg. The mean renal clearance was about 23.6 mL/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): LD 50 and Overdose Oral LD 50 in rats is 750 mg/kg. Intraperitoneal and subcutaneous LD 50 in mice are 191 mg/kg and 320 mg/kg, respectively. In placebo-controlled trials, there were increased incidences of mortality in elderly patients with dementia-related psychosis receiving antipsychotic medications. The risk of death in drug-treated patients was about 1.6 to 1.7 times that of placebo-treated patients. Deaths were largely resulting from cardiovascular, such as heart failure and sudden death, or infectious, such as pneumonia, conditions. Due to its antagonist action on dopamine receptors, prochlorperazine is associated with a risk for developing extrapyramidal symptoms such as tardive dyskinesia, which is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements. This risk is also conferred on other antipsychotic agents that block dopamine receptors. It is proposed that increased duration of the drug treatment is likely thus increased total cumulative dose of antipsychotic drugs administered to the patient leads to increased risk for developing the syndrome and the likelihood that it will become irreversible. As with other antipsychotic agents, prochlorperazine is associated with a risk for causing neuroleptic malignant syndrome (NMS), which is a potentially fatal symptom complex, which is manifested as hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. There is no known antidote for prochlorperazine thus overdose treatment should be supportive and symptomatic. Overdose of prochlorperazine may produce dystonic reactions that involve extrapyramidal mechanism. To reduce these symptoms, antiparkinsonism drugs, barbiturates, or diphenhydramine may be used. Symptoms of central nervous system depression, such as somnolence or coma, may also be observed. Amphetamine, destroamphetamine, or caffeine and sodium benzoate may be used to induce stimulatory effects. In contrast, agitation and restlessness may also be seen in case of overdose. Other possible manifestations include convulsions, EKG changes and cardiac arrhythmias, fever, and autonomic reactions such as hypotension, dry mouth and ileus. Hypotension can be responded with the standard measures for managing circulatory shock. Nonclinical Toxicology In a rat developmental or reproductive toxicity study, abnormalities in both the reproductive measures and neurobehavioral testing were observed following administration of 25 mg/kg of prochlorperazine. Use in specific populations As the use of antipsychotic agents during the third trimester of pregnancy is associated with a risk for extrapyramidal and/or withdrawal symptoms following delivery, the use of prochlorperazine in pregnant patients is generally not recommended and it should be limited after careful consideration of the potential benefit of drug therapy justifying the potential risk to the fetus. Caution should be exercised when prochlorperazine is administered to a nursing mother. While lower doses of prochlorperazine is reported to be safe for elderly patients, caution is still advised, especially those with higher susceptibility to hypotension and neuromuscular reactions. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Compazine, Compro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capazine Chlormeprazine Chloropernazine Prochlorperazin Prochlorpérazine Prochlorperazine Prochlorperazinum Prochlorpermazine Prochlorpromazine Procloperazine Proclorperazina •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): Prochlorperazine is a phenothiazine derivative used in the treatment of schizophrenia and anxiety and to relieve severe 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 Prochlorperazine interact? Information: •Drug A: Buserelin •Drug B: Prochlorperazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Prochlorperazine. •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): Indicated for the symptomatic treatment of severe nausea and vomiting. Indicated for the management of manifestations of psychotic disorders, such as schizophrenia and generalized non-psychotic anxiety. The use of prochlorperazine for the management of generalized non-psychotic anxiety is typically not a first-line therapy and should be limited to doses of less than 20 mg per day or for shorter than 12 weeks. Off-label uses include use in emergency settings for adult and pediatric migraines. The American Headache Society recommends the use of prochlorperazine as the first-line medication in this setting. In pediatric migraines, a non-steroidal anti-inflammatory agent is often used in combination with dopamine antagonist. •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): Prochlorperazine is an antipsychotic agent that works to promote postsynaptic inhibition of dopaminergic neurons. It also exerts its anti-emetic actions via anti-dopaminergic effects, where it displays similar efficacy as ondansteron, a 5HT-3 receptor antagonist and anti-emetic, in preventing delayed nausea and vomiting. Prochlorperazine was shown to inhibit histaminergic, cholinergic and alpha-1 adrenergic receptors. The blockade of alpha-1 adrenergic receptors may result in sedation, muscle relaxation, and hypotension. It displays anti-anxiety effects as well. Compared to other phenothiazine derivatives, prochlorperazine is less sedating and has a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. Other than its primary action on D2 receptors, one study showed that prochlorperazine may inhibit the P2X7 receptor in human macrophages, leading to inhibition of calcium ion influx. •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 prochlorperazine has not been fully determined, but may be primarily related to its anti-dopaminergic effects. Prochlorperazine blocks the D2 dopamine receptors in the brain, which are somatodendritic autoreceptors. Inhibition of D2 receptor signaling results in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Nausea and vomiting are proposed to arise from peripheral or central stimulation of serotonin type 3 (5-HT3) and dopamine type 2 receptors, the predominant receptors expressed at the chemoreceptor trigger zone (CTZ). Prochlorperazine exerts antiemetic effects and was shown to inhibit apomorphine-induced vomiting by blocking D2 dopamine receptors in the CTZ.. •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, prochlorperazine is reported to be well absorbed from the gastrointestinal tract. The onset of pharmacological action is about 30 to 40 minutes following oral administration and 10 to 20 minutes following intramuscular administration. The duration of action for all routes is about 3 to 4 hours. Following oral administration in healthy volunteers, the mean oral bioavailability was about 12.5%. In these patients, the time to reach the peak plasma concentrations was about 5 hours. Repeated oral dosing resulted in an accumulation of prochlorperazine and its metabolite. Following multiple twice daily dosing, the steady state of prochlorperazine was reached by 7 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): In a preliminary pharmacokinetic study involving healthy volunteers, the mean apparent volume of distribution following intravenous administration of 6.25 mg and 12.5 mg prochlorperazine were approximately 1401 L and 1548 L, respectively. Prochlorperazine is reported to be distributed to most body tissues with high concentrations being distributed into liver and spleen. There is evidence that phenothiazines are excreted in the breast milk of nursing mothers. •Protein binding (Drug A): 15% •Protein binding (Drug B): There is limited data on protein binding of prochlorperazine. •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): Prochlorperazine undergoes hepatic metabolism involving oxidation, hydroxylation, demethylation, sulfoxide formation and conjugation with glucuronic acid. The oxidation reaction is mediated by CYP2D6. N-desmethyl prochlorperazine was detected in the plasma, as well as prochlorperazine sulfoxide, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, following oral and buccal administration. Prochlorperazine may enter the enterohepatic 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): Prochlorperazine is reported to be mainly excreted via the feces and bile. Low quantities of unchanged prochlorperazine and its metabolite were detectable 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): Following intravenous and single oral dose administration, the terminal elimination half live were 9 and 8 hours, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean plasma clearance (CL) of prochlorperazine following intravenous administration in healthy volunteers was approximately 0.98L/h x kg. The mean renal clearance was about 23.6 mL/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): LD 50 and Overdose Oral LD 50 in rats is 750 mg/kg. Intraperitoneal and subcutaneous LD 50 in mice are 191 mg/kg and 320 mg/kg, respectively. In placebo-controlled trials, there were increased incidences of mortality in elderly patients with dementia-related psychosis receiving antipsychotic medications. The risk of death in drug-treated patients was about 1.6 to 1.7 times that of placebo-treated patients. Deaths were largely resulting from cardiovascular, such as heart failure and sudden death, or infectious, such as pneumonia, conditions. Due to its antagonist action on dopamine receptors, prochlorperazine is associated with a risk for developing extrapyramidal symptoms such as tardive dyskinesia, which is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements. This risk is also conferred on other antipsychotic agents that block dopamine receptors. It is proposed that increased duration of the drug treatment is likely thus increased total cumulative dose of antipsychotic drugs administered to the patient leads to increased risk for developing the syndrome and the likelihood that it will become irreversible. As with other antipsychotic agents, prochlorperazine is associated with a risk for causing neuroleptic malignant syndrome (NMS), which is a potentially fatal symptom complex, which is manifested as hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. There is no known antidote for prochlorperazine thus overdose treatment should be supportive and symptomatic. Overdose of prochlorperazine may produce dystonic reactions that involve extrapyramidal mechanism. To reduce these symptoms, antiparkinsonism drugs, barbiturates, or diphenhydramine may be used. Symptoms of central nervous system depression, such as somnolence or coma, may also be observed. Amphetamine, destroamphetamine, or caffeine and sodium benzoate may be used to induce stimulatory effects. In contrast, agitation and restlessness may also be seen in case of overdose. Other possible manifestations include convulsions, EKG changes and cardiac arrhythmias, fever, and autonomic reactions such as hypotension, dry mouth and ileus. Hypotension can be responded with the standard measures for managing circulatory shock. Nonclinical Toxicology In a rat developmental or reproductive toxicity study, abnormalities in both the reproductive measures and neurobehavioral testing were observed following administration of 25 mg/kg of prochlorperazine. Use in specific populations As the use of antipsychotic agents during the third trimester of pregnancy is associated with a risk for extrapyramidal and/or withdrawal symptoms following delivery, the use of prochlorperazine in pregnant patients is generally not recommended and it should be limited after careful consideration of the potential benefit of drug therapy justifying the potential risk to the fetus. Caution should be exercised when prochlorperazine is administered to a nursing mother. While lower doses of prochlorperazine is reported to be safe for elderly patients, caution is still advised, especially those with higher susceptibility to hypotension and neuromuscular reactions. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Compazine, Compro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capazine Chlormeprazine Chloropernazine Prochlorperazin Prochlorpérazine Prochlorperazine Prochlorperazinum Prochlorpermazine Prochlorpromazine Procloperazine Proclorperazina •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): Prochlorperazine is a phenothiazine derivative used in the treatment of schizophrenia and anxiety and to relieve severe 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 Promazine interact?

•Drug A: Buserelin •Drug B: Promazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Promazine. •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): Used as an adjunct for short term treatment of moderate and severe psychomotor agitation. Also used to treat agitation or restlessness in the elderly. •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): Promazine belongs to a group of medications known as the phenothiazine antipsychotics. It acts by blocking a variety of receptors in the brain, particularly dopamine receptors. Dopamine is involved in transmitting signals between brain cells. When there is an excess amount of dopamine in the brain it causes over-stimulation of dopamine receptors. These receptors normally act to modify behaviour and over-stimulation may result in psychotic illness. Promazine hydrochloride blocks these receptors and stops them becoming over-stimulated, thereby helping to control psychotic illness. Promazine has weak extrapyramidal and autonomic side effects which lead to its use in the elderly, for restless or psychotic patients. Its anti-psychotic effect is also weaker and it is not useful in general psychiatry. •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): Promazine is an antagonist at types 1, 2, and 4 dopamine receptors, 5-HT receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Promazine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Promazine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone. Antagonism at muscarinic receptors, H1-receptors, and alpha(1)-receptors also occurs with promazine. •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 may be erratic and peak plasma concentrations show large interindividual 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): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 94% •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, primarily to N-desmethylpromazine and promazine sulfoxide. •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): Side effects include: extrapyramidal symptoms, drowsiness, weight gain, dry mouth, constipation, endocrine effects (such as gynaecomastia and menstrual disturbance), sensitivity to sunlight and haemolytic anaemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Promazin Promazina Promazine Promazinum •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): Promazine is a phenothiazine used to manage schizophrenia.

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 Promazine interact? Information: •Drug A: Buserelin •Drug B: Promazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Promazine. •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): Used as an adjunct for short term treatment of moderate and severe psychomotor agitation. Also used to treat agitation or restlessness in the elderly. •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): Promazine belongs to a group of medications known as the phenothiazine antipsychotics. It acts by blocking a variety of receptors in the brain, particularly dopamine receptors. Dopamine is involved in transmitting signals between brain cells. When there is an excess amount of dopamine in the brain it causes over-stimulation of dopamine receptors. These receptors normally act to modify behaviour and over-stimulation may result in psychotic illness. Promazine hydrochloride blocks these receptors and stops them becoming over-stimulated, thereby helping to control psychotic illness. Promazine has weak extrapyramidal and autonomic side effects which lead to its use in the elderly, for restless or psychotic patients. Its anti-psychotic effect is also weaker and it is not useful in general psychiatry. •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): Promazine is an antagonist at types 1, 2, and 4 dopamine receptors, 5-HT receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Promazine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Promazine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone. Antagonism at muscarinic receptors, H1-receptors, and alpha(1)-receptors also occurs with promazine. •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 may be erratic and peak plasma concentrations show large interindividual 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): No volume of distribution available •Protein binding (Drug A): 15% •Protein binding (Drug B): 94% •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, primarily to N-desmethylpromazine and promazine sulfoxide. •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): Side effects include: extrapyramidal symptoms, drowsiness, weight gain, dry mouth, constipation, endocrine effects (such as gynaecomastia and menstrual disturbance), sensitivity to sunlight and haemolytic anaemia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Promazin Promazina Promazine Promazinum •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): Promazine is a phenothiazine used to manage schizophrenia. 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 Promethazine interact?

