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Does Abciximab and Secukinumab interact?

•Drug A: Abciximab •Drug B: Secukinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Secukinumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Secukinumab is indicated the treatment of moderate to severe plaque psoriasis in patients six years and older who are candidates for systemic therapy or phototherapy. In Europe, the drug is used in children and adolescents six to 18 years of age for this indication. It is also indicated for the treatment of active psoriatic arthritis (PsA). In the US, it is approved for patients two years of age and older while in Europe, it is used alone or in combination with methotrexate in patients six years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy. Secukinumab is also indicated in the treatment of active enthesitis-related arthritis (ERA). In the US, it is approved for patients four year of age and older. In Europe, it is used alone or in combination with methotrexate in patients six years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy. In the US, secukinumab is indicated for the treatment of adults with active ankylosing spondylitis, non-radiographic axial spondyloarthritis with objective signs of inflammation, moderate to severe hidradenitis suppurativa. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Secukinumab works to ameliorate inflammation in chronic inflammatory disorders by attenuating the release of proinflammatory cytokines and chemokines. Total serum IL-17A levels, representing free IL-17A and secukinumab-IL-17A complex, were increased to a plateau during drug treatment, then gradually decreased at the end of the treatment as the secukinumab-IL-17A complex was cleared from the body. In patients with plaque psoriasis, secukinumab reduced erythema, induration, and desquamation in plaque psoriasis lesions. Secukinumab also reduced acanthosis, parakeratosis, keratinocyte proliferation, and decrease in keratinocyte markers - all clinical manifestations of psoriasis. As the formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation, secukinumab can potentially alter the concentrations of CYP substrate drugs with a narrow therapeutic index. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin-17 (IL-17) is a family of proinflammatory cytokines that mediate normal inflammatory and immune responses. The production of IL-17 is mostly promoted by T cells, such as T-helper-17 (Th17) cells, but can also be caused by mast cells and neutrophils. IL-17 binds to IL-17 receptors, which are expressed on various cell types, including keratinocytes. IL-17 signalling pathway promotes angiogenesis and the release of proinflammatory cytokines, chemokines, and mediators of tissue damage. IL-17A is a member of IL-17 with the most prominent role in host defence and autoimmunity. IL-17A is often upregulated in several autoimmune disorders, such as psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis, making it an important therapeutic target. IL-17A is also more potent than IL-17F, another member of IL-17, with a much greater affinity to the IL-17 receptor. Secukinumab selectively binds to and inhibits IL-17A, preventing its interaction with the IL-17 receptor and activation of the IL-17 receptor signalling pathway associated with inflammatory processes. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following a single subcutaneous dose of either 150 mg - which is one-half the recommended dose - in patients with plaque psoriasis, the mean C max and serum trough concentrations were 13.7 ± 4.8 mcg/mL and 22.8 ± 10.2 mcg/mL, respectively. Following administration of 300 mg, the mean C max and serum trough concentrations were 27.3 ± 9.5 mcg/mL and 45.4 ± 21.2 mcg/mL, respectively. Following subcutaneous injection, the C max is reached in five to six days. Steady-state concentrations were achieved by week 24 following the every 4-week dosing regimens. In healthy subjects and subjects with plaque psoriasis, bioavailability ranged from 55% to 77% following subcutaneous administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean volume of distribution during the terminal phase (V z ) ranged from 7.10 to 8.60 L in plaque psoriasis subjects who received secukinumab intravenously. These values suggest that secukinumab undergoes limited distribution to peripheral compartments. The volume of distribution increases with body weight. Following subcutaneous administration of a single 300 mg dose, drug concentrations in interstitial fluid in lesional and non-lesional skin of plaque psoriasis subjects ranged from 27% to 40% of those in serum at one and two weeks. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Secukinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life ranged from 22 to 31 days in plaque psoriasis subjects following intravenous and subcutaneous administration across all psoriasis trials. The mean elimination half-life was 27 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean systemic clearance (CL) ranged from 0.14 L/day to 0.22 L/day. Clearance of secukinumab is dose- and time-independent, and is expected to increase with body weight. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information available regarding the LD50 of secukinumab. In clinical trials, doses up to 30 mg/kg intravenously have been administered without dose-limiting toxicity. In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Cosentyx •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Secukinumab is an immunomodulating agent and interleukin antagonist used to manage plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, along with other joint inflammatory disorders.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Secukinumab interact? Information: •Drug A: Abciximab •Drug B: Secukinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Secukinumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Secukinumab is indicated the treatment of moderate to severe plaque psoriasis in patients six years and older who are candidates for systemic therapy or phototherapy. In Europe, the drug is used in children and adolescents six to 18 years of age for this indication. It is also indicated for the treatment of active psoriatic arthritis (PsA). In the US, it is approved for patients two years of age and older while in Europe, it is used alone or in combination with methotrexate in patients six years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy. Secukinumab is also indicated in the treatment of active enthesitis-related arthritis (ERA). In the US, it is approved for patients four year of age and older. In Europe, it is used alone or in combination with methotrexate in patients six years and older whose disease has responded inadequately to, or who cannot tolerate, conventional therapy. In the US, secukinumab is indicated for the treatment of adults with active ankylosing spondylitis, non-radiographic axial spondyloarthritis with objective signs of inflammation, moderate to severe hidradenitis suppurativa. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Secukinumab works to ameliorate inflammation in chronic inflammatory disorders by attenuating the release of proinflammatory cytokines and chemokines. Total serum IL-17A levels, representing free IL-17A and secukinumab-IL-17A complex, were increased to a plateau during drug treatment, then gradually decreased at the end of the treatment as the secukinumab-IL-17A complex was cleared from the body. In patients with plaque psoriasis, secukinumab reduced erythema, induration, and desquamation in plaque psoriasis lesions. Secukinumab also reduced acanthosis, parakeratosis, keratinocyte proliferation, and decrease in keratinocyte markers - all clinical manifestations of psoriasis. As the formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation, secukinumab can potentially alter the concentrations of CYP substrate drugs with a narrow therapeutic index. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin-17 (IL-17) is a family of proinflammatory cytokines that mediate normal inflammatory and immune responses. The production of IL-17 is mostly promoted by T cells, such as T-helper-17 (Th17) cells, but can also be caused by mast cells and neutrophils. IL-17 binds to IL-17 receptors, which are expressed on various cell types, including keratinocytes. IL-17 signalling pathway promotes angiogenesis and the release of proinflammatory cytokines, chemokines, and mediators of tissue damage. IL-17A is a member of IL-17 with the most prominent role in host defence and autoimmunity. IL-17A is often upregulated in several autoimmune disorders, such as psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis, making it an important therapeutic target. IL-17A is also more potent than IL-17F, another member of IL-17, with a much greater affinity to the IL-17 receptor. Secukinumab selectively binds to and inhibits IL-17A, preventing its interaction with the IL-17 receptor and activation of the IL-17 receptor signalling pathway associated with inflammatory processes. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following a single subcutaneous dose of either 150 mg - which is one-half the recommended dose - in patients with plaque psoriasis, the mean C max and serum trough concentrations were 13.7 ± 4.8 mcg/mL and 22.8 ± 10.2 mcg/mL, respectively. Following administration of 300 mg, the mean C max and serum trough concentrations were 27.3 ± 9.5 mcg/mL and 45.4 ± 21.2 mcg/mL, respectively. Following subcutaneous injection, the C max is reached in five to six days. Steady-state concentrations were achieved by week 24 following the every 4-week dosing regimens. In healthy subjects and subjects with plaque psoriasis, bioavailability ranged from 55% to 77% following subcutaneous administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean volume of distribution during the terminal phase (V z ) ranged from 7.10 to 8.60 L in plaque psoriasis subjects who received secukinumab intravenously. These values suggest that secukinumab undergoes limited distribution to peripheral compartments. The volume of distribution increases with body weight. Following subcutaneous administration of a single 300 mg dose, drug concentrations in interstitial fluid in lesional and non-lesional skin of plaque psoriasis subjects ranged from 27% to 40% of those in serum at one and two weeks. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Secukinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life ranged from 22 to 31 days in plaque psoriasis subjects following intravenous and subcutaneous administration across all psoriasis trials. The mean elimination half-life was 27 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean systemic clearance (CL) ranged from 0.14 L/day to 0.22 L/day. Clearance of secukinumab is dose- and time-independent, and is expected to increase with body weight. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information available regarding the LD50 of secukinumab. In clinical trials, doses up to 30 mg/kg intravenously have been administered without dose-limiting toxicity. In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Cosentyx •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Secukinumab is an immunomodulating agent and interleukin antagonist used to manage plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, along with other joint inflammatory disorders. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Selegiline interact?

•Drug A: Abciximab •Drug B: Selegiline •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Selegiline is combined with Abciximab. •Extended Description: It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Monotherapy for initial treatment of Parkinson's disease, as well as an adjunct therapy in patients with a decreased response to levodopa/carbadopa. Also used for the palliative treatment of mild to moderate Alzheimer's disease and at higher doses, for the treatment of depression. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Dopamine is an essential chemical that occurs in many parts of the body. It is the premature degradation of dopamine that results in the symptoms of Parkinson's disease. Monoamine oxidase (MAO) is an enzyme which accelerates the breakdown of dopamine. Selegiline can prolong the effects of dopamine in the brain by preventing its breakdown through seletively blocking MAO-B. It also may prevent the removal of dopamine between nerve endings and enhance release of dopamine from nerve cells. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Although the mechanisms for selegiline's beneficial action in the treatment of Parkinson's disease are not fully understood, the selective, irreversible inhibition of monoamine oxidase type B (MAO-B) is thought to be of primary importance. MAO-B is involved in the oxidative deamination of dopamine in the brain. Selegiline binds to MAO-B within the nigrostriatal pathways in the central nervous system, thus blocking microsomal metabolism of dopamine and enhancing the dopaminergic activity in the substantial nigra. Selegiline may also increase dopaminergic activity through mechanisms other than inhibition of MAO-B. At higher doses, selegiline can also inhibit monozmine oxidase type A (MAO-A), allowing it to be used for the treatment of depression. •Absorption (Drug A): No absorption available •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 99.5% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.2-2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): LD 50 =63 mg/kg (rats, IV) •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Emsam, Zelapar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): L-Deprenalin Selegilina Selegiline Selegilinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Selegiline is a monoamine oxidase inhibitor used to treat major depressive disorder and Parkinson's.

It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. The severity of the interaction is moderate.

Question: Does Abciximab and Selegiline interact? Information: •Drug A: Abciximab •Drug B: Selegiline •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Selegiline is combined with Abciximab. •Extended Description: It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Monotherapy for initial treatment of Parkinson's disease, as well as an adjunct therapy in patients with a decreased response to levodopa/carbadopa. Also used for the palliative treatment of mild to moderate Alzheimer's disease and at higher doses, for the treatment of depression. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Dopamine is an essential chemical that occurs in many parts of the body. It is the premature degradation of dopamine that results in the symptoms of Parkinson's disease. Monoamine oxidase (MAO) is an enzyme which accelerates the breakdown of dopamine. Selegiline can prolong the effects of dopamine in the brain by preventing its breakdown through seletively blocking MAO-B. It also may prevent the removal of dopamine between nerve endings and enhance release of dopamine from nerve cells. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Although the mechanisms for selegiline's beneficial action in the treatment of Parkinson's disease are not fully understood, the selective, irreversible inhibition of monoamine oxidase type B (MAO-B) is thought to be of primary importance. MAO-B is involved in the oxidative deamination of dopamine in the brain. Selegiline binds to MAO-B within the nigrostriatal pathways in the central nervous system, thus blocking microsomal metabolism of dopamine and enhancing the dopaminergic activity in the substantial nigra. Selegiline may also increase dopaminergic activity through mechanisms other than inhibition of MAO-B. At higher doses, selegiline can also inhibit monozmine oxidase type A (MAO-A), allowing it to be used for the treatment of depression. •Absorption (Drug A): No absorption available •Absorption (Drug B): Rapidly absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 99.5% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.2-2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): LD 50 =63 mg/kg (rats, IV) •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Emsam, Zelapar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): L-Deprenalin Selegilina Selegiline Selegilinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Selegiline is a monoamine oxidase inhibitor used to treat major depressive disorder and Parkinson's. Output: It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. The severity of the interaction is moderate.

Does Abciximab and Sertraline interact?

•Drug A: Abciximab •Drug B: Sertraline •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Sertraline is combined with Abciximab. •Extended Description: The concomitant use of sertraline and anticoagulants can increase the risk of bleeding due to additive effects. Clinical studies and case reports have shown an association between serotonin reuptake inhibitors (such as sertraline) and increased incidence of gastrointestinal bleeding. Effects that also may occur include, epistaxis, ecchymosis, hematoma, and petechiae. In some cases severe and fatal hemorrhage can occur. Platelets normally release serotonin after a vascular injury, leading to vasoconstriction and alterations in platelet shape that ultimately lead to platelet aggregation. SSRI drugs such as sertraline are inhibitors of the serotonin transporter, which normally facilitates the uptake of serotonin into platelets, which cannot synthesize serotonin themselves. Reducing the amount of serotonin that is taken up into the cell inhibits the formation of clots, thereby increasing the risk of bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sertraline is indicated for the management of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder (PD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder (SAD). Common off-label uses for sertraline include the prevention of post stroke depression, generalized anxiety disorder (GAD), fibromyalgia, premature ejaculation, migraine prophylaxis, diabetic neuropathy, and neurocardiogenic syncope. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sertraline improves or relieves the symptoms of depression, OCD, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder via the inhibition of serotonin reuptake. Clinical studies have shown that it improves cognition in depressed patients. It has less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because it does not exert significant anticholinergic, antihistamine, or adrenergic (alpha1, alpha2, beta) blocking activity. The onset of action and beneficial effects are usually noticed after 4-6 weeks, for reasons that are not fully understood and currently under investigation. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sertraline selectively inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, thereby increasing serotonergic activity. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. These changes are believed to be responsible for the antidepressant action and beneficial effects in obsessive-compulsive (and other anxiety related disorders). It has been hypothesized that obsessive-compulsive disorder, like depression, is also caused by the disregulation of serotonin. In animal studies, chronic administration of sertraline results in down-regulation of brain norepinephrine receptors. Sertraline displays affinity for sigma-1 and 2 receptor binding sites, but binds with stronger affinity to sigma-1 binding sites. In vitro, sertraline shows little to no affinity for GABA, dopaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. It exerts weak inhibitory actions on the neuronal uptake of norepinephrine and dopamine and exhibits no inhibitory effects on the monoamine oxidase enzyme. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following once-daily administration of 50 to 200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours after administration, and measured at 20 to 55 μg/L. Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. Bioavailability has been estimated to be above 44%. The area under the curve in healthy volunteers after a 100mg dose of sertraline was 456 μg × h/mL in one study. Effects of food on absorption The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food. For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2.5 hours. For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20L/kg. Post-mortem studies in humans have measured liver tissue concentrations of 3.9–20 mg/kg for sertraline and between 1.4 to 11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS). Studies have also determined sertraline distributes into the brain, plasma, and serum. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sertraline is highly bound to serum proteins, at about 98%-99%. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sertraline is heavily metabolized in the liver and has one major active metabolite. It undergoes N-demethylation to form N-desmethylsertraline, which is much less potent in its pharmacological activity than sertraline. In addition to N-demethylation, sertraline metabolism involves N-hydroxylation, oxidative deamination, and finally, glucuronidation. The metabolism of sertraline is mainly catalyzed by CYP3A4 and CYP2B6, with some activity accounted for by CYP2C19 and CYP2D6. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life of sertraline is approximately 26 hours. One reference mentions an elimination half-life ranging from 22-36 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In pharmacokinetic studies, the clearance of a 200mg dose of sertraline in studies of both young and elderly patients ranged between 1.09 ± 0.38 L/h/kg - 1.35 ± 0.67 L/h/kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The LD50 of sertraline is >2000 mg/kg in rats according to the FDA label. One other references indicates an oral LD50 of in mice and rats of 419 - 548 mg/kg and 1327 - 1591mg/kg, respectively. The most common signs and symptoms associated with a non-fatal sertraline overdose are somnolence, vomiting, tachycardia, nausea, dizziness, agitation, and tremor. No cases of fatal overdose with only sertraline have been reported. Most fatal cases are associated with the ingestion of sertraline with other drugs. Consequences of a sertraline overdose may include serotonin syndrome, hypertension, hypotension, syncope, stupor, coma, bradycardia, bundle branch block, QT-prolongation, torsade de pointes, delirium, hallucinations, and pancreatitis. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zoloft •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sertralina Sertraline Sertralinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sertraline is a selective serotonin reuptake inhibitor (SSRI) indicated to treat major depressive disorder, social anxiety disorder and many other psychiatric conditions.

The concomitant use of sertraline and anticoagulants can increase the risk of bleeding due to additive effects. Clinical studies and case reports have shown an association between serotonin reuptake inhibitors (such as sertraline) and increased incidence of gastrointestinal bleeding. Effects that also may occur include, epistaxis, ecchymosis, hematoma, and petechiae. In some cases severe and fatal hemorrhage can occur. Platelets normally release serotonin after a vascular injury, leading to vasoconstriction and alterations in platelet shape that ultimately lead to platelet aggregation. SSRI drugs such as sertraline are inhibitors of the serotonin transporter, which normally facilitates the uptake of serotonin into platelets, which cannot synthesize serotonin themselves. Reducing the amount of serotonin that is taken up into the cell inhibits the formation of clots, thereby increasing the risk of bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Sertraline interact? Information: •Drug A: Abciximab •Drug B: Sertraline •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Sertraline is combined with Abciximab. •Extended Description: The concomitant use of sertraline and anticoagulants can increase the risk of bleeding due to additive effects. Clinical studies and case reports have shown an association between serotonin reuptake inhibitors (such as sertraline) and increased incidence of gastrointestinal bleeding. Effects that also may occur include, epistaxis, ecchymosis, hematoma, and petechiae. In some cases severe and fatal hemorrhage can occur. Platelets normally release serotonin after a vascular injury, leading to vasoconstriction and alterations in platelet shape that ultimately lead to platelet aggregation. SSRI drugs such as sertraline are inhibitors of the serotonin transporter, which normally facilitates the uptake of serotonin into platelets, which cannot synthesize serotonin themselves. Reducing the amount of serotonin that is taken up into the cell inhibits the formation of clots, thereby increasing the risk of bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sertraline is indicated for the management of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder (PD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder (SAD). Common off-label uses for sertraline include the prevention of post stroke depression, generalized anxiety disorder (GAD), fibromyalgia, premature ejaculation, migraine prophylaxis, diabetic neuropathy, and neurocardiogenic syncope. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sertraline improves or relieves the symptoms of depression, OCD, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder via the inhibition of serotonin reuptake. Clinical studies have shown that it improves cognition in depressed patients. It has less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because it does not exert significant anticholinergic, antihistamine, or adrenergic (alpha1, alpha2, beta) blocking activity. The onset of action and beneficial effects are usually noticed after 4-6 weeks, for reasons that are not fully understood and currently under investigation. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sertraline selectively inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, thereby increasing serotonergic activity. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. These changes are believed to be responsible for the antidepressant action and beneficial effects in obsessive-compulsive (and other anxiety related disorders). It has been hypothesized that obsessive-compulsive disorder, like depression, is also caused by the disregulation of serotonin. In animal studies, chronic administration of sertraline results in down-regulation of brain norepinephrine receptors. Sertraline displays affinity for sigma-1 and 2 receptor binding sites, but binds with stronger affinity to sigma-1 binding sites. In vitro, sertraline shows little to no affinity for GABA, dopaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. It exerts weak inhibitory actions on the neuronal uptake of norepinephrine and dopamine and exhibits no inhibitory effects on the monoamine oxidase enzyme. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following once-daily administration of 50 to 200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours after administration, and measured at 20 to 55 μg/L. Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. Bioavailability has been estimated to be above 44%. The area under the curve in healthy volunteers after a 100mg dose of sertraline was 456 μg × h/mL in one study. Effects of food on absorption The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food. For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2.5 hours. For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20L/kg. Post-mortem studies in humans have measured liver tissue concentrations of 3.9–20 mg/kg for sertraline and between 1.4 to 11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS). Studies have also determined sertraline distributes into the brain, plasma, and serum. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sertraline is highly bound to serum proteins, at about 98%-99%. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sertraline is heavily metabolized in the liver and has one major active metabolite. It undergoes N-demethylation to form N-desmethylsertraline, which is much less potent in its pharmacological activity than sertraline. In addition to N-demethylation, sertraline metabolism involves N-hydroxylation, oxidative deamination, and finally, glucuronidation. The metabolism of sertraline is mainly catalyzed by CYP3A4 and CYP2B6, with some activity accounted for by CYP2C19 and CYP2D6. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life of sertraline is approximately 26 hours. One reference mentions an elimination half-life ranging from 22-36 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In pharmacokinetic studies, the clearance of a 200mg dose of sertraline in studies of both young and elderly patients ranged between 1.09 ± 0.38 L/h/kg - 1.35 ± 0.67 L/h/kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The LD50 of sertraline is >2000 mg/kg in rats according to the FDA label. One other references indicates an oral LD50 of in mice and rats of 419 - 548 mg/kg and 1327 - 1591mg/kg, respectively. The most common signs and symptoms associated with a non-fatal sertraline overdose are somnolence, vomiting, tachycardia, nausea, dizziness, agitation, and tremor. No cases of fatal overdose with only sertraline have been reported. Most fatal cases are associated with the ingestion of sertraline with other drugs. Consequences of a sertraline overdose may include serotonin syndrome, hypertension, hypotension, syncope, stupor, coma, bradycardia, bundle branch block, QT-prolongation, torsade de pointes, delirium, hallucinations, and pancreatitis. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zoloft •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sertralina Sertraline Sertralinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sertraline is a selective serotonin reuptake inhibitor (SSRI) indicated to treat major depressive disorder, social anxiety disorder and many other psychiatric conditions. Output: The concomitant use of sertraline and anticoagulants can increase the risk of bleeding due to additive effects. Clinical studies and case reports have shown an association between serotonin reuptake inhibitors (such as sertraline) and increased incidence of gastrointestinal bleeding. Effects that also may occur include, epistaxis, ecchymosis, hematoma, and petechiae. In some cases severe and fatal hemorrhage can occur. Platelets normally release serotonin after a vascular injury, leading to vasoconstriction and alterations in platelet shape that ultimately lead to platelet aggregation. SSRI drugs such as sertraline are inhibitors of the serotonin transporter, which normally facilitates the uptake of serotonin into platelets, which cannot synthesize serotonin themselves. Reducing the amount of serotonin that is taken up into the cell inhibits the formation of clots, thereby increasing the risk of bleeding. The severity of the interaction is moderate.

Does Abciximab and Sildenafil interact?