•Drug A: Buserelin •Drug B: Promethazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Promethazine 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): Promethazine tablets and suppositories are indicated to treat rhinitis, allergic conjunctivitis, allergic reactions to blood or plasma, dermographism, anaphylactic reactions, sedation, nausea, vomiting, pain, motion sickness, and allergic skin reactions. Promethazine cough syrup with phenylephrine and codeine is indicated to relieve cough and upper respiratory symptoms, and nasal congestion associated with allergy or 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): Promethazine is is a histamine H1 antagonist that can be used for it's ability to induce sedation, reduce pain, and treat allergic reactions. Promethazine's effects generally last 4-6h but can last up to 12h. Patients should be counselled regarding CNS and respiratory depression, reduce seizure threshold, and bone marrow depression. •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): Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting. •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 25mg dose of intramuscular promethazine reaches a C max of 22ng/mL. Intravenous promethazine reaches a C max of 10.0ng/mL, with a T max of 4-10h, and an AUC of 14,466ng*h/mL. Oral promethazine is only 25% bioavailable due to first pass metabolism. Oral promethazine reaches a C max of 2.4-18.0ng/mL, with a T max of 1.5-3h, and an AUC of 11,511ng*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 volume of distribution of promethazine is approximately 970L or 30L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Promethazine is 93% protein bound in serum, mostly 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): Promethazine is predominantly metabolized to promethazine sulfoxide, and minorly to desmethylpromethazine and a hydroxy metabolite. Hydroxylation of promethazine is predominantly mediated by CYP2D6. •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): An intravenous dose of promethazine is 0.64% eliminated in the urine as the unchanged parent drug, 0.02-2.02% in the urine as desmethylpromethazine, 10% in the urine as promethazine sulfoxide. •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 promethazine is approximately 12-15h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The intravenous clearance of promethazine is approximately 1.14L/min. The renal clearance of promethazine is 5.9mL/min and the renal clearance of promethazine sulfoxide is 90.4mL/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): The intraperitoneal LD 50 in rats is 170mg/kg and in mice is 160mg/kg. The subcutaneous LD 50 in rats is 400mg/kg and in mice is 240mg/kg. The oral LD 50 in mice is 255mg/kg. Patients experiencing an overdose of promethazine may present with mild central nervous system and cardiovascular depression, hypotension, respiratory depression, unconciousness, hyperreflexia, hypertonia, ataxia, athetosis, extensor-plantar reflexes, convulsions, dry mouth, flushing, gastrointestinal symptoms, and fixed, dilated pupils. Treat overdoses with symptomatic and supportive treatment, which may include activated charcoal, sodium sulfate, magnesium sulfate, controlled ventilation, diazepam, intravenous fluids, vasopressors, norepinephrine, phenylephrine, anticholinergic antiparkinsonian agents, diphenhydramine, barbiturates, or oxygen. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Phenadoz, Phenergan, Promethazine DM, Promethegan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Proazamine Prometazina Promethazine Promethazinum •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): Promethazine is a first-generation antihistamine used for the treatment of allergic conditions, nausea and vomiting, and motion sickness.

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 Promethazine interact? Information: •Drug A: Buserelin •Drug B: Promethazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Promethazine 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): Promethazine tablets and suppositories are indicated to treat rhinitis, allergic conjunctivitis, allergic reactions to blood or plasma, dermographism, anaphylactic reactions, sedation, nausea, vomiting, pain, motion sickness, and allergic skin reactions. Promethazine cough syrup with phenylephrine and codeine is indicated to relieve cough and upper respiratory symptoms, and nasal congestion associated with allergy or 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): Promethazine is is a histamine H1 antagonist that can be used for it's ability to induce sedation, reduce pain, and treat allergic reactions. Promethazine's effects generally last 4-6h but can last up to 12h. Patients should be counselled regarding CNS and respiratory depression, reduce seizure threshold, and bone marrow depression. •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): Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting. •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 25mg dose of intramuscular promethazine reaches a C max of 22ng/mL. Intravenous promethazine reaches a C max of 10.0ng/mL, with a T max of 4-10h, and an AUC of 14,466ng*h/mL. Oral promethazine is only 25% bioavailable due to first pass metabolism. Oral promethazine reaches a C max of 2.4-18.0ng/mL, with a T max of 1.5-3h, and an AUC of 11,511ng*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 volume of distribution of promethazine is approximately 970L or 30L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Promethazine is 93% protein bound in serum, mostly 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): Promethazine is predominantly metabolized to promethazine sulfoxide, and minorly to desmethylpromethazine and a hydroxy metabolite. Hydroxylation of promethazine is predominantly mediated by CYP2D6. •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): An intravenous dose of promethazine is 0.64% eliminated in the urine as the unchanged parent drug, 0.02-2.02% in the urine as desmethylpromethazine, 10% in the urine as promethazine sulfoxide. •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 promethazine is approximately 12-15h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The intravenous clearance of promethazine is approximately 1.14L/min. The renal clearance of promethazine is 5.9mL/min and the renal clearance of promethazine sulfoxide is 90.4mL/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): The intraperitoneal LD 50 in rats is 170mg/kg and in mice is 160mg/kg. The subcutaneous LD 50 in rats is 400mg/kg and in mice is 240mg/kg. The oral LD 50 in mice is 255mg/kg. Patients experiencing an overdose of promethazine may present with mild central nervous system and cardiovascular depression, hypotension, respiratory depression, unconciousness, hyperreflexia, hypertonia, ataxia, athetosis, extensor-plantar reflexes, convulsions, dry mouth, flushing, gastrointestinal symptoms, and fixed, dilated pupils. Treat overdoses with symptomatic and supportive treatment, which may include activated charcoal, sodium sulfate, magnesium sulfate, controlled ventilation, diazepam, intravenous fluids, vasopressors, norepinephrine, phenylephrine, anticholinergic antiparkinsonian agents, diphenhydramine, barbiturates, or oxygen. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Phenadoz, Phenergan, Promethazine DM, Promethegan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Proazamine Prometazina Promethazine Promethazinum •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): Promethazine is a first-generation antihistamine used for the treatment of allergic conditions, nausea and vomiting, and motion sickness. 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 Propafenone interact?

•Drug A: Buserelin •Drug B: Propafenone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Propafenone. •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): Used to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. Also used for the treatment of life-threatening documented ventricular arrhythmias, such as sustained ventricular 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): Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. It is used in the treatment of atrial and ventricular arrhythmias. It acts by inhibiting sodium channels to restrict the entry of sodium into cardiac cells resulting in reduced excitation. Propafenone has local anesthetic activity approximately equal to procaine. •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 electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. •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): Nearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet). •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): 252 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 97% •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): Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations. •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 propafenone metabolites are excreted in the urine following administration of immediate release tablets. •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): 2-10 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 propafenone overdose (usually most severe within the first 3 hours) may include convulsions (rarely), heartbeat irregularities, low blood pressure, and sleepiness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rythmol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Propafenona Propafenone Propafenonum •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): Propafenone is a Class 1C antiarrhythmic agent used in the management of paroxysmal atrial fibrillation/flutter and ventricular arrhythmias.

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 Propafenone interact? Information: •Drug A: Buserelin •Drug B: Propafenone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Propafenone. •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): Used to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. Also used for the treatment of life-threatening documented ventricular arrhythmias, such as sustained ventricular 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): Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. It is used in the treatment of atrial and ventricular arrhythmias. It acts by inhibiting sodium channels to restrict the entry of sodium into cardiac cells resulting in reduced excitation. Propafenone has local anesthetic activity approximately equal to procaine. •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 electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. •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): Nearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet). •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): 252 L •Protein binding (Drug A): 15% •Protein binding (Drug B): 97% •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): Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations. •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 propafenone metabolites are excreted in the urine following administration of immediate release tablets. •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): 2-10 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 propafenone overdose (usually most severe within the first 3 hours) may include convulsions (rarely), heartbeat irregularities, low blood pressure, and sleepiness. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Rythmol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Propafenona Propafenone Propafenonum •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): Propafenone is a Class 1C antiarrhythmic agent used in the management of paroxysmal atrial fibrillation/flutter and ventricular arrhythmias. 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 Proparacaine interact?

•Drug A: Buserelin •Drug B: Proparacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Proparacaine. •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): Used as a local (ophthalmic) anesthetic. •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): Proparacaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. More specifically, proparacaine appears to bind or antagonize the function of voltage gated sodium channels. •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 whereby proparacaine and other local anesthetics influence the permeability of the cell membrane is unknown; however, several studies indicate that local anesthetics may limit sodium ion permeability through the lipid layer of the nerve cell membrane. Proparacaine may alter epithelial sodium channels through interaction with channel protein residues. This limitation prevents the fundamental change necessary for the generation of the action 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): 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): 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): Alcaine •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): Proparacaine is a topical anesthetic used for ophthalmic practice.

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 Proparacaine interact? Information: •Drug A: Buserelin •Drug B: Proparacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Proparacaine. •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): Used as a local (ophthalmic) anesthetic. •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): Proparacaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. More specifically, proparacaine appears to bind or antagonize the function of voltage gated sodium channels. •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 whereby proparacaine and other local anesthetics influence the permeability of the cell membrane is unknown; however, several studies indicate that local anesthetics may limit sodium ion permeability through the lipid layer of the nerve cell membrane. Proparacaine may alter epithelial sodium channels through interaction with channel protein residues. This limitation prevents the fundamental change necessary for the generation of the action 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): 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): 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): Alcaine •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): Proparacaine is a topical anesthetic used for ophthalmic practice. 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 Propofol interact?

•Drug A: Buserelin •Drug B: Propofol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Propofol 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 for induction and/or maintenance of anaesthesia and for management of refractory status epilepticus. •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): Propofol is a sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation). •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 action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A 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): Rapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes. •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): 60 L/kg [healthy adults] •Protein binding (Drug A): 15% •Protein binding (Drug B): 95 to 99%, primarily to serum albumin and hemoglobin •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): Hepatically metabolized mainly by glucuronidation at the C1-hydroxyl. Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid. Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol. •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 chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by 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): Initial distribution phase t 1/2α =1.8-9.5 minutes. Second redistirubtion phase t 1/2β =21-70 minutes. Terminal elimination phase t 1/2γ =1.5-31 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 23 - 50 mL/kg/min 1.6 - 3.4 L/min [70 Kg adults] •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 may increase pharmacologic and adverse effects or cause death. IV LD 50 =53 mg/kg (mice), 42 mg/kg (rats). Oral LD 50 (as a solution in soybean oil)=1230 mg/kg (mice), 600 mg/kg (rats) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diprivan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Propofol Propofolum •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): Propofol is a medication used in general anesthesia and for sedation.

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 Propofol interact? Information: •Drug A: Buserelin •Drug B: Propofol •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Propofol 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 for induction and/or maintenance of anaesthesia and for management of refractory status epilepticus. •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): Propofol is a sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation). •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 action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A 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): Rapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes. •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): 60 L/kg [healthy adults] •Protein binding (Drug A): 15% •Protein binding (Drug B): 95 to 99%, primarily to serum albumin and hemoglobin •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): Hepatically metabolized mainly by glucuronidation at the C1-hydroxyl. Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid. Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol. •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 chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by 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): Initial distribution phase t 1/2α =1.8-9.5 minutes. Second redistirubtion phase t 1/2β =21-70 minutes. Terminal elimination phase t 1/2γ =1.5-31 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 23 - 50 mL/kg/min 1.6 - 3.4 L/min [70 Kg adults] •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 may increase pharmacologic and adverse effects or cause death. IV LD 50 =53 mg/kg (mice), 42 mg/kg (rats). Oral LD 50 (as a solution in soybean oil)=1230 mg/kg (mice), 600 mg/kg (rats) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Diprivan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Propofol Propofolum •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): Propofol is a medication used in general anesthesia and for sedation. 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 Protriptyline interact?