•Drug A: Abciximab •Drug B: Sildenafil •Severity: MINOR •Description: The risk or severity of hemorrhage can be increased when Abciximab is combined with Sildenafil. •Extended Description: Sildenafil treatment can cause epistaxis (i.e. nosebleeds) as a side effect1 - the incidence of epistaxis is higher in patients receiving concomitant therapy with an oral vitamin K antagonist. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor that is predominantly employed for two primary indications: (1) the treatment of erectile dysfunction; and (2) treatment of pulmonary hypertension, where: a) the US FDA specifically indicates sildenafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%); b) the Canadian product monograph specifically indicates sildenafil for the treatment of primary pulmonary arterial hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) in adult patients with WHO functional class II or III who have not responded to conventional therapy. In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy; and c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test). •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient. Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%). In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg. When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses. Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29%. Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 %. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins. Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes. The predominant circulating metabolite results from the N-demethylation of sildenafil. This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug. Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects. This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance documented for sildenafil is 41 L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased. Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures. The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied. Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk. The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available. Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed. This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Liqrev, Revatio, Viagra, Vizarsin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sildenafil Sildenafilo •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sildenafil is a phosphodiesterase inhibitor used for the treatment of erectile dysfunction.

Sildenafil treatment can cause epistaxis (i.e. nosebleeds) as a side effect1 - the incidence of epistaxis is higher in patients receiving concomitant therapy with an oral vitamin K antagonist. The severity of the interaction is minor.

Question: Does Abciximab and Sildenafil interact? Information: •Drug A: Abciximab •Drug B: Sildenafil •Severity: MINOR •Description: The risk or severity of hemorrhage can be increased when Abciximab is combined with Sildenafil. •Extended Description: Sildenafil treatment can cause epistaxis (i.e. nosebleeds) as a side effect1 - the incidence of epistaxis is higher in patients receiving concomitant therapy with an oral vitamin K antagonist. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor that is predominantly employed for two primary indications: (1) the treatment of erectile dysfunction; and (2) treatment of pulmonary hypertension, where: a) the US FDA specifically indicates sildenafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%); b) the Canadian product monograph specifically indicates sildenafil for the treatment of primary pulmonary arterial hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) in adult patients with WHO functional class II or III who have not responded to conventional therapy. In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy; and c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test). •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient. Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%). In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg. When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses. Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29%. Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 %. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins. Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes. The predominant circulating metabolite results from the N-demethylation of sildenafil. This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug. Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects. This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The total body clearance documented for sildenafil is 41 L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased. Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures. The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied. Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk. The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available. Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed. This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Liqrev, Revatio, Viagra, Vizarsin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sildenafil Sildenafilo •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sildenafil is a phosphodiesterase inhibitor used for the treatment of erectile dysfunction. Output: Sildenafil treatment can cause epistaxis (i.e. nosebleeds) as a side effect1 - the incidence of epistaxis is higher in patients receiving concomitant therapy with an oral vitamin K antagonist. The severity of the interaction is minor.

Does Abciximab and Siltuximab interact?

•Drug A: Abciximab •Drug B: Siltuximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Siltuximab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Siltuximab is indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Siltuximab did not bind to virally produced IL-6 in a nonclinical study and was therefore not studied in patients with MCD who are HIV or HHV-8 positive. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods, therefore measurement of serum or plasma IL-6 concentrations should not be used as a pharmacodynamic marker during treatment. As well, cytochrome P450 enzymes in the liver are down regulated by infection and inflammation stimuli, which includes cytokines such as IL-6. By preventing IL-6 signalling through treatment with siltuximab, CYP450 activity may be increased leading to faster metabolism of drugs that are CYP450 substrates. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Siltuximab complexes with human IL-6 and prevents binding to soluble and membrane-bound IL-6 receptors, thereby inhibiting the proliferation of lymphocytes. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As siltuximab is an antibody, the expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean terminal half life after the first intravenous infusion of 11 mg/kg is 20.6 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Body weight was identified as the only statistically significant covariate of siltuximab clearance, therefore body weight based dosing is appropriate. Based on population pharmacokinetic analysis, the clearance of situximab in patients is 0.23 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The most common side effects that occurred during siltuximab treatment were pruritis, increased weight, rash, hyperuricemia, and upper respiratory tract infection. Siltuximab should not be administered to patients with severe infections as it may mask signs and symptoms of acute inflammation including suppression of fever and acute phase reactants such as C-reactive protein (CRP). Gastrointestinal perforation has been reported in clinical trials, therefore use with caution in patients who may be at increased risk for GI perforation. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Sylvant •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Siltuximab is an interleukin antagonist used to treat multicentric Castleman's disease (MCD) in patients who are HIV and HHV-8 negative.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Siltuximab interact? Information: •Drug A: Abciximab •Drug B: Siltuximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Siltuximab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Siltuximab is indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Siltuximab did not bind to virally produced IL-6 in a nonclinical study and was therefore not studied in patients with MCD who are HIV or HHV-8 positive. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods, therefore measurement of serum or plasma IL-6 concentrations should not be used as a pharmacodynamic marker during treatment. As well, cytochrome P450 enzymes in the liver are down regulated by infection and inflammation stimuli, which includes cytokines such as IL-6. By preventing IL-6 signalling through treatment with siltuximab, CYP450 activity may be increased leading to faster metabolism of drugs that are CYP450 substrates. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Siltuximab complexes with human IL-6 and prevents binding to soluble and membrane-bound IL-6 receptors, thereby inhibiting the proliferation of lymphocytes. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As siltuximab is an antibody, the expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean terminal half life after the first intravenous infusion of 11 mg/kg is 20.6 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Body weight was identified as the only statistically significant covariate of siltuximab clearance, therefore body weight based dosing is appropriate. Based on population pharmacokinetic analysis, the clearance of situximab in patients is 0.23 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The most common side effects that occurred during siltuximab treatment were pruritis, increased weight, rash, hyperuricemia, and upper respiratory tract infection. Siltuximab should not be administered to patients with severe infections as it may mask signs and symptoms of acute inflammation including suppression of fever and acute phase reactants such as C-reactive protein (CRP). Gastrointestinal perforation has been reported in clinical trials, therefore use with caution in patients who may be at increased risk for GI perforation. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Sylvant •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Siltuximab is an interleukin antagonist used to treat multicentric Castleman's disease (MCD) in patients who are HIV and HHV-8 negative. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Sirolimus interact?

•Drug A: Abciximab •Drug B: Sirolimus •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sirolimus. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. It is also used to treat lymphangioleiomyomatosis. In the US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months. Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued. Topical sirolimus is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients six years of age and older. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sirolimus is an immunosuppressant drug with antifungal and antitumour effects. In animal models, sirolimus prolonged allograft survival following various organ transplants and reversed an acute rejection of heart and kidney allografts in rats. Upon oral administration of 2 mg/day and 5 mg/day, sirolimus significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at six months following transplantation compared with either azathioprine or placebo. In some studies, the immunosuppressive effect of sirolimus lasted up to six months after discontinuation of therapy: this tolerization effect is alloantigen-specific. Sirolimus potently inhibits antigen-induced proliferation of T cells, B cells, and antibody production. In rodent models of autoimmune disease, sirolimus suppressed immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sirolimus works by inhibiting T-lymphocyte activation and proliferation stimulated by antigens and cytokines such as interleukin (IL)-2, IL-4, and IL-15. In target cells, sirolimus binds to the cytoplasmic receptor FK506-binding protein-12 (FKBP12), an immunophilin, to form an immunosuppressive complex. FKBP12-sirolimus complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, survival, mobility, and angiogenesis. mTOR regulates the downstream signalling pathways involved in cell survival, such as the phosphatidylinositol-3 kinase (PI3K)/Akt signalling pathway. Inhibition of mTOR leads to the suppression of cytokine-driven T-cell proliferation, thus the progression from the G1 to the S phase of the cell cycle is inhibited. Sirolimus also inhibits antibody production. In vitro, sirolimus and other mTOR inhibitors inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphangioleiomyomatosis is a disorder that primarily affects the lungs. It is characterized by lung tissue infiltration, unregulated alveolar smooth muscle proliferation, and cystic destruction of parenchyma. Although infrequent, it occurs as a symptomatic pulmonary complication in tuberous sclerosis complex (TSC), which is an inherited disorder caused by mutations in TSC genes. Loss of functional TSC gene leads to the aberrant activation of the mTOR signalling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and proliferation of alveolar smooth muscle cell proliferation. •Absorption (Drug A): No absorption available •Absorption (Drug B): In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to a C max of 14.4 ± 5.3 ng/mL for oral solution and 15.0 ± 4.9 ng/mL for oral tablets. The t max was 2.1 ± 0.8 hours for oral solution and 3.5 ± 2.4 hours for oral tablets. In healthy subjects, the t max is one hour. In a multi-dose study, steady-state was reached six days following repeated twice-daily administration without an initial loading dose, with the average trough concentration of sirolimus increased approximately 2- to 3-fold. It is suspected that a loading dose of three times the maintenance dose will provide near steady-state concentrations within one day in most patients. The systemic availability of sirolimus is approximately 14%. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 L in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (V ss/F ) of sirolimus is 12 ± 8 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sirolimus is 92% bound to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sirolimus undergoes extensive metabolism in the intestinal wall and liver. Sirolimus is primarily metabolized by O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive. Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following oral administration of [ C] sirolimus in healthy subjects, about 91% of the radioactivity was recovered from feces and only 2.2% of the radioactivity was detected in urine. Some of the metabolites of sirolimus are also detectable in feces and urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to oral clearance of 173 ± 50 mL/h/kg for oral solution and 139 ± 63 mL/h/kg for oral tablets. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral LD 50 of sirolimus is 800 mg/kg in rats and 2500 mg/kg in mouse. Sirolimus is a narrow therapeutic index drug. Although there are reports of overdose with sirolimus, there is limited information on overdose in the clinical setting. Symptoms of overdose are consistent with the adverse effects of sirolimus. General supportive measures are recommended in the event of an overdose. Because sirolimus has low aqueous solubility and high erythrocyte and plasma protein binding, it is not expected to be dialyzable to any significant extent. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Fyarro, Hyftor, Rapamune •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Rapamycin Sirolimús Sirolimus Sirolimusum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sirolimus is an mTOR inhibitor immunosuppressant used to prevent organ transplant rejections, treat lymphangioleiomyomatosis, and treat adults with perivascular epithelioid cell tumors.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Sirolimus interact? Information: •Drug A: Abciximab •Drug B: Sirolimus •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sirolimus. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. It is also used to treat lymphangioleiomyomatosis. In the US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months. Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued. Topical sirolimus is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients six years of age and older. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sirolimus is an immunosuppressant drug with antifungal and antitumour effects. In animal models, sirolimus prolonged allograft survival following various organ transplants and reversed an acute rejection of heart and kidney allografts in rats. Upon oral administration of 2 mg/day and 5 mg/day, sirolimus significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at six months following transplantation compared with either azathioprine or placebo. In some studies, the immunosuppressive effect of sirolimus lasted up to six months after discontinuation of therapy: this tolerization effect is alloantigen-specific. Sirolimus potently inhibits antigen-induced proliferation of T cells, B cells, and antibody production. In rodent models of autoimmune disease, sirolimus suppressed immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sirolimus works by inhibiting T-lymphocyte activation and proliferation stimulated by antigens and cytokines such as interleukin (IL)-2, IL-4, and IL-15. In target cells, sirolimus binds to the cytoplasmic receptor FK506-binding protein-12 (FKBP12), an immunophilin, to form an immunosuppressive complex. FKBP12-sirolimus complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, survival, mobility, and angiogenesis. mTOR regulates the downstream signalling pathways involved in cell survival, such as the phosphatidylinositol-3 kinase (PI3K)/Akt signalling pathway. Inhibition of mTOR leads to the suppression of cytokine-driven T-cell proliferation, thus the progression from the G1 to the S phase of the cell cycle is inhibited. Sirolimus also inhibits antibody production. In vitro, sirolimus and other mTOR inhibitors inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphangioleiomyomatosis is a disorder that primarily affects the lungs. It is characterized by lung tissue infiltration, unregulated alveolar smooth muscle proliferation, and cystic destruction of parenchyma. Although infrequent, it occurs as a symptomatic pulmonary complication in tuberous sclerosis complex (TSC), which is an inherited disorder caused by mutations in TSC genes. Loss of functional TSC gene leads to the aberrant activation of the mTOR signalling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and proliferation of alveolar smooth muscle cell proliferation. •Absorption (Drug A): No absorption available •Absorption (Drug B): In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to a C max of 14.4 ± 5.3 ng/mL for oral solution and 15.0 ± 4.9 ng/mL for oral tablets. The t max was 2.1 ± 0.8 hours for oral solution and 3.5 ± 2.4 hours for oral tablets. In healthy subjects, the t max is one hour. In a multi-dose study, steady-state was reached six days following repeated twice-daily administration without an initial loading dose, with the average trough concentration of sirolimus increased approximately 2- to 3-fold. It is suspected that a loading dose of three times the maintenance dose will provide near steady-state concentrations within one day in most patients. The systemic availability of sirolimus is approximately 14%. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 L in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (V ss/F ) of sirolimus is 12 ± 8 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sirolimus is 92% bound to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sirolimus undergoes extensive metabolism in the intestinal wall and liver. Sirolimus is primarily metabolized by O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive. Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following oral administration of [ C] sirolimus in healthy subjects, about 91% of the radioactivity was recovered from feces and only 2.2% of the radioactivity was detected in urine. Some of the metabolites of sirolimus are also detectable in feces and urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to oral clearance of 173 ± 50 mL/h/kg for oral solution and 139 ± 63 mL/h/kg for oral tablets. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral LD 50 of sirolimus is 800 mg/kg in rats and 2500 mg/kg in mouse. Sirolimus is a narrow therapeutic index drug. Although there are reports of overdose with sirolimus, there is limited information on overdose in the clinical setting. Symptoms of overdose are consistent with the adverse effects of sirolimus. General supportive measures are recommended in the event of an overdose. Because sirolimus has low aqueous solubility and high erythrocyte and plasma protein binding, it is not expected to be dialyzable to any significant extent. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Fyarro, Hyftor, Rapamune •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Rapamycin Sirolimús Sirolimus Sirolimusum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sirolimus is an mTOR inhibitor immunosuppressant used to prevent organ transplant rejections, treat lymphangioleiomyomatosis, and treat adults with perivascular epithelioid cell tumors. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Sodium citrate interact?

•Drug A: Abciximab •Drug B: Sodium citrate •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sodium citrate. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used as an anticoagulant during plasmophoresis as well as a neutralizing agent in the treatment of upset stomach and acidic urine. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Citrate prevents activation of the clotting cascade by chelating calcium ions. Citrate neutralizes acid in the stomach and urine, raising the pH. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Citrate chelates free calcium ions preventing them from forming a complex with tissue factor and coagulation factor VIIa to promote the activation of coagulation factor X. This inhibits the extrinsic initiation of the coagulation cascade. Citrate may also exert an anticoagulant effect via a so far unknown mechanism as restoration of calcium concentration does not fully reverse the effect of citrate. Citrate is a weak base and so reacts with hydrochloric acid in the stomach to raise the pH. It it further metabolized to bicarbonate which then acts as a systemic alkalizing agent, raising the pH of the blood and urine. It also acts as a diuretic and increases the urinary excretion of calcium. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tmax of 98-130min. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 19-39L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Citrate is metabolized to bicarbonate in the liver and plays a role as an intermediate in the citric acid cycle. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Largely eliminated through hepatic metabolism with very little cleared by the kidneys. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 18-54 min •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance of 313-1107mL/min. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Overdose toxicity is mainly due to alkalosis as well as tetany or depressed heart function due to lack of free calcium. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): As 3, Bss, Bss Ophthalmic Solution, Cpda-1 Blood Collection System, Dalmacol, EnLyte, Intersol, Leukotrap, Nauzene, Oracit, Tricitrasol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Natrii citras Natrocitral Trisodium citrate concentration Trisodium-citrate •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sodium citrate is an ingredient used for the anticoagulation of whole blood as part of automated apheresis procedures.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Sodium citrate interact? Information: •Drug A: Abciximab •Drug B: Sodium citrate •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sodium citrate. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used as an anticoagulant during plasmophoresis as well as a neutralizing agent in the treatment of upset stomach and acidic urine. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Citrate prevents activation of the clotting cascade by chelating calcium ions. Citrate neutralizes acid in the stomach and urine, raising the pH. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Citrate chelates free calcium ions preventing them from forming a complex with tissue factor and coagulation factor VIIa to promote the activation of coagulation factor X. This inhibits the extrinsic initiation of the coagulation cascade. Citrate may also exert an anticoagulant effect via a so far unknown mechanism as restoration of calcium concentration does not fully reverse the effect of citrate. Citrate is a weak base and so reacts with hydrochloric acid in the stomach to raise the pH. It it further metabolized to bicarbonate which then acts as a systemic alkalizing agent, raising the pH of the blood and urine. It also acts as a diuretic and increases the urinary excretion of calcium. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tmax of 98-130min. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 19-39L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Citrate is metabolized to bicarbonate in the liver and plays a role as an intermediate in the citric acid cycle. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Largely eliminated through hepatic metabolism with very little cleared by the kidneys. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 18-54 min •Clearance (Drug A): No clearance available •Clearance (Drug B): Total clearance of 313-1107mL/min. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Overdose toxicity is mainly due to alkalosis as well as tetany or depressed heart function due to lack of free calcium. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): As 3, Bss, Bss Ophthalmic Solution, Cpda-1 Blood Collection System, Dalmacol, EnLyte, Intersol, Leukotrap, Nauzene, Oracit, Tricitrasol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Natrii citras Natrocitral Trisodium citrate concentration Trisodium-citrate •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sodium citrate is an ingredient used for the anticoagulation of whole blood as part of automated apheresis procedures. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Sorafenib interact?

•Drug A: Abciximab •Drug B: Sorafenib •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sorafenib. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. In the US, it is also indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma that is refractory to radioactive iodine treatment. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sorafenib decreases tumour cell proliferation in vitro. It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines. Antiviral effects of sorafenib have been documented, as it was shown to inhibit hepatitis C viral replication in vitro. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Kinases are involved in tumour cell signalling, proliferation, angiogenesis, and apoptosis. Sorafenib inhibits multiple intracellular serine/threonine kinases in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf, and mutant B-Raf. Sorafenib inhibits cell surface tyrosine kinase receptors such as KIT, FMS-like tyrosine kinase 3 (FLT-3), RET, RET/PTC, vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-β (PDGFR-β). Sorafenib is thought to exhibit a dual mechanism of action: it blocks tumour proliferation and growth by inhibiting the RAF/MEK/extracellular signal-regulated kinase (ERK) pathway on tumour cells, and reduces tumour angiogenesis by inhibiting VEGFR and PDGFR signalling in tumour vasculature. •Absorption (Drug A): No absorption available •Absorption (Drug B): The administration of multiple doses for seven days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2. Mean C max and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. The T max is approximately three hours. The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets. A high-fat meal reduced bioavailability by 29%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Sorafenib is widely distributed to tissues, indicating that it is lipophilic. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, sorafenib is 99.5% bound to human plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sorafenib undergoes oxidative metabolism by CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys. At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma. About eight metabolites of sorafenib have been identified, of which five were detected in plasma. The main circulating metabolite was the pyridine N-oxide form, which comprises approximately 9–16% of the total circulating dose at steady-state: the pharmacological activity of this metabolite was comparable to the parent drug. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following oral administration of a 100 mg dose of sorafenib, about 96% of the dose was recovered within 14 days, with 77% of the dose being excreted in feces and 19% of the dose being excreted in urine as glucuronidated metabolites. Unchanged sorafenib accounted for 51% of the dose excreted in feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean elimination half-life of sorafenib was approximately 25 to 48 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral lowest published toxic dose (Toxic Dose Low, TDLo) is 2.84 mg/kg/21D (intermittent). The oral LD 50 of sorafenib tosylate in rats is >2000 mg/kg. The adverse reactions observed at 800 mg sorafenib twice daily (twice the recommended dose) were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals. The prescribing information recommends the discontinuation of sorafenib treatment and initiation of supportive care in cases of suspected overdose. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Nexavar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sorafenib Sorafénib Sorafenibum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sorafenib is a kinase inhibitor used to treat unresectable liver carcinoma, advanced renal carcinoma, and differentiated thyroid carcinoma.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Sorafenib interact? Information: •Drug A: Abciximab •Drug B: Sorafenib •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sorafenib. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. In the US, it is also indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma that is refractory to radioactive iodine treatment. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sorafenib decreases tumour cell proliferation in vitro. It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines. Antiviral effects of sorafenib have been documented, as it was shown to inhibit hepatitis C viral replication in vitro. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Kinases are involved in tumour cell signalling, proliferation, angiogenesis, and apoptosis. Sorafenib inhibits multiple intracellular serine/threonine kinases in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf, and mutant B-Raf. Sorafenib inhibits cell surface tyrosine kinase receptors such as KIT, FMS-like tyrosine kinase 3 (FLT-3), RET, RET/PTC, vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-β (PDGFR-β). Sorafenib is thought to exhibit a dual mechanism of action: it blocks tumour proliferation and growth by inhibiting the RAF/MEK/extracellular signal-regulated kinase (ERK) pathway on tumour cells, and reduces tumour angiogenesis by inhibiting VEGFR and PDGFR signalling in tumour vasculature. •Absorption (Drug A): No absorption available •Absorption (Drug B): The administration of multiple doses for seven days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2. Mean C max and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. The T max is approximately three hours. The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets. A high-fat meal reduced bioavailability by 29%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Sorafenib is widely distributed to tissues, indicating that it is lipophilic. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, sorafenib is 99.5% bound to human plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sorafenib undergoes oxidative metabolism by CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys. At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma. About eight metabolites of sorafenib have been identified, of which five were detected in plasma. The main circulating metabolite was the pyridine N-oxide form, which comprises approximately 9–16% of the total circulating dose at steady-state: the pharmacological activity of this metabolite was comparable to the parent drug. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following oral administration of a 100 mg dose of sorafenib, about 96% of the dose was recovered within 14 days, with 77% of the dose being excreted in feces and 19% of the dose being excreted in urine as glucuronidated metabolites. Unchanged sorafenib accounted for 51% of the dose excreted in feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean elimination half-life of sorafenib was approximately 25 to 48 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral lowest published toxic dose (Toxic Dose Low, TDLo) is 2.84 mg/kg/21D (intermittent). The oral LD 50 of sorafenib tosylate in rats is >2000 mg/kg. The adverse reactions observed at 800 mg sorafenib twice daily (twice the recommended dose) were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals. The prescribing information recommends the discontinuation of sorafenib treatment and initiation of supportive care in cases of suspected overdose. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Nexavar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sorafenib Sorafénib Sorafenibum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sorafenib is a kinase inhibitor used to treat unresectable liver carcinoma, advanced renal carcinoma, and differentiated thyroid carcinoma. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Sotrovimab interact?