•Drug A: Buserelin •Drug B: Protriptyline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Protriptyline 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 depression. •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): Protriptyline is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by nerve cells. The effectiveness of antidepressants appear after approximately two weeks following recommended adminsitration schedule. Gradual changes are thought to occur in the cerebral cortex and hippocampus, involved in emotion regulation as part of the limbic system, as receptor sensitivity is enhanced. While α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also reported to alter the perceptions of pain, including neuropathic or neuralgic pain, so they may exhibit analgesic properties. The mechanism of action behind this analgesic property is not fully understood; however, it is thought to involve modulation of endogenous opioid systems in the CNS via an indirect serotonergic route. Tricyclic antidepressants are also effective in relieving migraine prophylaxis, but not in abortion of acute migraine attack, potentially via their 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): Protriptyline 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): 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): Protriptyline is reported to undergo cumulative urinary excretion during 16 days, which accounts for approximately 50% of the total drug administered. The fecal excretion pathway seems to play a minimal role in drug 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): Side effects include anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal discomfort, 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): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amimetilina Protriptilina Protriptylin Protriptyline Protriptylinum •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): Protriptyline is a tricyclic antidepressant that is indicated in the treatment of depression only under close clinical supervision.

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 Protriptyline interact? Information: •Drug A: Buserelin •Drug B: Protriptyline •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Protriptyline 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 depression. •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): Protriptyline is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by nerve cells. The effectiveness of antidepressants appear after approximately two weeks following recommended adminsitration schedule. Gradual changes are thought to occur in the cerebral cortex and hippocampus, involved in emotion regulation as part of the limbic system, as receptor sensitivity is enhanced. While α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also reported to alter the perceptions of pain, including neuropathic or neuralgic pain, so they may exhibit analgesic properties. The mechanism of action behind this analgesic property is not fully understood; however, it is thought to involve modulation of endogenous opioid systems in the CNS via an indirect serotonergic route. Tricyclic antidepressants are also effective in relieving migraine prophylaxis, but not in abortion of acute migraine attack, potentially via their 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): Protriptyline 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): 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): Protriptyline is reported to undergo cumulative urinary excretion during 16 days, which accounts for approximately 50% of the total drug administered. The fecal excretion pathway seems to play a minimal role in drug 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): Side effects include anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal discomfort, 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): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amimetilina Protriptilina Protriptylin Protriptyline Protriptylinum •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): Protriptyline is a tricyclic antidepressant that is indicated in the treatment of depression only under close clinical supervision. 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 Quetiapine interact?

•Drug A: Buserelin •Drug B: Quetiapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Quetiapine. •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): Quetiapine is used in the symptomatic treatment of schizophrenia. In addition, it may be used for the management of acute manic or mixed episodes in patients with bipolar I disorder, as a monotherapy or combined with other drugs. It may be used to manage depressive episodes in bipolar disorder. In addition to the above indications, quetiapine is used in combination with antidepressant drugs for the treatment of major depression. Some off-label uses for this drug include the management of post-traumatic stress disorder (PTSD), generalized anxiety disorder, and psychosis associated with 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): Quetiapine improves the positive and negative symptoms of schizophrenia and major depression by acting on various neurotransmitter receptors, such as the serotonin and dopamine receptors. In bipolar disorder, it improves both depressive and manic symptoms. A note on suicidality in young patients and administration in the elderly Quetiapine can cause suicidal thinking or behavior in children and adolescents and should not be given to children under 10 years of age. It is important to monitor for suicidality if this drug is given to younger patients. In addition, this drug is not indicated for the treatment of psychosis related to dementia due to an increased death rate in elderly patients taking this drug. •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 mechanism of action of quetiapine is not fully understood, several proposed mechanisms exist. In schizophrenia, its actions could occur from the antagonism of dopamine type 2 (D2) and serotonin 2A (5HT2A) receptors. In bipolar depression and major depression, quetiapine's actions may be attributed to the binding of this drug or its metabolite to the norepinephrine transporter. Additional effects of quetiapine, including somnolence, orthostatic hypotension, and anticholinergic effects, may result from the antagonism of H1 receptors, adrenergic α1 receptors, and muscarinic M1 receptors, respectively. •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): Quetiapine is rapidly and well absorbed after administration of an oral dose. Steady-state is achieved within 48 hours Peak plasma concentrations are achieved within 1.5 hours. The bioavailability of a tablet is 100%. The steady-state Cmax of quetiapine in Han Chinese patients with schizophrenia after a 300 mg oral dose of the extended released formulation was approximately 467 ng/mL and the AUC at steady-state was 5094 ng·h/mL. Absorption of quetiapine is affected by food, with Cmax increased by 25% and AUC increased by 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): Quetiapine distributes throughout body tissues. The apparent volume of distribution of this drug is about 10±4 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of quetiapine is 83%. •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 quetiapine occurs mainly in the liver. Sulfoxidation and oxidation are the main metabolic pathways of this drug. According to in vitro studies, cytochrome P450 3A4 metabolizes quetiapine to an inactive sulfoxide metabolite and also participates in the metabolism of its active metabolite, N-desalkyl quetiapine. CYP2D6 also regulates the metabolism of quetiapine. In one study, three metabolites of N-desalkylquetiapine were identified. Two of the metabolites were identified as N-desalkylquetiapine sulfoxide and 7-hydroxy-N-desalkylquetiapine. CYP2D6 has been found to be responsible for metabolism of quetiapine to 7-hydroxy-N-desalkylquetiapine, a pharmacologically active metabolite. Individual differences in CYP2D6 metabolism may be present, which may affect the concentrations of the active 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): After an oral dose of radiolabeled quetiapine, less than 1% of unchanged drug was detected in the urine, suggesting that quetiapine is heavily metabolized. About 73% of a dose was detected in the urine, and about 20% 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 average terminal half-life of quetiapine is about 6-7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of quetiapine healthy volunteers in the fasted state during a clinical study was 101.04±39.11 L/h. Elderly patients may require lower doses of quetiapine, as clearance in these patients may be reduced by up to 50%. Those with liver dysfunction may also require lower doses. •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 if quetiapine in rats is 2000 mg/kg. Overdose information Some signs and symptoms of a quetiapine overdose include sedation, drowsiness, tachycardia, and hypotension. Clinical trials demonstrate that overdoses of up to 30 grams of quetiapine did not result in death. A lethal outcome was reported in a clinical trial after an overdose of 13.6 grams of quetiapine. In the case of an acute overdose, ensure to maintain an airway and provide adequate ventilation and oxygenation. Gastric lavage following intubation (if necessary) along with activated charcoal and a laxative may be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiac monitoring should also take place. A note on QT-interval prolongation in an overdose Postmarketing reports reveal increases in the cardiac QT interval in cases of quetiapine overdose, concomitant illness, and in those taking drugs that increase QT interval or affect electrolyte levels. Note that disopyramide, procainamide, and quinidine may exert additive QT-prolonging effects when administered in patients who have overdosed with quetiapine, and should be avoided. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Seroquel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Quetiapina Quétiapine Quetiapine Quetiapinum •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): Quetiapine is an atypical antipsychotic agent used for the management of bipolar disorder, schizophrenia, and major depressive 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 Quetiapine interact? Information: •Drug A: Buserelin •Drug B: Quetiapine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Quetiapine. •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): Quetiapine is used in the symptomatic treatment of schizophrenia. In addition, it may be used for the management of acute manic or mixed episodes in patients with bipolar I disorder, as a monotherapy or combined with other drugs. It may be used to manage depressive episodes in bipolar disorder. In addition to the above indications, quetiapine is used in combination with antidepressant drugs for the treatment of major depression. Some off-label uses for this drug include the management of post-traumatic stress disorder (PTSD), generalized anxiety disorder, and psychosis associated with 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): Quetiapine improves the positive and negative symptoms of schizophrenia and major depression by acting on various neurotransmitter receptors, such as the serotonin and dopamine receptors. In bipolar disorder, it improves both depressive and manic symptoms. A note on suicidality in young patients and administration in the elderly Quetiapine can cause suicidal thinking or behavior in children and adolescents and should not be given to children under 10 years of age. It is important to monitor for suicidality if this drug is given to younger patients. In addition, this drug is not indicated for the treatment of psychosis related to dementia due to an increased death rate in elderly patients taking this drug. •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 mechanism of action of quetiapine is not fully understood, several proposed mechanisms exist. In schizophrenia, its actions could occur from the antagonism of dopamine type 2 (D2) and serotonin 2A (5HT2A) receptors. In bipolar depression and major depression, quetiapine's actions may be attributed to the binding of this drug or its metabolite to the norepinephrine transporter. Additional effects of quetiapine, including somnolence, orthostatic hypotension, and anticholinergic effects, may result from the antagonism of H1 receptors, adrenergic α1 receptors, and muscarinic M1 receptors, respectively. •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): Quetiapine is rapidly and well absorbed after administration of an oral dose. Steady-state is achieved within 48 hours Peak plasma concentrations are achieved within 1.5 hours. The bioavailability of a tablet is 100%. The steady-state Cmax of quetiapine in Han Chinese patients with schizophrenia after a 300 mg oral dose of the extended released formulation was approximately 467 ng/mL and the AUC at steady-state was 5094 ng·h/mL. Absorption of quetiapine is affected by food, with Cmax increased by 25% and AUC increased by 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): Quetiapine distributes throughout body tissues. The apparent volume of distribution of this drug is about 10±4 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): The protein binding of quetiapine is 83%. •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 quetiapine occurs mainly in the liver. Sulfoxidation and oxidation are the main metabolic pathways of this drug. According to in vitro studies, cytochrome P450 3A4 metabolizes quetiapine to an inactive sulfoxide metabolite and also participates in the metabolism of its active metabolite, N-desalkyl quetiapine. CYP2D6 also regulates the metabolism of quetiapine. In one study, three metabolites of N-desalkylquetiapine were identified. Two of the metabolites were identified as N-desalkylquetiapine sulfoxide and 7-hydroxy-N-desalkylquetiapine. CYP2D6 has been found to be responsible for metabolism of quetiapine to 7-hydroxy-N-desalkylquetiapine, a pharmacologically active metabolite. Individual differences in CYP2D6 metabolism may be present, which may affect the concentrations of the active 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): After an oral dose of radiolabeled quetiapine, less than 1% of unchanged drug was detected in the urine, suggesting that quetiapine is heavily metabolized. About 73% of a dose was detected in the urine, and about 20% 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 average terminal half-life of quetiapine is about 6-7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of quetiapine healthy volunteers in the fasted state during a clinical study was 101.04±39.11 L/h. Elderly patients may require lower doses of quetiapine, as clearance in these patients may be reduced by up to 50%. Those with liver dysfunction may also require lower doses. •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 if quetiapine in rats is 2000 mg/kg. Overdose information Some signs and symptoms of a quetiapine overdose include sedation, drowsiness, tachycardia, and hypotension. Clinical trials demonstrate that overdoses of up to 30 grams of quetiapine did not result in death. A lethal outcome was reported in a clinical trial after an overdose of 13.6 grams of quetiapine. In the case of an acute overdose, ensure to maintain an airway and provide adequate ventilation and oxygenation. Gastric lavage following intubation (if necessary) along with activated charcoal and a laxative may be considered. The possibility of obtundation, seizure or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiac monitoring should also take place. A note on QT-interval prolongation in an overdose Postmarketing reports reveal increases in the cardiac QT interval in cases of quetiapine overdose, concomitant illness, and in those taking drugs that increase QT interval or affect electrolyte levels. Note that disopyramide, procainamide, and quinidine may exert additive QT-prolonging effects when administered in patients who have overdosed with quetiapine, and should be avoided. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Seroquel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Quetiapina Quétiapine Quetiapine Quetiapinum •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): Quetiapine is an atypical antipsychotic agent used for the management of bipolar disorder, schizophrenia, and major depressive 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 Quinidine interact?