•Drug A: Abciximab •Drug B: Sotrovimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Sotrovimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In Europe, sotrovimab is indicated for the treatment of COVID-19 in patients ≥12 years old and weighing ≥40kg who do not require supplemental oxygen and are at high risk of progressing to severe disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sotrovimab is a monoclonal antibody that treats mild-to-moderate COVID-19 by binding to and neutralizing the spike protein of SARS-CoV-2. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sotrovimab is a recombinant human IgG1κ monoclonal antibody that acts by binding to a conserved epitope located on the spike protein receptor-binding domain of SARS-CoV-2, the virus causing COVID-19. The epitope is highly conserved, discouraging the development of viral resistance to the antibody. This prevents the spike protein mediated binding of SARS-CoV-2 and entry into human cells. Sotrovimab does not compete with human ACE2 receptor binding and inhibits an undefined step that occurs after viral attachment and before the fusion of the viral and cell membranes. The Fc component of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that result in a longer half-life. •Absorption (Drug A): No absorption available •Absorption (Drug B): A non-compartmental analysis determined that the mean Cmax after a 1 hour IV infusion of sotrovimab was 137 µg/mL and the mean Day 29 concentration was 34 µg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Sotrovimab is an Fc-enhanced human immunoglobulin G (IgG), and therefore has the potential for placental transfer. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): This antibody has undergone modifications for a potentially extended half-life and enhanced lung bioavailability. The half-life of sotrovimab is longer than Fc-unmodified IgG due to the LS modification, however, specific values are not available in the literature. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There are currently no data available regarding an overdose with sotrovimab, and LD50 information is not available. If an overdose occurs, provide symptomatic and supportive treatment as required. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sotrovimab is a monoclonal antibody for the treatment of mild-to-moderate COVID-19 in patients at increased risk for death or hospitalization.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Sotrovimab interact? Information: •Drug A: Abciximab •Drug B: Sotrovimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Sotrovimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In Europe, sotrovimab is indicated for the treatment of COVID-19 in patients ≥12 years old and weighing ≥40kg who do not require supplemental oxygen and are at high risk of progressing to severe disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sotrovimab is a monoclonal antibody that treats mild-to-moderate COVID-19 by binding to and neutralizing the spike protein of SARS-CoV-2. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sotrovimab is a recombinant human IgG1κ monoclonal antibody that acts by binding to a conserved epitope located on the spike protein receptor-binding domain of SARS-CoV-2, the virus causing COVID-19. The epitope is highly conserved, discouraging the development of viral resistance to the antibody. This prevents the spike protein mediated binding of SARS-CoV-2 and entry into human cells. Sotrovimab does not compete with human ACE2 receptor binding and inhibits an undefined step that occurs after viral attachment and before the fusion of the viral and cell membranes. The Fc component of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that result in a longer half-life. •Absorption (Drug A): No absorption available •Absorption (Drug B): A non-compartmental analysis determined that the mean Cmax after a 1 hour IV infusion of sotrovimab was 137 µg/mL and the mean Day 29 concentration was 34 µg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Sotrovimab is an Fc-enhanced human immunoglobulin G (IgG), and therefore has the potential for placental transfer. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): This antibody has undergone modifications for a potentially extended half-life and enhanced lung bioavailability. The half-life of sotrovimab is longer than Fc-unmodified IgG due to the LS modification, however, specific values are not available in the literature. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There are currently no data available regarding an overdose with sotrovimab, and LD50 information is not available. If an overdose occurs, provide symptomatic and supportive treatment as required. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sotrovimab is a monoclonal antibody for the treatment of mild-to-moderate COVID-19 in patients at increased risk for death or hospitalization. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Soybean oil interact?

•Drug A: Abciximab •Drug B: Soybean oil •Severity: MINOR •Description: The therapeutic efficacy of Abciximab can be decreased when used in combination with Soybean oil. •Extended Description: Soybean oil is a food source of high vitamin K1.1 Vitamin K1 serves as a vitamin required for blood coagulation,3 and may counteract the anticoagulant activity of vitamin K antagonists such as warfarin. While there were no drug-interaction studies that examined the effect of soybean on the therapeutic efficacy of anticoagulant drugs, one case report documents a patient who was stable on warfarin therapy developing subtherapeutic INR values after ingesting soy milk. The case study suggests the cause of this effect to be increased consumption of vitamin K. Upon discontinuation of the soy milk, INR values returned to therapeutic concentrations within two weeks. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Absorption (Drug A): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Route of elimination (Drug A): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Clearance (Drug A): No clearance available •Toxicity (Drug A): No toxicity available •Brand Names (Drug A): No brand names available •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Summary not found

Soybean oil is a food source of high vitamin K1.1 Vitamin K1 serves as a vitamin required for blood coagulation,3 and may counteract the anticoagulant activity of vitamin K antagonists such as warfarin. While there were no drug-interaction studies that examined the effect of soybean on the therapeutic efficacy of anticoagulant drugs, one case report documents a patient who was stable on warfarin therapy developing subtherapeutic INR values after ingesting soy milk. The case study suggests the cause of this effect to be increased consumption of vitamin K. Upon discontinuation of the soy milk, INR values returned to therapeutic concentrations within two weeks. The severity of the interaction is minor.

Question: Does Abciximab and Soybean oil interact? Information: •Drug A: Abciximab •Drug B: Soybean oil •Severity: MINOR •Description: The therapeutic efficacy of Abciximab can be decreased when used in combination with Soybean oil. •Extended Description: Soybean oil is a food source of high vitamin K1.1 Vitamin K1 serves as a vitamin required for blood coagulation,3 and may counteract the anticoagulant activity of vitamin K antagonists such as warfarin. While there were no drug-interaction studies that examined the effect of soybean on the therapeutic efficacy of anticoagulant drugs, one case report documents a patient who was stable on warfarin therapy developing subtherapeutic INR values after ingesting soy milk. The case study suggests the cause of this effect to be increased consumption of vitamin K. Upon discontinuation of the soy milk, INR values returned to therapeutic concentrations within two weeks. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Absorption (Drug A): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Route of elimination (Drug A): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Clearance (Drug A): No clearance available •Toxicity (Drug A): No toxicity available •Brand Names (Drug A): No brand names available •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Summary not found Output: Soybean oil is a food source of high vitamin K1.1 Vitamin K1 serves as a vitamin required for blood coagulation,3 and may counteract the anticoagulant activity of vitamin K antagonists such as warfarin. While there were no drug-interaction studies that examined the effect of soybean on the therapeutic efficacy of anticoagulant drugs, one case report documents a patient who was stable on warfarin therapy developing subtherapeutic INR values after ingesting soy milk. The case study suggests the cause of this effect to be increased consumption of vitamin K. Upon discontinuation of the soy milk, INR values returned to therapeutic concentrations within two weeks. The severity of the interaction is minor.

Does Abciximab and Spesolimab interact?

•Drug A: Abciximab •Drug B: Spesolimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Spesolimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Spesolimab is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Spesolimab works to reduce inflammation in GPP in a rapid and sustained manner by blocking inflammatory pathways. In clinical trials, spesolimab reduced pustules and improved other disease measures in patients with GPP, irrespective of IL36RN gene mutation status. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Pustular psoriasis is a type of psoriasis, a chronic and recurrent immune-mediated multisystem disorder. Based on the characteristics and distribution of pustules, the disorder has different phenotypes, such as GPP. While the pathophysiology of psoriasis is not fully understood, some pro-inflammatory cytokines involved in innate and adaptive immune systems have been implicated as key mediators of psoriatic disease. Interleukin (IL)-36 is one of those cytokines whereby unregulated activation and expression of IL-36 - often due to IL36RN gene mutations - can result in pathological autoinflammatory responses in pustular psoriasis. IL-36 is expressed in epithelial and immune cells and has three members, IL-36α, IL-36β, and IL-36γ, that bind to a receptor complex to activate pro-inflammatory and pro-fibrotic downstream signalling pathways, such as increased expression and actions of pro-inflammatory cells and factors. The heterodimeric receptor complex IL-36R comprises an IL-1RL2 subunit - to which IL-36 binds - and an IL-1RAcP co-receptor. The exact mechanism of action of spesolimab in managing psoriatic flares is unclear; however, it is believed to ameliorate inflammation by inhibiting IL-36 signalling. Spesolimab binds to the IL-36R receptor complex, preventing the binding of IL-36 downstream activation of receptor signalling pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP, and patients with other diseases. After a single intravenous dose of 900 mg of spesolimab, the population PK model-estimated AUC 0-∞ (95% CI) and C max (95% CI) in a typical anti-drug antibody (ADA)-negative patient with GPP were 4750 (4510, 4970) mcg x day/mL and 238 (218, 256) mcg/mL, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Based on the population pharmacokinetic analysis, the typical total volume of distribution at steady state was 6.4 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information available. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolic pathway of spesolimab-sbzo has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab-sbzo is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): There is no information available. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal half-life is 25.5 (24.4, 26.3) days. •Clearance (Drug A): No clearance available •Clearance (Drug B): In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab-sbzo clearance (95% CI) in a typical GPP patient without anti-drug antibodies, weighing 70 kg was 0.184 (0.175, 0.194) L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information available regarding the LD 50, acute toxicity profile, and overdose of spesolimab. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Spevigo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Spesolimab is an interleukin-36 receptor antagonist used to treat generalized pustular psoriasis flares in adults.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Spesolimab interact? Information: •Drug A: Abciximab •Drug B: Spesolimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Spesolimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Spesolimab is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Spesolimab works to reduce inflammation in GPP in a rapid and sustained manner by blocking inflammatory pathways. In clinical trials, spesolimab reduced pustules and improved other disease measures in patients with GPP, irrespective of IL36RN gene mutation status. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Pustular psoriasis is a type of psoriasis, a chronic and recurrent immune-mediated multisystem disorder. Based on the characteristics and distribution of pustules, the disorder has different phenotypes, such as GPP. While the pathophysiology of psoriasis is not fully understood, some pro-inflammatory cytokines involved in innate and adaptive immune systems have been implicated as key mediators of psoriatic disease. Interleukin (IL)-36 is one of those cytokines whereby unregulated activation and expression of IL-36 - often due to IL36RN gene mutations - can result in pathological autoinflammatory responses in pustular psoriasis. IL-36 is expressed in epithelial and immune cells and has three members, IL-36α, IL-36β, and IL-36γ, that bind to a receptor complex to activate pro-inflammatory and pro-fibrotic downstream signalling pathways, such as increased expression and actions of pro-inflammatory cells and factors. The heterodimeric receptor complex IL-36R comprises an IL-1RL2 subunit - to which IL-36 binds - and an IL-1RAcP co-receptor. The exact mechanism of action of spesolimab in managing psoriatic flares is unclear; however, it is believed to ameliorate inflammation by inhibiting IL-36 signalling. Spesolimab binds to the IL-36R receptor complex, preventing the binding of IL-36 downstream activation of receptor signalling pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP, and patients with other diseases. After a single intravenous dose of 900 mg of spesolimab, the population PK model-estimated AUC 0-∞ (95% CI) and C max (95% CI) in a typical anti-drug antibody (ADA)-negative patient with GPP were 4750 (4510, 4970) mcg x day/mL and 238 (218, 256) mcg/mL, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Based on the population pharmacokinetic analysis, the typical total volume of distribution at steady state was 6.4 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information available. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolic pathway of spesolimab-sbzo has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab-sbzo is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): There is no information available. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal half-life is 25.5 (24.4, 26.3) days. •Clearance (Drug A): No clearance available •Clearance (Drug B): In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab-sbzo clearance (95% CI) in a typical GPP patient without anti-drug antibodies, weighing 70 kg was 0.184 (0.175, 0.194) L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information available regarding the LD 50, acute toxicity profile, and overdose of spesolimab. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Spevigo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Spesolimab is an interleukin-36 receptor antagonist used to treat generalized pustular psoriasis flares in adults. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Streptokinase interact?

•Drug A: Abciximab •Drug B: Streptokinase •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Streptokinase. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of acute evolving transmural myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis or emolism and occlusion of arteriovenous cannulae •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Streptokinase creates an active complex which promotes the cleavage of the Arg/Val bond in plasminogen to form the proteolytic enzyme plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Plasminogen is an inactive molecule that becomes activated to plasmin when the Arg/Val bond is cleaved. Plasmin breaks down fibrin clots created by the blood clotting cascade. Streptokinase forms a highly specific 1:1 enzymatic complex with plasminogen which converts inactive plasminogen molecules into active plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. This in turn leads to the degradation of blood clots. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Streptokinase is a purified fibrinolytic bacterial protein used to breakdown thrombosis in myocardial infarction, pulmonary embolism, and venous thromboembolism.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Streptokinase interact? Information: •Drug A: Abciximab •Drug B: Streptokinase •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Streptokinase. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of acute evolving transmural myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis or emolism and occlusion of arteriovenous cannulae •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Streptokinase creates an active complex which promotes the cleavage of the Arg/Val bond in plasminogen to form the proteolytic enzyme plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Plasminogen is an inactive molecule that becomes activated to plasmin when the Arg/Val bond is cleaved. Plasmin breaks down fibrin clots created by the blood clotting cascade. Streptokinase forms a highly specific 1:1 enzymatic complex with plasminogen which converts inactive plasminogen molecules into active plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. This in turn leads to the degradation of blood clots. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Streptokinase is a purified fibrinolytic bacterial protein used to breakdown thrombosis in myocardial infarction, pulmonary embolism, and venous thromboembolism. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Streptozocin interact?

•Drug A: Abciximab •Drug B: Streptozocin •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Streptozocin. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of malignant neoplasms of pancreas (metastatic islet cell carcinoma). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Streptozocin is an antitumour antibiotic consisting of a nitrosourea moiety interposed between a methyl group and a glucosamine. Streptozocin is indicated in the treatment of metastatic islet cell carcinoma of the pancreas. Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal effects. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Although its mechanism of action is not completely clear, streptozocin is known to inhibit DNA synthesis, interfere with biochemical reactions of NAD and NADH, and inhibit some enzymes involved in gluconeogenesis. Its activity appears to occur as a result of formation of methylcarbonium ions, which alkylate or bind with many intracellular molecular structures including nucleic acids. Its cytotoxic action is probably due to cross-linking of strands of DNA, resulting in inhibition of DNA synthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Poor oral absorption (17-25%) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Primarily hepatic •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5-15 minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include nausea and vomiting, anorexia, myelosuppression; and nephrotoxicity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zanosar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estreptozocina Streptozocin Streptozocine Streptozocinium Streptozocinum Streptozotocin •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Streptozocin is a nitrosourea antineoplastic agent used in the treatment of metastatic pancreatic islet cell carcinoma.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Streptozocin interact? Information: •Drug A: Abciximab •Drug B: Streptozocin •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Streptozocin. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of malignant neoplasms of pancreas (metastatic islet cell carcinoma). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Streptozocin is an antitumour antibiotic consisting of a nitrosourea moiety interposed between a methyl group and a glucosamine. Streptozocin is indicated in the treatment of metastatic islet cell carcinoma of the pancreas. Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal effects. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Although its mechanism of action is not completely clear, streptozocin is known to inhibit DNA synthesis, interfere with biochemical reactions of NAD and NADH, and inhibit some enzymes involved in gluconeogenesis. Its activity appears to occur as a result of formation of methylcarbonium ions, which alkylate or bind with many intracellular molecular structures including nucleic acids. Its cytotoxic action is probably due to cross-linking of strands of DNA, resulting in inhibition of DNA synthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Poor oral absorption (17-25%) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Primarily hepatic •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5-15 minutes •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include nausea and vomiting, anorexia, myelosuppression; and nephrotoxicity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zanosar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estreptozocina Streptozocin Streptozocine Streptozocinium Streptozocinum Streptozotocin •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Streptozocin is a nitrosourea antineoplastic agent used in the treatment of metastatic pancreatic islet cell carcinoma. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Sugammadex interact?

•Drug A: Abciximab •Drug B: Sugammadex •Severity: MINOR •Description: The risk or severity of bleeding and hemorrhage can be increased when Abciximab is combined with Sugammadex. •Extended Description: Coagulopathy and bleeding events have been observed with sugammadex therapy; co-administration of drugs affecting hemostasis and known to cause bleeding, such as anticoagulants, with sugammadex may lead to increased risk for bleeding and hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide in adults and pediatric patients ≥2 years old who are undergoing surgery. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sugammadex is a modified gamma-cyclodextrin which forms very tight water soluble complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium >> pancuronium). Sugammadex creates a concentration gradient which favors movement of rocurionium from the neuromuscular junction into the plasma, which quickly reverses rocuronium-induced neuromuscular blockade. The free rocuronium in the plasma are then bound tightly to sugammadex, assisting the diffusion of the remaining rocuronium molecules out of the neuromuscular junction and increasing bound and free rocuronium in the plasma. •Absorption (Drug A): No absorption available •Absorption (Drug B): Sugammadex is administered intravenously. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): At steady state, the volume of distribution is 11-14 L in adult patients with normal renal function. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sugammadex does not bind plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolites of sugammadex were observed during clinical studies. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Renal excretion of unchanged product. >90 of dose is excreted within 24 hours. 0.02% is excreted in feces and air. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): About 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 88L/min •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Patients with severe renal impairment (with creatinine clearance below 30 mL/min) should avoid use of drug as their clearance of the drug is reduced and there is inconsistent evidence about its safety in this subset of patients. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Bridion •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sugammadex is a modified gamma cyclodextrin used to reverse neuromuscular blockade induced by vecuronium bromide and rocuronium bromide which are agents used for anesthesia.

Coagulopathy and bleeding events have been observed with sugammadex therapy; co-administration of drugs affecting hemostasis and known to cause bleeding, such as anticoagulants, with sugammadex may lead to increased risk for bleeding and hemorrhage. The severity of the interaction is minor.

Question: Does Abciximab and Sugammadex interact? Information: •Drug A: Abciximab •Drug B: Sugammadex •Severity: MINOR •Description: The risk or severity of bleeding and hemorrhage can be increased when Abciximab is combined with Sugammadex. •Extended Description: Coagulopathy and bleeding events have been observed with sugammadex therapy; co-administration of drugs affecting hemostasis and known to cause bleeding, such as anticoagulants, with sugammadex may lead to increased risk for bleeding and hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sugammadex is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide in adults and pediatric patients ≥2 years old who are undergoing surgery. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sugammadex is a modified gamma-cyclodextrin which forms very tight water soluble complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium >> pancuronium). Sugammadex creates a concentration gradient which favors movement of rocurionium from the neuromuscular junction into the plasma, which quickly reverses rocuronium-induced neuromuscular blockade. The free rocuronium in the plasma are then bound tightly to sugammadex, assisting the diffusion of the remaining rocuronium molecules out of the neuromuscular junction and increasing bound and free rocuronium in the plasma. •Absorption (Drug A): No absorption available •Absorption (Drug B): Sugammadex is administered intravenously. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): At steady state, the volume of distribution is 11-14 L in adult patients with normal renal function. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sugammadex does not bind plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolites of sugammadex were observed during clinical studies. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Renal excretion of unchanged product. >90 of dose is excreted within 24 hours. 0.02% is excreted in feces and air. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): About 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 88L/min •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Patients with severe renal impairment (with creatinine clearance below 30 mL/min) should avoid use of drug as their clearance of the drug is reduced and there is inconsistent evidence about its safety in this subset of patients. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Bridion •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sugammadex is a modified gamma cyclodextrin used to reverse neuromuscular blockade induced by vecuronium bromide and rocuronium bromide which are agents used for anesthesia. Output: Coagulopathy and bleeding events have been observed with sugammadex therapy; co-administration of drugs affecting hemostasis and known to cause bleeding, such as anticoagulants, with sugammadex may lead to increased risk for bleeding and hemorrhage. The severity of the interaction is minor.

Does Abciximab and Sulfasalazine interact?

•Drug A: Abciximab •Drug B: Sulfasalazine •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Sulfasalazine is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In the US, sulfasalazine is indicated to treat mild to moderate ulcerative colitis and to prolong the remission period between acute attacks of ulcerative colitis. Sulfasalazine is also indicated as an adjunct therapy in severe ulcerative colitis. For the delayed-release tablet formulation, sulfasalazine is also indicated to treat rheumatoid arthritis in pediatric patients who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs or polyarticular-course juvenile rheumatoid arthritis with the same patients' characteristics. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid have indicated that the major therapeutic action may reside in the 5-aminosalicylic acid moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Although the exact mechanism of action of sulfasalazine is not fully understood, it is thought to be mediated through the inhibition of various inflammatory molecules. Research have found that sulfasalazine and its metabolites, mesalazine and sulfapyridine, can inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathway. Specific enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following oral administration of 1 g of sulfasalazine to 9 healthy males, less than 15% of a dose of sulfasalazine is absorbed as the parent drug. Detectable serum concentrations of sulfasalazine have been found in healthy subjects within 90 minutes after ingestion. Maximum concentrations of sulfasalazine occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous injection, the calculated volume of distribution for sulfasalazine was 7.5 ± 1.6 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sulfasalazine is highly bound to albumin (>99.3%) while sulfapyridine is only about 70% bound to albumin. Acetylsulfapyridine, the principal metabolite of sulfapyridine, is approximately 90% bound to plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): In the intestine, sulfasalazine is metabolized by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid. Of the two species, sulfapyridine is relatively well absorbed from the intestine and highly metabolized, while 5-aminosalicylic acid is much less well absorbed. Approximately 15% of a dose of sulfasalazine is absorbed as the parent drug and is metabolized to some extent in the liver to the same two species. Sulfapyridine can also be metabolized to 5-hydroxysulfapyridine and N-acetyl-5-hydroxy sulfapyridine. 5-aminosalicylic acid is primarily metabolized in both the liver and intestine to N-acetyl-5 aminosalicylic acid via a non-acetylation phenotype-dependent route. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hours. In fast acetylators, the mean plasma half-life of sulfapyridine is 10.4 hours while in slow acetylators, it is 14.8 hours. Due to low plasma levels produced by 5-aminosalicylic acid after oral administration, reliable estimates of plasma half-life are not possible. •Clearance (Drug A): No clearance available •Clearance (Drug B): The calculated clearance of sulfasalazine following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Two-year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2), and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed an equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated IBD pregnancies as well as to pregnancies in the general population. A study of 1,455 pregnancies associated with exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation. A review of the medical literature covering 1,155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population. No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Azulfidine, Salazopyrin, Salazopyrin En-tabs •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azopyrin Salazosulfapiridina Salazosulfapyridine Salazosulfapyridinum Salicylazosulfapyridine Sulfasalazin Sulfasalazina Sulfasalazine Sulfasalazinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulfasalazine is a salicylate used to treat Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Sulfasalazine interact? Information: •Drug A: Abciximab •Drug B: Sulfasalazine •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Sulfasalazine is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In the US, sulfasalazine is indicated to treat mild to moderate ulcerative colitis and to prolong the remission period between acute attacks of ulcerative colitis. Sulfasalazine is also indicated as an adjunct therapy in severe ulcerative colitis. For the delayed-release tablet formulation, sulfasalazine is also indicated to treat rheumatoid arthritis in pediatric patients who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs or polyarticular-course juvenile rheumatoid arthritis with the same patients' characteristics. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid have indicated that the major therapeutic action may reside in the 5-aminosalicylic acid moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Although the exact mechanism of action of sulfasalazine is not fully understood, it is thought to be mediated through the inhibition of various inflammatory molecules. Research have found that sulfasalazine and its metabolites, mesalazine and sulfapyridine, can inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathway. Specific enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following oral administration of 1 g of sulfasalazine to 9 healthy males, less than 15% of a dose of sulfasalazine is absorbed as the parent drug. Detectable serum concentrations of sulfasalazine have been found in healthy subjects within 90 minutes after ingestion. Maximum concentrations of sulfasalazine occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous injection, the calculated volume of distribution for sulfasalazine was 7.5 ± 1.6 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sulfasalazine is highly bound to albumin (>99.3%) while sulfapyridine is only about 70% bound to albumin. Acetylsulfapyridine, the principal metabolite of sulfapyridine, is approximately 90% bound to plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): In the intestine, sulfasalazine is metabolized by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid. Of the two species, sulfapyridine is relatively well absorbed from the intestine and highly metabolized, while 5-aminosalicylic acid is much less well absorbed. Approximately 15% of a dose of sulfasalazine is absorbed as the parent drug and is metabolized to some extent in the liver to the same two species. Sulfapyridine can also be metabolized to 5-hydroxysulfapyridine and N-acetyl-5-hydroxy sulfapyridine. 5-aminosalicylic acid is primarily metabolized in both the liver and intestine to N-acetyl-5 aminosalicylic acid via a non-acetylation phenotype-dependent route. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hours. In fast acetylators, the mean plasma half-life of sulfapyridine is 10.4 hours while in slow acetylators, it is 14.8 hours. Due to low plasma levels produced by 5-aminosalicylic acid after oral administration, reliable estimates of plasma half-life are not possible. •Clearance (Drug A): No clearance available •Clearance (Drug B): The calculated clearance of sulfasalazine following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Two-year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2), and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed an equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated IBD pregnancies as well as to pregnancies in the general population. A study of 1,455 pregnancies associated with exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation. A review of the medical literature covering 1,155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population. No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Azulfidine, Salazopyrin, Salazopyrin En-tabs •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azopyrin Salazosulfapiridina Salazosulfapyridine Salazosulfapyridinum Salicylazosulfapyridine Sulfasalazin Sulfasalazina Sulfasalazine Sulfasalazinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulfasalazine is a salicylate used to treat Crohn's disease, ulcerative colitis, and rheumatoid arthritis. Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Sulfinpyrazone interact?