•Drug A: Buserelin •Drug B: Quinidine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Quinidine. •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): Quinidine is indicated for the management and prophylactic therapy of atrial fibrillation/flutter, as well as the suppression of recurrent documented ventricular arrhythmias. It is also used in the treatment of Brugada syndrome, short QT syndrome and idiopathic ventricular fibrillation.. •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): Quinidine is an antimalarial schizonticide, and a class Ia antiarrhythmic agent used to interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, such as atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. In most patients, quinidine can lead to an increase in the sinus rate. Quinidine also causes a marked prolongation of the QT interval in a dose-related manner, acts peripherally as an α-adrenergic antagonist, and has anticholinergic and negative inotropic activity. The QT interval prolongation caused by quinidine can lead to increased ventricular automaticity and polymorphic ventricular tachycardias, such as torsades de pointes. The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia or high serum levels of quinidine. However, this type of rhythm disturbance may appear in the absence of any of them. Patients treated with quinidine may also be at risk of a paradoxical increase in ventricular rate in atrial flutter/fibrillation, and patients with sick sinus syndrome treated with quinidine may develop marked sinus node depression and bradycardia. •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): Quinidine has a complex electrophysiological profile that has not been fully elucidated. The antiarrhythmic actions of this drug are mediated through effects on sodium channels in Purkinje fibers. Quinidine blocks the rapid sodium channel (I Na ), decreasing the phase zero of rapid depolarization of the action potential. Quinidine also reduces repolarizing K currents (I Kr, I Ks ), the inward rectifier potassium current (I K1 ), and the transient outward potassium current I to, as well as the L-type calcium current I Ca and the late I Na inward current. The reduction of these currents leads to the prolongation of the action potential duration. By shortening the plateau but prolonging late depolarization, quinidine facilitates the formation of early afterdepolarisation (EAD). Additionally, in patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, and is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum. •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 absolute bioavailability of quinidine sulfate is approximately 70%, but it ranges from 45% to 100%. The less-than-complete quinidine sulfate bioavailability is a result of first-pass metabolism in the liver. In contrast, the absolute bioavailability of quinidine gluconate ranges from 70% to 80%, and relative to quinidine sulfate, quinidine from quinidine gluconate has a bioavailability of 1.03. The t max of quinidine sulfate extended-release tablets is approximately 6 h, while the t max of quinidine gluconate goes from 3 to 5 h. The peak serum concentration reached with immediate-release quinidine sulfate is delayed for about an hour when taken with food. Furthermore, the ingestion of grapefruit juice may decrease the rate of absorption of quinidine. •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): Quinidine has a volume of distribution of 2-3 L/kg in healthy young adults, 0.5 L/kg in patients with congestive heart failure, and 3-5 L/kg in patients with liver cirrhosis. •Protein binding (Drug A): 15% •Protein binding (Drug B): From 6.5 to 16.2 µmol/L, 80 to 88% of quinidine is bound to plasma proteins, mainly α1-acid glycoprotein and albumin. This fraction is lower in pregnant women, and it may be as low as 50 to 70% in infants and neonates. •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): Quinidine is mainly metabolized in the liver by cytochrome P450 enzymes, specifically CYP3A4. The major metabolite of quinidine is 3-hydroxy-quinidine, which has a volume of distribution larger than quinidine and an elimination half-life of about 12 hours. Non-clinical and clinical studies suggest that 3-hydroxy-quinidine has approximately half the antiarrhythmic activity of quinidine; therefore, this metabolite is partly responsible for the effects detected with the chronic use of quinidine. •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 quinidine is achieved by the renal excretion of the unchanged drug (15 to 40% of total clearance) and its hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). When urine has a pH lower than 7, 20% of administered quinidine appears in urine unchanged. However, this proportion decreases to as little as 5% as it becomes more alkaline. The renal clearance of quinidine involves both glomerular filtration and active tubular secretion, moderated by pH-dependent tubular reabsorption. •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 quinidine is 6-8 hours in adults and 3-4 hours in pediatric patients. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of quinidine ranges from 3 to 5 mL/min/kg in adults. In pediatric patients, quinidine clearance may be two or three times as rapid. •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): Quinidine overdoses have been well described. The ingestion of 5 g of quinidine resulted in the death of a toddler, while an adolescent was reported to survive after ingesting 8 g of quinidine. A 16-month that ingested quinidine tablets developed a concretion of bezoar in the stomach, which led to non-declining toxic levels of quinidine. A gastric aspirate revealed that quinidine levels were 50 times higher than the ones detected in plasma. In cases of massive overdose, it may be appropriate to perform an endoscopy. Acute quinidine overdoses are characterized by ventricular arrhythmias and hypotension. Other signs and symptoms of quinidine overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion and delirium. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nuedexta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (8R,9S)-Quinidine beta-Quinine Chinidin Chinidinum CIN-QUIN Conchinin Conquinine Pitayine Quinidina •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): Quinidine is a medication used to restore normal sinus rhythm, treat atrial fibrillation and flutter, and treat ventricular arrhythmias.

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 Quinidine interact? Information: •Drug A: Buserelin •Drug B: Quinidine •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Quinidine. •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): Quinidine is indicated for the management and prophylactic therapy of atrial fibrillation/flutter, as well as the suppression of recurrent documented ventricular arrhythmias. It is also used in the treatment of Brugada syndrome, short QT syndrome and idiopathic ventricular fibrillation.. •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): Quinidine is an antimalarial schizonticide, and a class Ia antiarrhythmic agent used to interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, such as atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. In most patients, quinidine can lead to an increase in the sinus rate. Quinidine also causes a marked prolongation of the QT interval in a dose-related manner, acts peripherally as an α-adrenergic antagonist, and has anticholinergic and negative inotropic activity. The QT interval prolongation caused by quinidine can lead to increased ventricular automaticity and polymorphic ventricular tachycardias, such as torsades de pointes. The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia or high serum levels of quinidine. However, this type of rhythm disturbance may appear in the absence of any of them. Patients treated with quinidine may also be at risk of a paradoxical increase in ventricular rate in atrial flutter/fibrillation, and patients with sick sinus syndrome treated with quinidine may develop marked sinus node depression and bradycardia. •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): Quinidine has a complex electrophysiological profile that has not been fully elucidated. The antiarrhythmic actions of this drug are mediated through effects on sodium channels in Purkinje fibers. Quinidine blocks the rapid sodium channel (I Na ), decreasing the phase zero of rapid depolarization of the action potential. Quinidine also reduces repolarizing K currents (I Kr, I Ks ), the inward rectifier potassium current (I K1 ), and the transient outward potassium current I to, as well as the L-type calcium current I Ca and the late I Na inward current. The reduction of these currents leads to the prolongation of the action potential duration. By shortening the plateau but prolonging late depolarization, quinidine facilitates the formation of early afterdepolarisation (EAD). Additionally, in patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, and is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum. •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 absolute bioavailability of quinidine sulfate is approximately 70%, but it ranges from 45% to 100%. The less-than-complete quinidine sulfate bioavailability is a result of first-pass metabolism in the liver. In contrast, the absolute bioavailability of quinidine gluconate ranges from 70% to 80%, and relative to quinidine sulfate, quinidine from quinidine gluconate has a bioavailability of 1.03. The t max of quinidine sulfate extended-release tablets is approximately 6 h, while the t max of quinidine gluconate goes from 3 to 5 h. The peak serum concentration reached with immediate-release quinidine sulfate is delayed for about an hour when taken with food. Furthermore, the ingestion of grapefruit juice may decrease the rate of absorption of quinidine. •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): Quinidine has a volume of distribution of 2-3 L/kg in healthy young adults, 0.5 L/kg in patients with congestive heart failure, and 3-5 L/kg in patients with liver cirrhosis. •Protein binding (Drug A): 15% •Protein binding (Drug B): From 6.5 to 16.2 µmol/L, 80 to 88% of quinidine is bound to plasma proteins, mainly α1-acid glycoprotein and albumin. This fraction is lower in pregnant women, and it may be as low as 50 to 70% in infants and neonates. •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): Quinidine is mainly metabolized in the liver by cytochrome P450 enzymes, specifically CYP3A4. The major metabolite of quinidine is 3-hydroxy-quinidine, which has a volume of distribution larger than quinidine and an elimination half-life of about 12 hours. Non-clinical and clinical studies suggest that 3-hydroxy-quinidine has approximately half the antiarrhythmic activity of quinidine; therefore, this metabolite is partly responsible for the effects detected with the chronic use of quinidine. •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 quinidine is achieved by the renal excretion of the unchanged drug (15 to 40% of total clearance) and its hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). When urine has a pH lower than 7, 20% of administered quinidine appears in urine unchanged. However, this proportion decreases to as little as 5% as it becomes more alkaline. The renal clearance of quinidine involves both glomerular filtration and active tubular secretion, moderated by pH-dependent tubular reabsorption. •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 quinidine is 6-8 hours in adults and 3-4 hours in pediatric patients. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of quinidine ranges from 3 to 5 mL/min/kg in adults. In pediatric patients, quinidine clearance may be two or three times as rapid. •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): Quinidine overdoses have been well described. The ingestion of 5 g of quinidine resulted in the death of a toddler, while an adolescent was reported to survive after ingesting 8 g of quinidine. A 16-month that ingested quinidine tablets developed a concretion of bezoar in the stomach, which led to non-declining toxic levels of quinidine. A gastric aspirate revealed that quinidine levels were 50 times higher than the ones detected in plasma. In cases of massive overdose, it may be appropriate to perform an endoscopy. Acute quinidine overdoses are characterized by ventricular arrhythmias and hypotension. Other signs and symptoms of quinidine overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion and delirium. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Nuedexta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (8R,9S)-Quinidine beta-Quinine Chinidin Chinidinum CIN-QUIN Conchinin Conquinine Pitayine Quinidina •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): Quinidine is a medication used to restore normal sinus rhythm, treat atrial fibrillation and flutter, and treat ventricular arrhythmias. 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 Quinine interact?

•Drug A: Buserelin •Drug B: Quinine •Severity: MODERATE •Description: The therapeutic efficacy of Quinine 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 malaria and leg cramps •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): Quinine is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria. Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is thought to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine. •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 theorized mechanism of action for quinine and related anti-malarial drugs is that these drugs are toxic to the malaria parasite. Specifically, the drugs interfere with the parasite's ability to break down and digest hemoglobin. Consequently, the parasite starves and/or builds up toxic levels of partially degraded hemoglobin in itself. •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): 76 - 88% •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): 1.43 ± 0.18 L/kg [Healthy Pediatric Controls] 0.87 ± 0.12 L/kg [P. falciparum Malaria Pediatric Patients] 2.5 to 7.1 L/kg [healthy subjects who received a single oral 600 mg dose] •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 70% •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, over 80% metabolized 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): Quinine is eliminated primarily via hepatic biotransformation. Approximately 20% of quinine is excreted unchanged 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): Approximately 18 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.17 L/h/kg [healthy] 0.09 L/h/kg [patients with uncomplicated malaria] 18.4 L/h [healthy adult subjects with administration of multiple-dose activated charcoal] 11.8 L/h [healthy adult subjects without administration of multiple-dose activated charcoal] Oral cl=0.06 L/h/kg [elderly 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): Quinine is a documented causative agent of drug induced thrombocytopenia (DIT). Thrombocytopenia is a low amount of platelets in the blood. Quinine induces production of antibodies against glycoprotein (GP) Ib-IX complex in the majority of cases of DIT, or more rarely, the platelet-glycoprotein complex GPIIb-IIIa. Increased antibodies against these complexes increases platelet clearance, leading to the observed thrombocytopenia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Qualaquin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (8S,9R)-quinine 6'-Methoxycinchonidine Chinin Chinine Chininum Quinina Quinine •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): Quinine is an alkaloid used to treat uncomplicated Plasmodium falciparum malaria.

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 Quinine interact? Information: •Drug A: Buserelin •Drug B: Quinine •Severity: MODERATE •Description: The therapeutic efficacy of Quinine 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 malaria and leg cramps •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): Quinine is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria. Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is thought to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine. •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 theorized mechanism of action for quinine and related anti-malarial drugs is that these drugs are toxic to the malaria parasite. Specifically, the drugs interfere with the parasite's ability to break down and digest hemoglobin. Consequently, the parasite starves and/or builds up toxic levels of partially degraded hemoglobin in itself. •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): 76 - 88% •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): 1.43 ± 0.18 L/kg [Healthy Pediatric Controls] 0.87 ± 0.12 L/kg [P. falciparum Malaria Pediatric Patients] 2.5 to 7.1 L/kg [healthy subjects who received a single oral 600 mg dose] •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 70% •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, over 80% metabolized 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): Quinine is eliminated primarily via hepatic biotransformation. Approximately 20% of quinine is excreted unchanged 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): Approximately 18 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.17 L/h/kg [healthy] 0.09 L/h/kg [patients with uncomplicated malaria] 18.4 L/h [healthy adult subjects with administration of multiple-dose activated charcoal] 11.8 L/h [healthy adult subjects without administration of multiple-dose activated charcoal] Oral cl=0.06 L/h/kg [elderly 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): Quinine is a documented causative agent of drug induced thrombocytopenia (DIT). Thrombocytopenia is a low amount of platelets in the blood. Quinine induces production of antibodies against glycoprotein (GP) Ib-IX complex in the majority of cases of DIT, or more rarely, the platelet-glycoprotein complex GPIIb-IIIa. Increased antibodies against these complexes increases platelet clearance, leading to the observed thrombocytopenia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Qualaquin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (8S,9R)-quinine 6'-Methoxycinchonidine Chinin Chinine Chininum Quinina Quinine •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): Quinine is an alkaloid used to treat uncomplicated Plasmodium falciparum malaria. 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 Quizartinib interact?