•Drug A: Abciximab •Drug B: Sulfinpyrazone •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Sulfinpyrazone is combined with Abciximab. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of gout and gouty arthritis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sulfinpyrazone's pharmacologic activity is the potentiation of the urinary excretion of uric acid. It is useful for reducing the blood urate levels in patients with chronic tophaceous gout and acute intermittent gout, and for promoting the resorption of tophi. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sulfinpyrazone is an oral uricosuric agent (pyrazolone derivative) used to treat chronic or intermittent gouty arthritis. Sulfinpyrazone competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby facilitating urinary excretion of uric acid and decreasing plasma urate concentrations. This is likely done through inhibition of the urate anion transporter (hURAT1) as well as the human organic anion transporter 4 (hOAT4). Sulfinpyrazone is not intended for the treatment of acute attacks because it lacks therapeutically useful analgesic and anti-inflammatory effects. Sulfinpyrazone and its sulfide metabolite possess COX inhibitory effects. Sulfinpyrazone has also been shown to be a UDP-glucuronsyltransferase inhibitor and a very potent CYP2C9 inhibitor. Sulfinpyrazone is also known to be a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor as well as an inhibitor of several multridrug resistance proteins (MRPs). •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98-99% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Approximately 4-6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include nausea, vomiting, diarrhea, epigastric pain, ataxia, labored respiration, convulsions, coma. Possible symptoms, seen after overdosage with other pyrazolone derivatives: anemia, jaundice, and ulceration. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sulfinpyrazone Sulfoxyphenylpyrazolidine Sulphinpyrazone •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulfinpyrazone is a platelet inhibitory and uricosuric agent used to inhibit thrombotic and embolic processes and to manage the chronic phases of gout .

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Sulfinpyrazone interact? Information: •Drug A: Abciximab •Drug B: Sulfinpyrazone •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Sulfinpyrazone is combined with Abciximab. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of gout and gouty arthritis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sulfinpyrazone's pharmacologic activity is the potentiation of the urinary excretion of uric acid. It is useful for reducing the blood urate levels in patients with chronic tophaceous gout and acute intermittent gout, and for promoting the resorption of tophi. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sulfinpyrazone is an oral uricosuric agent (pyrazolone derivative) used to treat chronic or intermittent gouty arthritis. Sulfinpyrazone competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby facilitating urinary excretion of uric acid and decreasing plasma urate concentrations. This is likely done through inhibition of the urate anion transporter (hURAT1) as well as the human organic anion transporter 4 (hOAT4). Sulfinpyrazone is not intended for the treatment of acute attacks because it lacks therapeutically useful analgesic and anti-inflammatory effects. Sulfinpyrazone and its sulfide metabolite possess COX inhibitory effects. Sulfinpyrazone has also been shown to be a UDP-glucuronsyltransferase inhibitor and a very potent CYP2C9 inhibitor. Sulfinpyrazone is also known to be a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor as well as an inhibitor of several multridrug resistance proteins (MRPs). •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98-99% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Approximately 4-6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include nausea, vomiting, diarrhea, epigastric pain, ataxia, labored respiration, convulsions, coma. Possible symptoms, seen after overdosage with other pyrazolone derivatives: anemia, jaundice, and ulceration. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sulfinpyrazone Sulfoxyphenylpyrazolidine Sulphinpyrazone •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulfinpyrazone is a platelet inhibitory and uricosuric agent used to inhibit thrombotic and embolic processes and to manage the chronic phases of gout . Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Sulindac interact?

•Drug A: Abciximab •Drug B: Sulindac •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Sulindac is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For acute or long-term use in the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sulindac is a non-steroidal anti-inflammatory indene derivative, also possessing analgesic and antipyretic activities. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sulindac's exact mechanism of action is unknown. Its antiinflammatory effects are believed to be due to inhibition of both COX-1 and COX-2 which leads to the inhibition of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Approximately 90% absorbed in humans following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At 1 mcg/ml concentrations, approximately 93% sulindac and 98% of its sulfide metabolite are bound to human serum albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Undergoes two major biotransformations: reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Sulindac and its sulfide and sulfone metabolites undergo extensive enterohepatic circulation. Available evidence indicates that the biological activity resides with the sulfide metabolite. Side chain hydroxylation and hydration of the double bond also occur. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk. Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Hepatic metabolism is an important elimination pathway. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean half-life of sulindac is 7.8 hours while the mean half-life of the sulfide metabolite is 16.4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal cl=68.12 +/- 27.56 mL/min [NORMAL (19-41 yrs)] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Acute oral toxicity (LD 50 ) in rats is 264 mg/kg. Cases of overdose have been reported and rarely, deaths have occurred. The following signs and symptoms may be observed following overdose: stupor, coma, diminished urine output and hypotension. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sulindac Sulindaco Sulindacum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulindac is an NSAID used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute subacromial bursitis or supraspinatus tendinitis, and acute gouty arthritis.

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Sulindac interact? Information: •Drug A: Abciximab •Drug B: Sulindac •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Sulindac is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For acute or long-term use in the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sulindac is a non-steroidal anti-inflammatory indene derivative, also possessing analgesic and antipyretic activities. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Sulindac's exact mechanism of action is unknown. Its antiinflammatory effects are believed to be due to inhibition of both COX-1 and COX-2 which leads to the inhibition of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Approximately 90% absorbed in humans following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At 1 mcg/ml concentrations, approximately 93% sulindac and 98% of its sulfide metabolite are bound to human serum albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Undergoes two major biotransformations: reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Sulindac and its sulfide and sulfone metabolites undergo extensive enterohepatic circulation. Available evidence indicates that the biological activity resides with the sulfide metabolite. Side chain hydroxylation and hydration of the double bond also occur. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk. Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Hepatic metabolism is an important elimination pathway. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean half-life of sulindac is 7.8 hours while the mean half-life of the sulfide metabolite is 16.4 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal cl=68.12 +/- 27.56 mL/min [NORMAL (19-41 yrs)] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Acute oral toxicity (LD 50 ) in rats is 264 mg/kg. Cases of overdose have been reported and rarely, deaths have occurred. The following signs and symptoms may be observed following overdose: stupor, coma, diminished urine output and hypotension. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sulindac Sulindaco Sulindacum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulindac is an NSAID used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute subacromial bursitis or supraspinatus tendinitis, and acute gouty arthritis. Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Sulodexide interact?