•Drug A: Buserelin •Drug B: Quizartinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Quizartinib. •Extended Description: Quizartinib is known to cause QT prolongation in a dose- and concentration-dependent manner. The mechanism is due to the inhibition of the slow delayed rectifier potassium current, I, which has been implicated significantly in drug-induced QT prolongation, as opposed to other QT-prolonging agents that tend to inhibit the rapid delayed rectifier potassium current, I. With both currents being inhibited, this poses a danger for patients with limited cardiac reserve. Therefore, the concomitant use of quizartinib with another QT-prolonging medication can further increase the risk of 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): Quizartinib is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test. •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): Quizartinib showed antitumor activity in a mouse model of FLT3-ITD-dependent leukemia. In vitro, studies have shown that quizartinib is a predominant inhibitor of the slow delayed rectifier potassium current, IKs. In AML patients receiving quizartinib at a dose of 90 mg/day for females and 135 mg/day for males on a 28-day schedule, the median levels of phospho-FLT3 (pFLT3) and total FLT3 (tFLT3) decreased from 3312 RLU or 5639 RLU respectively at day 1 to 1235 RLU and 142 RLU respectively at day 8. Additionally, pFLT3 levels are statistically significantly higher (p < 0.0001, Mann Whitney test) for the ITD+ subjects on day 1; however, pFLT3 levels was reduced to a similar level in patients with or without the ITD mutation. The exposure-response analysis predicted a concentration-dependent QTcF interval median prolongation of 18 and 24 ms [upper bound of 2-sided 90% confidence interval (CI): 21 and 27 ms] at the median steady-state Cmax of quizartinib at the 26.5 mg and 53 mg dose level during maintenance 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): Quizartinib is a small molecule inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major active metabolite AC886 bind to the adenosine triphosphate (ATP) binding domain of FLT3 with comparable affinity, and both had 10-fold lower affinity towards FLT3-ITD mutation compared to FLT3 in a binding assay. Quizartinib and AC886 inhibited FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting downstream FLT3 receptor signaling and blocking FLT3-ITD-dependent cell proliferation. •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 mean (SD) absolute bioavailability of quizartinib from the tablet formulation was 71% (±7%) in healthy subjects. After oral administration under fasted conditions, time to peak concentration (median T max ) of quizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively, in healthy subjects. Following the administration of 35.4 mg quizartinib once daily in patients with newly diagnosed acute myeloid leukemia, the C max and AUC 0-24h were calculated to be 140 ng/mL (71%) and 2,680 ng.h/mL (85%) respectively during the induction therapy and 204 ng/mL (64%) and 3,930 ng.h/mL (78%) respectively during the consolidation therapy. For the metabolite AC886, the C max and AUC 0-24h were estimated to be 163 ng/mL (52%) and 3,590 ng.h/mL (51%) respectively during the induction therapy and 172 ng/mL (47%) and 3,800 ng.h/mL (46%) respectively during the consolidation therapy. Increasing the once daily dose of quizartinib to 53 mg also increases the C max and AUC 0-24h of quizartinib to 529 ng/mL (60%) and 10,200 ng.h/mL (75%) respectively at steady state. The C max and AUC 0-24h of the metabolite AC886 also increases to 262 ng/mL (48%) and 5,790 ng•h/mL (46%) respectively. No clinically significant differences in the pharmacokinetics of quizartinib were observed when administered with a high-fat, high-calorie meal. •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): Volume of distribution at steady state in healthy subjects was estimated to be 275 L (17%). •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro plasma protein binding of quizartinib and AC886 is 99% or greater. In vitro blood-to-plasma ratio for quizartinib and AC886 ranges from 0.79-1.30 and 1.36-3.19, 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): In vitro quizartinib is primarily metabolized via oxidation by CYP3A4/5 and AC886 is formed and metabolized by 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): Following a single radiolabeled dose of quizartinib 53 mg to healthy subjects, 76.3% of the total radioactivity was recovered in feces (4% unchanged) and 1.64% 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): The mean (SD) effective half-lives (t1/2) in patients with newly diagnosed AML for quizartinib and AC886 during maintenance therapy are 81 hours (±73) and 136 hours (±113), respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total body clearance of quizartinib in healthy subjects was estimated to be 2.23 L/hour (29%). •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 findings from animal studies and its mechanism of action, quizartinib can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on quizartinib use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of quizartinib to pregnant rats during organogenesis resulted in adverse developmental outcomes including structural abnormalities and alterations to growth at maternal exposures approximately 3 times those in patients at the maximum recommended human dose (MRHD) of 53 mg/day (see Data). Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been conducted with quizartinib. Quizartinib was mutagenic in a bacterial reverse mutation (Ames) assay and not mutagenic in an in vivo transgenic rat mutation assay. Quizartinib was not genotoxic in vitro in mouse lymphoma thymidine kinase mutation and human lymphocyte chromosome aberration assays, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with quizartinib. However, adverse findings in male and female reproductive systems were observed in repeat dose toxicity studies in rats and monkeys. Findings in female animals (rats or monkeys) included ovarian cysts, vaginal mucosal modifications, and atrophy of the uterus, ovary, and vagina, starting at exposures (AUC) approximately 0.2 times the MRHD of 53 mg/day. In male animals (rats and monkeys), findings included testicular seminiferous tubular degeneration, failure of sperm release, germ cell depletion in the testes, and oligospermia/aspermia, starting at exposures approximately 0.4 times the MRHD. After approximately one month of recovery period, all these findings except the vaginal mucosal modifications in the female rats were reversible. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Vanflyta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Quizartinib Quizartinibum •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): Quizartinib is a FLT3 inhibitor used in combination with cytarabine and anthracycline to treat acute myeloid leukemia with FLT3 internal tandem duplication

Quizartinib is known to cause QT prolongation in a dose- and concentration-dependent manner. The mechanism is due to the inhibition of the slow delayed rectifier potassium current, I, which has been implicated significantly in drug-induced QT prolongation, as opposed to other QT-prolonging agents that tend to inhibit the rapid delayed rectifier potassium current, I. With both currents being inhibited, this poses a danger for patients with limited cardiac reserve. Therefore, the concomitant use of quizartinib with another QT-prolonging medication can further increase the risk of QT prolongation. The severity of the interaction is moderate.

Question: Does Buserelin and Quizartinib interact? Information: •Drug A: Buserelin •Drug B: Quizartinib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Quizartinib. •Extended Description: Quizartinib is known to cause QT prolongation in a dose- and concentration-dependent manner. The mechanism is due to the inhibition of the slow delayed rectifier potassium current, I, which has been implicated significantly in drug-induced QT prolongation, as opposed to other QT-prolonging agents that tend to inhibit the rapid delayed rectifier potassium current, I. With both currents being inhibited, this poses a danger for patients with limited cardiac reserve. Therefore, the concomitant use of quizartinib with another QT-prolonging medication can further increase the risk of 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): Quizartinib is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test. •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): Quizartinib showed antitumor activity in a mouse model of FLT3-ITD-dependent leukemia. In vitro, studies have shown that quizartinib is a predominant inhibitor of the slow delayed rectifier potassium current, IKs. In AML patients receiving quizartinib at a dose of 90 mg/day for females and 135 mg/day for males on a 28-day schedule, the median levels of phospho-FLT3 (pFLT3) and total FLT3 (tFLT3) decreased from 3312 RLU or 5639 RLU respectively at day 1 to 1235 RLU and 142 RLU respectively at day 8. Additionally, pFLT3 levels are statistically significantly higher (p < 0.0001, Mann Whitney test) for the ITD+ subjects on day 1; however, pFLT3 levels was reduced to a similar level in patients with or without the ITD mutation. The exposure-response analysis predicted a concentration-dependent QTcF interval median prolongation of 18 and 24 ms [upper bound of 2-sided 90% confidence interval (CI): 21 and 27 ms] at the median steady-state Cmax of quizartinib at the 26.5 mg and 53 mg dose level during maintenance 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): Quizartinib is a small molecule inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major active metabolite AC886 bind to the adenosine triphosphate (ATP) binding domain of FLT3 with comparable affinity, and both had 10-fold lower affinity towards FLT3-ITD mutation compared to FLT3 in a binding assay. Quizartinib and AC886 inhibited FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting downstream FLT3 receptor signaling and blocking FLT3-ITD-dependent cell proliferation. •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 mean (SD) absolute bioavailability of quizartinib from the tablet formulation was 71% (±7%) in healthy subjects. After oral administration under fasted conditions, time to peak concentration (median T max ) of quizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively, in healthy subjects. Following the administration of 35.4 mg quizartinib once daily in patients with newly diagnosed acute myeloid leukemia, the C max and AUC 0-24h were calculated to be 140 ng/mL (71%) and 2,680 ng.h/mL (85%) respectively during the induction therapy and 204 ng/mL (64%) and 3,930 ng.h/mL (78%) respectively during the consolidation therapy. For the metabolite AC886, the C max and AUC 0-24h were estimated to be 163 ng/mL (52%) and 3,590 ng.h/mL (51%) respectively during the induction therapy and 172 ng/mL (47%) and 3,800 ng.h/mL (46%) respectively during the consolidation therapy. Increasing the once daily dose of quizartinib to 53 mg also increases the C max and AUC 0-24h of quizartinib to 529 ng/mL (60%) and 10,200 ng.h/mL (75%) respectively at steady state. The C max and AUC 0-24h of the metabolite AC886 also increases to 262 ng/mL (48%) and 5,790 ng•h/mL (46%) respectively. No clinically significant differences in the pharmacokinetics of quizartinib were observed when administered with a high-fat, high-calorie meal. •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): Volume of distribution at steady state in healthy subjects was estimated to be 275 L (17%). •Protein binding (Drug A): 15% •Protein binding (Drug B): In vitro plasma protein binding of quizartinib and AC886 is 99% or greater. In vitro blood-to-plasma ratio for quizartinib and AC886 ranges from 0.79-1.30 and 1.36-3.19, 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): In vitro quizartinib is primarily metabolized via oxidation by CYP3A4/5 and AC886 is formed and metabolized by 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): Following a single radiolabeled dose of quizartinib 53 mg to healthy subjects, 76.3% of the total radioactivity was recovered in feces (4% unchanged) and 1.64% 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): The mean (SD) effective half-lives (t1/2) in patients with newly diagnosed AML for quizartinib and AC886 during maintenance therapy are 81 hours (±73) and 136 hours (±113), respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): Total body clearance of quizartinib in healthy subjects was estimated to be 2.23 L/hour (29%). •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 findings from animal studies and its mechanism of action, quizartinib can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on quizartinib use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of quizartinib to pregnant rats during organogenesis resulted in adverse developmental outcomes including structural abnormalities and alterations to growth at maternal exposures approximately 3 times those in patients at the maximum recommended human dose (MRHD) of 53 mg/day (see Data). Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been conducted with quizartinib. Quizartinib was mutagenic in a bacterial reverse mutation (Ames) assay and not mutagenic in an in vivo transgenic rat mutation assay. Quizartinib was not genotoxic in vitro in mouse lymphoma thymidine kinase mutation and human lymphocyte chromosome aberration assays, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with quizartinib. However, adverse findings in male and female reproductive systems were observed in repeat dose toxicity studies in rats and monkeys. Findings in female animals (rats or monkeys) included ovarian cysts, vaginal mucosal modifications, and atrophy of the uterus, ovary, and vagina, starting at exposures (AUC) approximately 0.2 times the MRHD of 53 mg/day. In male animals (rats and monkeys), findings included testicular seminiferous tubular degeneration, failure of sperm release, germ cell depletion in the testes, and oligospermia/aspermia, starting at exposures approximately 0.4 times the MRHD. After approximately one month of recovery period, all these findings except the vaginal mucosal modifications in the female rats were reversible. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Vanflyta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Quizartinib Quizartinibum •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): Quizartinib is a FLT3 inhibitor used in combination with cytarabine and anthracycline to treat acute myeloid leukemia with FLT3 internal tandem duplication Output: Quizartinib is known to cause QT prolongation in a dose- and concentration-dependent manner. The mechanism is due to the inhibition of the slow delayed rectifier potassium current, I, which has been implicated significantly in drug-induced QT prolongation, as opposed to other QT-prolonging agents that tend to inhibit the rapid delayed rectifier potassium current, I. With both currents being inhibited, this poses a danger for patients with limited cardiac reserve. Therefore, the concomitant use of quizartinib with another QT-prolonging medication can further increase the risk of QT prolongation. The severity of the interaction is moderate.

Does Buserelin and Ranolazine interact?

•Drug A: Buserelin •Drug B: Ranolazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ranolazine. •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): Ranolazine is indicated for the treatment of chronic angina. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors. Ranolazine has also been used off-label for the treatment of certain arrhythmias, including ventricular tachycardia, however, this use is not strongly supported by scientific evidence. Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control, which are not yet approved indications. •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): Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise. •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): Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others. The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed. Ranolazine inhibits sodium and potassium ion channel currents. It has been shown to exert weak activity on L-type calcium channels making it a weak direct vasodilator and exerts minimal direct effects on atrioventricular nodal conduction. Some additional mechanisms have been elucidated. Ranolazine exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation. •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 time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%. •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 apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for 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): Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine. Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated. •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): From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as 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): The apparent terminal half-life of ranolazine is 7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%. •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 LD50 of oral ranolazine in the rat is 980 mg/kg. High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aspruzyo Sprinkle, Ranexa •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): Ranolazine is an anti-anginal drug used for the treatment of chronic 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 Ranolazine interact? Information: •Drug A: Buserelin •Drug B: Ranolazine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ranolazine. •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): Ranolazine is indicated for the treatment of chronic angina. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors. Ranolazine has also been used off-label for the treatment of certain arrhythmias, including ventricular tachycardia, however, this use is not strongly supported by scientific evidence. Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control, which are not yet approved indications. •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): Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise. •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): Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others. The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed. Ranolazine inhibits sodium and potassium ion channel currents. It has been shown to exert weak activity on L-type calcium channels making it a weak direct vasodilator and exerts minimal direct effects on atrioventricular nodal conduction. Some additional mechanisms have been elucidated. Ranolazine exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation. •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 time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%. •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 apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for 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): Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine. Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated. •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): From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as 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): The apparent terminal half-life of ranolazine is 7 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%. •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 LD50 of oral ranolazine in the rat is 980 mg/kg. High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Aspruzyo Sprinkle, Ranexa •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): Ranolazine is an anti-anginal drug used for the treatment of chronic 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 Relugolix interact?

•Drug A: Buserelin •Drug B: Relugolix •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Relugolix. •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): Relugolix is indicated for the treatment of adult patients with advanced prostate cancer. In a combination product with estradiol and norethindrone, relugolix is indicated for the once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. •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): Approximately 56% of patients achieved castrate-level testosterone concentrations (<50 ng/dL) by day 4 of therapy and 97% of patients maintain these levels through 48 weeks of therapy. Relugolix requires once-daily oral administration to maintain the desired testosterone concentrations. Androgen deprivation therapies may prolong the QTc interval and should therefore be used with caution in patients having a high baseline risk of QTc prolongation, such as those with electrolyte abnormalities, congestive heart failure, or using other medications known to prolong the QTc interval. Based on its mechanism of action and data from animal studies, relugolix may result in fetal harm if administered to pregnant females - male patients with female partners should be advised to use effective contraception throughout therapy and for 2 weeks following cessation of therapy to prevent inadvertent fetal exposure. •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 pathogenesis and progression of prostate cancer appear driven, at least in part, by the effects of testosterone. Androgen deprivation has been demonstrated to result in cell death and tumor regression in many well-differentiated prostate cancer cell lines - for this reason, androgen deprivation therapy (ADT) has become a standard in the treatment of prostate cancer, particularly in advanced disease. Testosterone production in males is carried out in the Leydig cells of testes and is stimulated by luteinizing hormone (LH), which itself is produced in the pituitary gland following the binding of gonadotropin-releasing hormone (GnRH) to corresponding GnRH receptors. Relugolix is a competitive antagonist of these GnRH receptors, thereby decreasing the release of LH and, ultimately, testosterone. •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 C max and AUC of orally-administered relugolix increase proportionally following single doses - in contrast, with repeat dosing the AUC remains proportional to the dose while the C max increases greater than proportionally to the dose. Following the administration of 120mg once daily, the steady-state AUC and C max of relugolix were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The absolute oral bioavailability of relugolix is approximately 12% and the median T max following oral administration is 2.25 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): Relugolix is 68-71% protein-bound in plasma, primarily to albumin and, to a lesser extent, α1-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): Relugolix is metabolized mainly by the CYP3A subfamily of P450 enzymes, with a smaller contribution by CYP2C8. •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 81% of an orally administered dose was recovered in the feces, of which 4.2% was unchanged parent drug, while 4.1% of the dose was recovered in the urine, of which 2.2% remained 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 average effective half-life of relugolix is 25 hours, while the average terminal elimination half-life is 60.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average renal clearance of relugolix is 8 L/h with a total clearance of 26.4 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): Data regarding overdose of relugolix are unavailable. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Myfembree, Orgovyx •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): Relugolix is an oral GnRH receptor antagonist for androgen deprivation therapy in the treatment 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 Relugolix interact? Information: •Drug A: Buserelin •Drug B: Relugolix •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Relugolix. •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): Relugolix is indicated for the treatment of adult patients with advanced prostate cancer. In a combination product with estradiol and norethindrone, relugolix is indicated for the once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. •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): Approximately 56% of patients achieved castrate-level testosterone concentrations (<50 ng/dL) by day 4 of therapy and 97% of patients maintain these levels through 48 weeks of therapy. Relugolix requires once-daily oral administration to maintain the desired testosterone concentrations. Androgen deprivation therapies may prolong the QTc interval and should therefore be used with caution in patients having a high baseline risk of QTc prolongation, such as those with electrolyte abnormalities, congestive heart failure, or using other medications known to prolong the QTc interval. Based on its mechanism of action and data from animal studies, relugolix may result in fetal harm if administered to pregnant females - male patients with female partners should be advised to use effective contraception throughout therapy and for 2 weeks following cessation of therapy to prevent inadvertent fetal exposure. •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 pathogenesis and progression of prostate cancer appear driven, at least in part, by the effects of testosterone. Androgen deprivation has been demonstrated to result in cell death and tumor regression in many well-differentiated prostate cancer cell lines - for this reason, androgen deprivation therapy (ADT) has become a standard in the treatment of prostate cancer, particularly in advanced disease. Testosterone production in males is carried out in the Leydig cells of testes and is stimulated by luteinizing hormone (LH), which itself is produced in the pituitary gland following the binding of gonadotropin-releasing hormone (GnRH) to corresponding GnRH receptors. Relugolix is a competitive antagonist of these GnRH receptors, thereby decreasing the release of LH and, ultimately, testosterone. •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 C max and AUC of orally-administered relugolix increase proportionally following single doses - in contrast, with repeat dosing the AUC remains proportional to the dose while the C max increases greater than proportionally to the dose. Following the administration of 120mg once daily, the steady-state AUC and C max of relugolix were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The absolute oral bioavailability of relugolix is approximately 12% and the median T max following oral administration is 2.25 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): Relugolix is 68-71% protein-bound in plasma, primarily to albumin and, to a lesser extent, α1-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): Relugolix is metabolized mainly by the CYP3A subfamily of P450 enzymes, with a smaller contribution by CYP2C8. •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 81% of an orally administered dose was recovered in the feces, of which 4.2% was unchanged parent drug, while 4.1% of the dose was recovered in the urine, of which 2.2% remained 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 average effective half-life of relugolix is 25 hours, while the average terminal elimination half-life is 60.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The average renal clearance of relugolix is 8 L/h with a total clearance of 26.4 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): Data regarding overdose of relugolix are unavailable. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Myfembree, Orgovyx •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): Relugolix is an oral GnRH receptor antagonist for androgen deprivation therapy in the treatment 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 Repaglinide interact?

•Drug A: Buserelin •Drug B: Repaglinide •Severity: MODERATE •Description: The therapeutic efficacy of Repaglinide 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): 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): Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-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): Repaglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, repaglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, repaglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of repaglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Repaglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue. •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 completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). The absolute bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours. When a single 2 mg dose of repaglinide is given to healthy subjects, the area under the curve (AUC) is 18.0 - 18.7 (ng/mL/h)^3. •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): 31 L following IV administration in healthy individuals •Protein binding (Drug A): 15% •Protein binding (Drug B): >98% (e.g. to to albumin and α1-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): Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic 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): 90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as 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): 1 hour •Clearance (Drug A): No clearance available •Clearance (Drug B): 33-38 L/hour following IV administration •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 >1 g/kg (rat) (W. Grell) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Enyglid, Gluconorm, Prandin •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): Repaglinide is a antihyperglycemic used to improve glycemic control in diabetes.

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 Repaglinide interact? Information: •Drug A: Buserelin •Drug B: Repaglinide •Severity: MODERATE •Description: The therapeutic efficacy of Repaglinide 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): 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): Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-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): Repaglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, repaglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, repaglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of repaglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Repaglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue. •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 completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). The absolute bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours. When a single 2 mg dose of repaglinide is given to healthy subjects, the area under the curve (AUC) is 18.0 - 18.7 (ng/mL/h)^3. •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): 31 L following IV administration in healthy individuals •Protein binding (Drug A): 15% •Protein binding (Drug B): >98% (e.g. to to albumin and α1-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): Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic 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): 90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as 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): 1 hour •Clearance (Drug A): No clearance available •Clearance (Drug B): 33-38 L/hour following IV administration •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 >1 g/kg (rat) (W. Grell) •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Enyglid, Gluconorm, Prandin •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): Repaglinide is a antihyperglycemic used to improve glycemic control in diabetes. 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 Ribociclib interact?

•Drug A: Buserelin •Drug B: Ribociclib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ribociclib. •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): Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably. •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): Inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) may provide protection against oncogenic processes in specific tissue types. For example, CDK4 is not required for normal mammary tissue development based on knockout mouse studies, but it is needed for growth of Ras-induced mammary tumors, suggesting a potential therapeutic window for treatment with lower toxicity. Ribociclib was reported to be a most selective CDK4/6 inhibitor and to have dose dependent antitumor activity in a number of preclinical models. It inhibited growth of tumor cells by arresting the cells at the G1 checkpoint, which prevents the tumor cells from proliferating. •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): Ribociclib is orally bioavailable, highly selective inhibitor of CDK4/6 kinases with inhibitory IC50 concentrations in the low nanomolar range. Following oral dosing, ribociclib was rapidly absorbed with median Tmax ranging from 1 to 5 hours. Plasma concentrations increased approximately 2- to 3-fold from Cycle 1 Day 1 to Cycle 1 Day 18/21 due to accumulation, with steady state reached by approximately Day 8 on the basis of trough concentrations after repeated daily dosing. Dose-proportionality analyses demonstrated that exposure to ribociclib increased with dose, with both Cmax and area under the curve (AUC) increasing slightly more than proportional to dose, over the dose range 50–1,200 mg/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): 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): 32.6 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): Kisqali 200 Mg Daily Dose Carton, Kisqali Femara Co-pack •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): Ribociclib is a kinase inhibitor used to treat HR+, HER2- advanced or metastatic breast cancer.

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 Ribociclib interact? Information: •Drug A: Buserelin •Drug B: Ribociclib •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Ribociclib. •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): Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably. •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): Inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) may provide protection against oncogenic processes in specific tissue types. For example, CDK4 is not required for normal mammary tissue development based on knockout mouse studies, but it is needed for growth of Ras-induced mammary tumors, suggesting a potential therapeutic window for treatment with lower toxicity. Ribociclib was reported to be a most selective CDK4/6 inhibitor and to have dose dependent antitumor activity in a number of preclinical models. It inhibited growth of tumor cells by arresting the cells at the G1 checkpoint, which prevents the tumor cells from proliferating. •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): Ribociclib is orally bioavailable, highly selective inhibitor of CDK4/6 kinases with inhibitory IC50 concentrations in the low nanomolar range. Following oral dosing, ribociclib was rapidly absorbed with median Tmax ranging from 1 to 5 hours. Plasma concentrations increased approximately 2- to 3-fold from Cycle 1 Day 1 to Cycle 1 Day 18/21 due to accumulation, with steady state reached by approximately Day 8 on the basis of trough concentrations after repeated daily dosing. Dose-proportionality analyses demonstrated that exposure to ribociclib increased with dose, with both Cmax and area under the curve (AUC) increasing slightly more than proportional to dose, over the dose range 50–1,200 mg/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): 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): 32.6 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): Kisqali 200 Mg Daily Dose Carton, Kisqali Femara Co-pack •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): Ribociclib is a kinase inhibitor used to treat HR+, HER2- advanced or metastatic breast cancer. 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 Rilpivirine interact?

•Drug A: Buserelin •Drug B: Rilpivirine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Rilpivirine. •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): Rilpivirine, in combination with other agents, is indicated for the treatment of HIV-1 infections in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL and CD4+ cell count >200 cells/mm. The FDA combination therapy approval of rilpivirine and dolutegravir is indicated for adults and adolescents 12 years of age and older weighing at least 35 kg with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without a history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy. Rilpivirine in combination with cabotegravir is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents - ≥12 years old and weighing at least 35kg - to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. •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): Rilpivirine is a non-nucleoside reverse transcriptase inhibitor that inhibits the replication of HIV-1. It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly. Patients should be counselled regarding the risk of hypersensitivity reactions, hepatotoxicity, depressive disorders, and the redistribution or accumulation of body fat. •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): Rilpivirine is a non-competitive NNRTI that binds to reverse transcriptase. Its binding results in the blockage of RNA and DNA- dependent DNA polymerase activities, like HIV-1 replication. It does not present activity against human DNA polymerases α, β and γ. Rilpivirine's flexible structure around the aromatic rings allows the adaptation to changes in the non-nucleoside RT binding pocket, reducing the likelihood of viral mutations conferring resistance. •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): Rilpivirine has a T max of 3-4 hours and has a mean AUC of 2235 ± 851 ng*h/mL. A 25mg dose reaches a C max of 247 ng/mL in healthy subjects and 138.6 ng/mL in patients with HIV-1. •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 HIV-1 patients, the apparent volume of distribution in the central compartment was 152-173 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Rilpivirine is >99% bound to plasma protein, most commonly 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): Rilpivirine is predominantly metabolized by CYP3A4 and CYP3A5 to the hydroxylated metabolites M1, M2, M3, and M4. UGT1A1 glucuronidates the M2 metabolite to form M6, UGT1A4 glucuronidates rilpivirine to form M5, and an unknown UGT glucuronidates the M4 metabolite to form M7. •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): Rilpivirine is 85% eliminated in the feces and 6.1% eliminated in the urine. 25% of a dose is recovered in the feces as the unchanged parent drug, while <1% of a dose is recovered in the urine 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): Rilpivirine has a terminal half-life of 34-55 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In HIV-1 patients, the apparent total clearance is estimated to be 6.89-8.66 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 the event of an overdose, contact a poison control centre. Patients should be treated with symptomatic and supportive measures, including monitoring of the QT interval. Dialysis is not expected to remove significant amounts of the drug from plasma as it is highly bound to albumin. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Complera, Edurant, Juluca, Odefsey •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Rilpivirina Rilpivirine •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): Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with other antiretrovirals to specifically treat human immunodeficiency virus type 1 (HIV-1).

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 Rilpivirine interact? Information: •Drug A: Buserelin •Drug B: Rilpivirine •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Rilpivirine. •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): Rilpivirine, in combination with other agents, is indicated for the treatment of HIV-1 infections in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL and CD4+ cell count >200 cells/mm. The FDA combination therapy approval of rilpivirine and dolutegravir is indicated for adults and adolescents 12 years of age and older weighing at least 35 kg with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without a history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy. Rilpivirine in combination with cabotegravir is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents - ≥12 years old and weighing at least 35kg - to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. •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): Rilpivirine is a non-nucleoside reverse transcriptase inhibitor that inhibits the replication of HIV-1. It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly. Patients should be counselled regarding the risk of hypersensitivity reactions, hepatotoxicity, depressive disorders, and the redistribution or accumulation of body fat. •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): Rilpivirine is a non-competitive NNRTI that binds to reverse transcriptase. Its binding results in the blockage of RNA and DNA- dependent DNA polymerase activities, like HIV-1 replication. It does not present activity against human DNA polymerases α, β and γ. Rilpivirine's flexible structure around the aromatic rings allows the adaptation to changes in the non-nucleoside RT binding pocket, reducing the likelihood of viral mutations conferring resistance. •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): Rilpivirine has a T max of 3-4 hours and has a mean AUC of 2235 ± 851 ng*h/mL. A 25mg dose reaches a C max of 247 ng/mL in healthy subjects and 138.6 ng/mL in patients with HIV-1. •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 HIV-1 patients, the apparent volume of distribution in the central compartment was 152-173 L. •Protein binding (Drug A): 15% •Protein binding (Drug B): Rilpivirine is >99% bound to plasma protein, most commonly 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): Rilpivirine is predominantly metabolized by CYP3A4 and CYP3A5 to the hydroxylated metabolites M1, M2, M3, and M4. UGT1A1 glucuronidates the M2 metabolite to form M6, UGT1A4 glucuronidates rilpivirine to form M5, and an unknown UGT glucuronidates the M4 metabolite to form M7. •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): Rilpivirine is 85% eliminated in the feces and 6.1% eliminated in the urine. 25% of a dose is recovered in the feces as the unchanged parent drug, while <1% of a dose is recovered in the urine 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): Rilpivirine has a terminal half-life of 34-55 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In HIV-1 patients, the apparent total clearance is estimated to be 6.89-8.66 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 the event of an overdose, contact a poison control centre. Patients should be treated with symptomatic and supportive measures, including monitoring of the QT interval. Dialysis is not expected to remove significant amounts of the drug from plasma as it is highly bound to albumin. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Complera, Edurant, Juluca, Odefsey •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Rilpivirina Rilpivirine •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): Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with other antiretrovirals to specifically treat human immunodeficiency virus type 1 (HIV-1). 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 Risperidone interact?

•Drug A: Buserelin •Drug B: Risperidone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Risperidone 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): Risperidone is indicated for the treatment of schizophrenia and irritability associated with autistic disorder. It is also indicated as monotherapy, or adjunctly with lithium or valproic acid, for the treatment of acute mania or mixed episodes associated with bipolar I disorder. Risperidone is additionally indicated in Canada for the short-term symptomatic management of aggression or psychotic symptoms in patients with severe dementia of the Alzheimer type unresponsive to nonpharmacological approaches. Risperidone is also used off-label for a number of conditions including as an adjunct to antidepressants in treatment-resistant depression. •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 primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 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): Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time. •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. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. •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 risperidone is approximately 1 to 2 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Risperidone and its active metabolite, 9-hydroxyrisperidone, are ~88% and ~77% protein-bound in human plasma, respectively. They each bind 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): Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone (i.e. paliperidone ), which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent. •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): Risperidone is extensively metabolized in the liver. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives are prolonged compared to young healthy subjects. •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 hours in extensive metabolizers Up to 20 hours in poor metabolizers •Clearance (Drug A): No clearance available •Clearance (Drug B): Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with a creatinine clearance (ClCr) between 15-59 mL/min, in whom clearance is decreased by approximately 60%. •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 lethargy, dystonia/spasm, tachycardia, bradycardia, and seizures. LD 50 =57.7 mg/kg (rat, oral) and 34 mg/kg (rat, intravenous). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Perseris, Risperdal, Rykindo, Uzedy •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): Risperidone is a second-generation antipsychotic medication used to treat a number of mental health disorders including schizophrenia, bipolar mania, psychosis, or as an adjunct in severe 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 Risperidone interact? Information: •Drug A: Buserelin •Drug B: Risperidone •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Risperidone 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): Risperidone is indicated for the treatment of schizophrenia and irritability associated with autistic disorder. It is also indicated as monotherapy, or adjunctly with lithium or valproic acid, for the treatment of acute mania or mixed episodes associated with bipolar I disorder. Risperidone is additionally indicated in Canada for the short-term symptomatic management of aggression or psychotic symptoms in patients with severe dementia of the Alzheimer type unresponsive to nonpharmacological approaches. Risperidone is also used off-label for a number of conditions including as an adjunct to antidepressants in treatment-resistant depression. •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 primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 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): Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time. •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. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. •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 risperidone is approximately 1 to 2 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Risperidone and its active metabolite, 9-hydroxyrisperidone, are ~88% and ~77% protein-bound in human plasma, respectively. They each bind 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): Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone (i.e. paliperidone ), which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent. •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): Risperidone is extensively metabolized in the liver. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives are prolonged compared to young healthy subjects. •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 hours in extensive metabolizers Up to 20 hours in poor metabolizers •Clearance (Drug A): No clearance available •Clearance (Drug B): Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with a creatinine clearance (ClCr) between 15-59 mL/min, in whom clearance is decreased by approximately 60%. •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 lethargy, dystonia/spasm, tachycardia, bradycardia, and seizures. LD 50 =57.7 mg/kg (rat, oral) and 34 mg/kg (rat, intravenous). •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Perseris, Risperdal, Rykindo, Uzedy •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): Risperidone is a second-generation antipsychotic medication used to treat a number of mental health disorders including schizophrenia, bipolar mania, psychosis, or as an adjunct in severe 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 Ritonavir interact?

•Drug A: Buserelin •Drug B: Ritonavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ritonavir 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): Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. In the US, Europe, and Canada, ritonavir, in combination with nirmatrelvir, is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. In Europe, this therapeutic indication is approved under conditional marketing authorization. •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): Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. 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. Ritonavir 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. Modern protease inhibitors require the use of low-dose ritonavir to boost pharmacokinetic exposure through inhibition of metabolism via the cytochrome P450 3A4 enzyme pathway. •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): Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as gag and pol. Gag encodes proteins involved in the core and the nucleocapsid, while pol encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease. The pol -encoded proteins are initially translated in the form of a larger precursoe polypeptide, gag-pol, and needs to be cleaved by HIV protease to form other complement proteins. Ritonavir prevents the cleavage of the gag-pol polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver. It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase. Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels. •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 absolute bioavailability of ritonavir has not been determined. Following oral administration, peak concentrations are reached after approximately 2 hours and 4 hours (T max ) after dosing under fasting and non-fasting conditions, respectively. It should be noted that ritonavir capsules and tablets are not considered bioequivalent. •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 estimated volume of distribution of ritonavir is 0.41 ± 0.25 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ritonavir is highly protein-bound in plasma (~98-99%), primarily to albumin and alpha-1 acid glycoprotein over the standard concentration range. •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): Ritonavir circulates in the plasma predominantly as unchanged drug. Five metabolites have been identified. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite in low plasma concentrations and retains similar antiviral activity to unchanged ritonavir. The cytochrome P450 enzymes CYP3A and CYP2D6 are the enzymes primarily involved in the metabolism of ritonavir. •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): Ritonavir is primarily eliminated in the feces. Following oral administration of a single 600mg dose of radiolabeled ritonavir, approximately 11.3 ± 2.8% of the dose was excreted into the urine, of which 3.5 ± 1.8% was unchanged parent drug. The same study found that 86.4 ± 2.9% of the dose was excreted in the feces, of which 33.8 ± 10.8% was 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): The approximate half-life of ritonavir is 3-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent oral clearance at steady-state is 8.8 ± 3.2 L/h. Renal clearance is minimal and estimated to be <0.1 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): Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. Oral LD value in rats is >2500 mg/kg. Adverse effects of ritonavir may arise from drug-drug interactions. Other effects include hepatotoxicity, pancreatitis, and allergic reactions/hypersensitivity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Kaletra, Norvir, Paxlovid, Viekira Pak •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): Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection.

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 Ritonavir interact? Information: •Drug A: Buserelin •Drug B: Ritonavir •Severity: MINOR •Description: The risk or severity of QTc prolongation can be increased when Ritonavir 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): Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. In the US, Europe, and Canada, ritonavir, in combination with nirmatrelvir, is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. In Europe, this therapeutic indication is approved under conditional marketing authorization. •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): Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. 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. Ritonavir 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. Modern protease inhibitors require the use of low-dose ritonavir to boost pharmacokinetic exposure through inhibition of metabolism via the cytochrome P450 3A4 enzyme pathway. •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): Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as gag and pol. Gag encodes proteins involved in the core and the nucleocapsid, while pol encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease. The pol -encoded proteins are initially translated in the form of a larger precursoe polypeptide, gag-pol, and needs to be cleaved by HIV protease to form other complement proteins. Ritonavir prevents the cleavage of the gag-pol polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver. It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase. Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels. •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 absolute bioavailability of ritonavir has not been determined. Following oral administration, peak concentrations are reached after approximately 2 hours and 4 hours (T max ) after dosing under fasting and non-fasting conditions, respectively. It should be noted that ritonavir capsules and tablets are not considered bioequivalent. •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 estimated volume of distribution of ritonavir is 0.41 ± 0.25 L/kg. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ritonavir is highly protein-bound in plasma (~98-99%), primarily to albumin and alpha-1 acid glycoprotein over the standard concentration range. •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): Ritonavir circulates in the plasma predominantly as unchanged drug. Five metabolites have been identified. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite in low plasma concentrations and retains similar antiviral activity to unchanged ritonavir. The cytochrome P450 enzymes CYP3A and CYP2D6 are the enzymes primarily involved in the metabolism of ritonavir. •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): Ritonavir is primarily eliminated in the feces. Following oral administration of a single 600mg dose of radiolabeled ritonavir, approximately 11.3 ± 2.8% of the dose was excreted into the urine, of which 3.5 ± 1.8% was unchanged parent drug. The same study found that 86.4 ± 2.9% of the dose was excreted in the feces, of which 33.8 ± 10.8% was 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): The approximate half-life of ritonavir is 3-5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The apparent oral clearance at steady-state is 8.8 ± 3.2 L/h. Renal clearance is minimal and estimated to be <0.1 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): Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. Oral LD value in rats is >2500 mg/kg. Adverse effects of ritonavir may arise from drug-drug interactions. Other effects include hepatotoxicity, pancreatitis, and allergic reactions/hypersensitivity. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Kaletra, Norvir, Paxlovid, Viekira Pak •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): Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection. 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 Romidepsin interact?

•Drug A: Buserelin •Drug B: Romidepsin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Romidepsin. •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): Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic 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): 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): Romidepsin is a prodrug, where it becomes active once taken up into the cell. The active metabolite has a free thiol group, which interacts with zinc ions in the active site of class 1 and 2 HDAC enzymes, resulting in inhibition of its enzymatic activity. Certain tumors have over expressed HDACs and downregulated/mutated histone acetyltransferases. This imbalance of HDAC relative to histone acetyltransferase can lead to a decrease in regulatory genes, ensuing tumorigenesis. Inhibition of HDAC may restore normal gene expression in cancer cells and result in cell cycle arrest and 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): Romidepsin exhibited linear pharmacokinetics at standard doses. •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): 44.5L •Protein binding (Drug A): 15% •Protein binding (Drug B): Highly protein bound in plasma (92%-94%) •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): Romidepsin undergoes extensive hepatic metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6 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): 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): Approximately 3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 8.4L/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): Risk factor D in pregnancy. It is not known if romidepsin is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother. The majority of patients receiving romidepsin experience nausea, vomiting, and anorexia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Istodax •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): Romidepsin is a histone deacetylase (HDAC) inhibitor used to treat cutaneous T-cell lymphoma.

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 Romidepsin interact? Information: •Drug A: Buserelin •Drug B: Romidepsin •Severity: MODERATE •Description: The risk or severity of QTc prolongation can be increased when Buserelin is combined with Romidepsin. •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): Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic 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): 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): Romidepsin is a prodrug, where it becomes active once taken up into the cell. The active metabolite has a free thiol group, which interacts with zinc ions in the active site of class 1 and 2 HDAC enzymes, resulting in inhibition of its enzymatic activity. Certain tumors have over expressed HDACs and downregulated/mutated histone acetyltransferases. This imbalance of HDAC relative to histone acetyltransferase can lead to a decrease in regulatory genes, ensuing tumorigenesis. Inhibition of HDAC may restore normal gene expression in cancer cells and result in cell cycle arrest and 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): Romidepsin exhibited linear pharmacokinetics at standard doses. •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): 44.5L •Protein binding (Drug A): 15% •Protein binding (Drug B): Highly protein bound in plasma (92%-94%) •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): Romidepsin undergoes extensive hepatic metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6 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): 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): Approximately 3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 8.4L/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): Risk factor D in pregnancy. It is not known if romidepsin is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother. The majority of patients receiving romidepsin experience nausea, vomiting, and anorexia. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Istodax •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): Romidepsin is a histone deacetylase (HDAC) inhibitor used to treat cutaneous T-cell lymphoma. 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 Ropivacaine interact?

•Drug A: Buserelin •Drug B: Ropivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Ropivacaine. •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): Ropivacaine is indicated in adult patients for the induction of regional or local anesthesia for surgery or acute pain 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): In contrast to most other local anesthetics, the presence of epinephrine does not affect the time of onset, duration of action, or the systemic absorption of ropivacaine. •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 like ropivacaine block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Specifically, they block the sodium channel and decrease chances of depolarization and consequent action potentials. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. •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): Ropivacaine pharmacokinetics are highly dependent on the dose, route of administration, and patient condition. Following epidural administration ropivacaine undergoes complete and biphasic 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): Following intravascular infusion, ropivacaine has a steady-state volume of distribution of 41 ± 7 liters. Ropivacaine is able to readily cross the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ropivacaine is 94% protein-bound in plasma, primarily to α1-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): Ropivacaine undergoes extensive metabolism, primarily via CYP1A2-mediated aromatic hydroxylation to 3-OH-ropivacaine. The main metabolites excreted in the urine are the N-dealkylated metabolite (PPX) and 3-OH-ropivacaine. Other identified metabolites include 4-OH-ropivacaine, the 3-hydroxy-N-dealkylated (3-OH-PPX) and 4-hydroxy-N-dealkylated (4-OH-PPX) metabolites, and 2-hydroxy-methyl-ropivacaine (which has been identified but not quantified). Unbound PPX, 3-hydroxy-, and 4-hydroxy-ropivacaine have demonstrated pharmacological activity in animal models less than that of ropivacaine. •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, 86% of the administered dose of ropivacaine is excreted in the urine, 1% of which comprises 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): The mean terminal half-life of ropivacaine is 1.8 ± 0.7 hours after intravascular administration and 4.2 ± 1 hour after epidural administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, ropivacaine has a mean plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 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): High systemic doses of ropivacaine can result in central nervous system (CNS) and cardiovascular effects, with the CNS effects usually occurring at lower blood plasma concentrations and additional cardiovascular effects occurring at higher concentrations (although cardiovascular collapse may occur at lower concentrations). CNS effects include CNS excitation involving nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, and seizures. CNS depressant effects may follow, associated with drowsiness, loss of consciousness, respiratory depression and apnea. Cardiovascular events may be caused by hypoxemia secondary to respiratory depression and include hypotension, bradycardia, arrhythmias, and/or cardiac arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Naropin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-ropivacaine Ropivacaina Ropivacaine Ropivacainum •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): Ropivacaine is an amide-type local anesthetic used for local or regional anesthesia during surgery and for short-term management of acute 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 Ropivacaine interact? Information: •Drug A: Buserelin •Drug B: Ropivacaine •Severity: MODERATE •Description: The risk or severity of methemoglobinemia can be increased when Buserelin is combined with Ropivacaine. •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): Ropivacaine is indicated in adult patients for the induction of regional or local anesthesia for surgery or acute pain 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): In contrast to most other local anesthetics, the presence of epinephrine does not affect the time of onset, duration of action, or the systemic absorption of ropivacaine. •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 like ropivacaine block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Specifically, they block the sodium channel and decrease chances of depolarization and consequent action potentials. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. •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): Ropivacaine pharmacokinetics are highly dependent on the dose, route of administration, and patient condition. Following epidural administration ropivacaine undergoes complete and biphasic 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): Following intravascular infusion, ropivacaine has a steady-state volume of distribution of 41 ± 7 liters. Ropivacaine is able to readily cross the placenta. •Protein binding (Drug A): 15% •Protein binding (Drug B): Ropivacaine is 94% protein-bound in plasma, primarily to α1-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): Ropivacaine undergoes extensive metabolism, primarily via CYP1A2-mediated aromatic hydroxylation to 3-OH-ropivacaine. The main metabolites excreted in the urine are the N-dealkylated metabolite (PPX) and 3-OH-ropivacaine. Other identified metabolites include 4-OH-ropivacaine, the 3-hydroxy-N-dealkylated (3-OH-PPX) and 4-hydroxy-N-dealkylated (4-OH-PPX) metabolites, and 2-hydroxy-methyl-ropivacaine (which has been identified but not quantified). Unbound PPX, 3-hydroxy-, and 4-hydroxy-ropivacaine have demonstrated pharmacological activity in animal models less than that of ropivacaine. •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, 86% of the administered dose of ropivacaine is excreted in the urine, 1% of which comprises 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): The mean terminal half-life of ropivacaine is 1.8 ± 0.7 hours after intravascular administration and 4.2 ± 1 hour after epidural administration. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous administration, ropivacaine has a mean plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 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): High systemic doses of ropivacaine can result in central nervous system (CNS) and cardiovascular effects, with the CNS effects usually occurring at lower blood plasma concentrations and additional cardiovascular effects occurring at higher concentrations (although cardiovascular collapse may occur at lower concentrations). CNS effects include CNS excitation involving nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, and seizures. CNS depressant effects may follow, associated with drowsiness, loss of consciousness, respiratory depression and apnea. Cardiovascular events may be caused by hypoxemia secondary to respiratory depression and include hypotension, bradycardia, arrhythmias, and/or cardiac arrest. •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Naropin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-ropivacaine Ropivacaina Ropivacaine Ropivacainum •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): Ropivacaine is an amide-type local anesthetic used for local or regional anesthesia during surgery and for short-term management of acute 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 Rosiglitazone interact?

•Drug A: Buserelin •Drug B: Rosiglitazone •Severity: MODERATE •Description: The therapeutic efficacy of Rosiglitazone 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): Rosiglitazone 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): When rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over 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): Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to 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): The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C max and a delay in T max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range. •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): 17.6 L [oral volume of distribution Vss/F] 13.5 L [population mean, pediatric patients] •Protein binding (Drug A): 15% •Protein binding (Drug B): 99.8% bound 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): Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone. •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 or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, 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): 3-4 hours (single oral dose, independent of dose) •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting] Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting] Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting] Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed] 3.15 L/hr [Population mean, Pediatric patients] •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): Side effects include fluid retention, congestive heart failure (CHF), liver disease •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Avandamet, Avandia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Rosiglitazon Rosiglitazona Rosiglitazone Rosiglitazonum •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): Rosiglitazone is a thiazolidinedione indicated as an adjunct to diet and exercise to maintain glycemic control in type 2 diabetes.

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 Rosiglitazone interact? Information: •Drug A: Buserelin •Drug B: Rosiglitazone •Severity: MODERATE •Description: The therapeutic efficacy of Rosiglitazone 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): Rosiglitazone 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): When rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over 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): Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to 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): The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C max and a delay in T max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range. •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): 17.6 L [oral volume of distribution Vss/F] 13.5 L [population mean, pediatric patients] •Protein binding (Drug A): 15% •Protein binding (Drug B): 99.8% bound 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): Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone. •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 or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, 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): 3-4 hours (single oral dose, independent of dose) •Clearance (Drug A): No clearance available •Clearance (Drug B): Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting] Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting] Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting] Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed] 3.15 L/hr [Population mean, Pediatric patients] •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): Side effects include fluid retention, congestive heart failure (CHF), liver disease •Brand Names (Drug A): Suprefact •Brand Names (Drug B): Avandamet, Avandia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Rosiglitazon Rosiglitazona Rosiglitazone Rosiglitazonum •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): Rosiglitazone is a thiazolidinedione indicated as an adjunct to diet and exercise to maintain glycemic control in type 2 diabetes. 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 Tolbutamide interact?

•Drug A: Buserelin •Drug B: Tolbutamide •Severity: MODERATE •Description: The therapeutic efficacy of Tolbutamide 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 (non-insulin-dependent diabetes mellitus) 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): Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. •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 lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. •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 following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. •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 95% 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): Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. •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): Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 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 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. •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 = 2600 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolbutamida Tolbutamide Tolbutamidum Tolylsulfonylbutylurea •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): Tolbutamide is a sulfonylurea 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 Tolbutamide interact? Information: •Drug A: Buserelin •Drug B: Tolbutamide •Severity: MODERATE •Description: The therapeutic efficacy of Tolbutamide 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 (non-insulin-dependent diabetes mellitus) 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): Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. •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 lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. •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 following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. •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 95% 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): Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. •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): Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 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 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. •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 = 2600 mg/kg •Brand Names (Drug A): Suprefact •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolbutamida Tolbutamide Tolbutamidum Tolylsulfonylbutylurea •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): Tolbutamide is a sulfonylurea 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.