•Drug A: Abciximab •Drug B: Sulodexide •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sulodexide. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sulodexide has been used clinically for the prophylaxis and treatment of vascular diseases with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarc-tion. Also investigated in the treatment of diabetic kidney disease and diabetic neuropathy. New anti-inflammatory properties have also extended its use in venous disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sulodexide is extensively absorbed owing to its low molecular weight compared to unfractionated heparin. It offers the potential advantages of a longer half-life and reduced global anticoagulation effects, properties which differ from other glycosaminoglycans. Sulodexide potentiates antithrombin III and heparin cofactor II due to the presence of both glycoaminoglycan fractions. It is capable of inhibiting both anti-IIa and anti-Xa. It promotes fibrinolytic activity by releasing tissue plasminogen activator and reduces plasminogen activator inhibitor. The drug also blocks platelet adhesion and platelet function induced by cathepsin G and thrombin. Research has also shown that Sulodexide had endothelial protective properties by inducing the overexpression of growth factors important for the protection of organs. It has anti-inflammatory properties via its effect on the release of inflammatory mediators from macrophages. This results in anti-proliferative effects such as the regulation of growth factors like VEGF and FGF. The intravenous administration has also been shown capable of releasing tissue factor pathway inhibitor from the endothelium, which also contributes to the anti-thrombotic effects of Sulodexide. Lastly, this drug is known for its ability to inhibit the secretion of MMPs, particularly MMP-9, from leukocytes in a dose dependent manner, resulting in the restoration of the balance with their tissue inhibitors. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Thrombin inhibition produced by sulodexide is due to the additive effect of its components, namely, heparin cofactor II (HCII) catalysis by dermatan sulfate and antithrombin-III catalysis by fast moving heparin (FMH). •Absorption (Drug A): No absorption available •Absorption (Drug B): Sulodexide can be administered via the oral route, IV and IM routes. After oral dosing, the absorption rate being equivalent, the bioavailability is 40-60%. either calculated from the fast-moving heparin fraction or from the dermatan fraction. Bioavailability following IM administration is approximately 90%. After a rapid absorption in the intestine, the dermatan and heparin components start to appear in the plasma. Sulodexide is degraded after ingestion and loses its sulfate groups and both sulfated and unsulfated groups circulate in the blood for up to 24hours. AUC=22.83+/-4.44mg.h/L. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Cmax=516+/-77.54ng/mL, Tmax=1.33+/-0.58h, Vd=71.24+/-14.06L (b phase). Sulodexide reaches high concentrations in the plasma and is widely distributed in the endothelial layer. Binding to endothelial cell receptors in arteries and veins contributes to its rapid distribution profile. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): It is mainly metabolized in the liver. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Sulodexide is eliminated via the renal, fecal and bile routes. The main clearance occurs renally and accounts for elimination of 55+2.9% of the drug over 96 hours. The fecal and bile routes remove the rest of the drug over 48 hours, which accounts for 23.5+/-2.5% for both routes. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life was 11.7 +/- 2.0 h after intravenous administration, 18.7 +/- 4.1 h after 50 mg per os, and 25.8 +/- 1.9 h after 100 mg per os. •Clearance (Drug A): No clearance available •Clearance (Drug B): 2.70+/-0.58L/h •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Sulodexide seems to be well tolerated. Most adverse effects reported are related to the GI system and seem to be transient in nature. Among others adverse reactions are diarrhea, epigastralgia, dyspepsia, heartburn and dizziness. Allergic reactions, such as skin rash, have also been reported but are very rare. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulodexide is a drug used to treat chronic venous ulcers in the legs.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Sulodexide interact? Information: •Drug A: Abciximab •Drug B: Sulodexide •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Sulodexide. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sulodexide has been used clinically for the prophylaxis and treatment of vascular diseases with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarc-tion. Also investigated in the treatment of diabetic kidney disease and diabetic neuropathy. New anti-inflammatory properties have also extended its use in venous disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Sulodexide is extensively absorbed owing to its low molecular weight compared to unfractionated heparin. It offers the potential advantages of a longer half-life and reduced global anticoagulation effects, properties which differ from other glycosaminoglycans. Sulodexide potentiates antithrombin III and heparin cofactor II due to the presence of both glycoaminoglycan fractions. It is capable of inhibiting both anti-IIa and anti-Xa. It promotes fibrinolytic activity by releasing tissue plasminogen activator and reduces plasminogen activator inhibitor. The drug also blocks platelet adhesion and platelet function induced by cathepsin G and thrombin. Research has also shown that Sulodexide had endothelial protective properties by inducing the overexpression of growth factors important for the protection of organs. It has anti-inflammatory properties via its effect on the release of inflammatory mediators from macrophages. This results in anti-proliferative effects such as the regulation of growth factors like VEGF and FGF. The intravenous administration has also been shown capable of releasing tissue factor pathway inhibitor from the endothelium, which also contributes to the anti-thrombotic effects of Sulodexide. Lastly, this drug is known for its ability to inhibit the secretion of MMPs, particularly MMP-9, from leukocytes in a dose dependent manner, resulting in the restoration of the balance with their tissue inhibitors. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Thrombin inhibition produced by sulodexide is due to the additive effect of its components, namely, heparin cofactor II (HCII) catalysis by dermatan sulfate and antithrombin-III catalysis by fast moving heparin (FMH). •Absorption (Drug A): No absorption available •Absorption (Drug B): Sulodexide can be administered via the oral route, IV and IM routes. After oral dosing, the absorption rate being equivalent, the bioavailability is 40-60%. either calculated from the fast-moving heparin fraction or from the dermatan fraction. Bioavailability following IM administration is approximately 90%. After a rapid absorption in the intestine, the dermatan and heparin components start to appear in the plasma. Sulodexide is degraded after ingestion and loses its sulfate groups and both sulfated and unsulfated groups circulate in the blood for up to 24hours. AUC=22.83+/-4.44mg.h/L. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Cmax=516+/-77.54ng/mL, Tmax=1.33+/-0.58h, Vd=71.24+/-14.06L (b phase). Sulodexide reaches high concentrations in the plasma and is widely distributed in the endothelial layer. Binding to endothelial cell receptors in arteries and veins contributes to its rapid distribution profile. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): It is mainly metabolized in the liver. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Sulodexide is eliminated via the renal, fecal and bile routes. The main clearance occurs renally and accounts for elimination of 55+2.9% of the drug over 96 hours. The fecal and bile routes remove the rest of the drug over 48 hours, which accounts for 23.5+/-2.5% for both routes. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life was 11.7 +/- 2.0 h after intravenous administration, 18.7 +/- 4.1 h after 50 mg per os, and 25.8 +/- 1.9 h after 100 mg per os. •Clearance (Drug A): No clearance available •Clearance (Drug B): 2.70+/-0.58L/h •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Sulodexide seems to be well tolerated. Most adverse effects reported are related to the GI system and seem to be transient in nature. Among others adverse reactions are diarrhea, epigastralgia, dyspepsia, heartburn and dizziness. Allergic reactions, such as skin rash, have also been reported but are very rare. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sulodexide is a drug used to treat chronic venous ulcers in the legs. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Susoctocog alfa interact?

•Drug A: Abciximab •Drug B: Susoctocog alfa •Severity: MAJOR •Description: The therapeutic efficacy of Susoctocog alfa can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for the treatment of bleeding episodes in adults with acquired hemophilia A. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Following susoctocog alfa administration, the activated partial thromboplastin time (aPTT) is expected to normalize indicating restored biological activity of factor VIII and normal clotting time. In a prospective, open-label clinical trail involving 28 subjects with acquired haemophilia A, all subjects had a positive response to treatment for the initial bleeding episodes at 24 hours after dosing where bleeding was either stopped or substantially reduced. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Factor VIII circulates in the plasma as a hemostatically active protein complex that consists of factor VIII and a large carrier protein von Willebrand factor via a non-covalent binding interaction. This protein complex remains inactive until the coagulation cascade is activated which in turn activates factor VIII to be released from factor VIII/von Willebrand factor complex. Activated factor VIII acts as a cofactor for factor IX-mediated conversion of factor X to activated factor X. Activated factor X is critical in converting prothrombin into thrombin and sequentially, thrombin converts fibrinogen to fibrin for the formation of a blood clot. Acquired haemophilia is a rare bleeding disorder where patients with normal Factor VIII genes spontaneously develop inhibitory autoantibodies directed against Factor VIII. These autoantibodies are IgG1 and IgG4 autoantibodies that bind to the A2, A3 and C2 domains of the FVIII molecules to inactivate them. The autoantibodies neutralize circulating human factor VIII and create a functional deficiency of this procoagulant protein. Susoctocog alfa serves to temporarily restore the inhibited endogenous Factor VIII for effective hemostasis. Circulating inhibitory autoantibodies have minimal or no cross-reactivity against susoctocog alfa. •Absorption (Drug A): No absorption available •Absorption (Drug B): The time to reach peak plasma concentrations (Tmax) is approximately 26 minutes or 0.42 hour following intravenous administration of 5000U susoctocog alfa in patients with acquired haemophilia in a non-bleeding state. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous dose of 5000U to patients with acquired haemophilia in a non-bleeding state, the volume of distribution at steady state was 30.7 U/%. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Circulating susoctocog alfa binds to endogenous von Willebrand factor endogenously present in the circulation. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal half-life ranges from 2-17 hours in a non-bleeding state. Following intravenous dose of 5000U to patients with acquired haemophilia in a non-bleeding state, the terminal half life was approximately 3.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous dose of 5000U to patients with acquired haemophilia in a non-bleeding state, the clearance rate was approximately 4.80 U/% * t. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Long-term studies in animals to evaluate the carcinogenic potential, genotoxicity and effects on fertility have not been performed with susoctocog alfa. In repeated-dose studies, the incidence and severity of glomerulopathy observed in monkeys intravenously administered susoctocog alfa at doses of 75, 225 and 750 U/kg/day tended to increase over time. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Obizur •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Susoctocog alfa is a recombinant Factor VIII used to treat and prevent bleeding in hemophilia A.

Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Question: Does Abciximab and Susoctocog alfa interact? Information: •Drug A: Abciximab •Drug B: Susoctocog alfa •Severity: MAJOR •Description: The therapeutic efficacy of Susoctocog alfa can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for the treatment of bleeding episodes in adults with acquired hemophilia A. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Following susoctocog alfa administration, the activated partial thromboplastin time (aPTT) is expected to normalize indicating restored biological activity of factor VIII and normal clotting time. In a prospective, open-label clinical trail involving 28 subjects with acquired haemophilia A, all subjects had a positive response to treatment for the initial bleeding episodes at 24 hours after dosing where bleeding was either stopped or substantially reduced. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Factor VIII circulates in the plasma as a hemostatically active protein complex that consists of factor VIII and a large carrier protein von Willebrand factor via a non-covalent binding interaction. This protein complex remains inactive until the coagulation cascade is activated which in turn activates factor VIII to be released from factor VIII/von Willebrand factor complex. Activated factor VIII acts as a cofactor for factor IX-mediated conversion of factor X to activated factor X. Activated factor X is critical in converting prothrombin into thrombin and sequentially, thrombin converts fibrinogen to fibrin for the formation of a blood clot. Acquired haemophilia is a rare bleeding disorder where patients with normal Factor VIII genes spontaneously develop inhibitory autoantibodies directed against Factor VIII. These autoantibodies are IgG1 and IgG4 autoantibodies that bind to the A2, A3 and C2 domains of the FVIII molecules to inactivate them. The autoantibodies neutralize circulating human factor VIII and create a functional deficiency of this procoagulant protein. Susoctocog alfa serves to temporarily restore the inhibited endogenous Factor VIII for effective hemostasis. Circulating inhibitory autoantibodies have minimal or no cross-reactivity against susoctocog alfa. •Absorption (Drug A): No absorption available •Absorption (Drug B): The time to reach peak plasma concentrations (Tmax) is approximately 26 minutes or 0.42 hour following intravenous administration of 5000U susoctocog alfa in patients with acquired haemophilia in a non-bleeding state. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Following intravenous dose of 5000U to patients with acquired haemophilia in a non-bleeding state, the volume of distribution at steady state was 30.7 U/%. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Circulating susoctocog alfa binds to endogenous von Willebrand factor endogenously present in the circulation. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal half-life ranges from 2-17 hours in a non-bleeding state. Following intravenous dose of 5000U to patients with acquired haemophilia in a non-bleeding state, the terminal half life was approximately 3.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Following intravenous dose of 5000U to patients with acquired haemophilia in a non-bleeding state, the clearance rate was approximately 4.80 U/% * t. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Long-term studies in animals to evaluate the carcinogenic potential, genotoxicity and effects on fertility have not been performed with susoctocog alfa. In repeated-dose studies, the incidence and severity of glomerulopathy observed in monkeys intravenously administered susoctocog alfa at doses of 75, 225 and 750 U/kg/day tended to increase over time. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Obizur •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Susoctocog alfa is a recombinant Factor VIII used to treat and prevent bleeding in hemophilia A. Output: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Does Abciximab and Sutimlimab interact?

•Drug A: Abciximab •Drug B: Sutimlimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Sutimlimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sutimlimab is indicated to treat hemolysis in adults with cold agglutinin disease (CAD) and decrease the need for red blood cell transfusion in these patients. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Following a single sutimlimab injection, >90% inhibition of the complement pathway was observed, and this inhibition was sustained when concentrations of sutimlimab were ≥100 mcg/mL. As sutimlimab can impair the complement-mediated immune response, patients requiring therapy should receive all appropriate vaccinations against encapsulated bacteria at least 2 weeks prior to its initiation. Patients undergoing treatment with sutimlimab are at a higher risk of serious infections, especially those caused by encapsulated bacteria such as Neisseria meningitides or Streptococcus pneumoniae, and should be monitored closely throughout therapy for evidence of developing or ongoing infections. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Hemolysis associated with cold agglutinin disease is driven by the activation of the complement system. Cold agglutinins transiently bind erythrocytes as they circulate through cooler parts of the body (e.g. the extremities) - as they circulate back to warmer areas, C1q esterase activates C4 and C2, which generates C3 convertase, an enzyme which cleaves C3 into C3a and C3b. At this stage, the erythrocytes tagged with C3b can be sequestered by macrophages in the reticuloendothelial system, ultimately leading to extravascular hemolysis. Alternatively, C3b may be further cleaved into C3c and C3d - if complement activation continues past the C3 step, the membrane attack complex with C5b-C9 may form, which causes intravascular hemolysis. Sutimlimab is a humanized IgG4 monoclonal antibody targeted at the complement C1s subunit, a serine protease responsible for the activation of the classic complement pathway. By inhibiting the complement cascade at the level of C1s, sutimlimab prevents the deposition of complement opsinins on erythrocytes, thus preventing their eventual hemolysis. •Absorption (Drug A): No absorption available •Absorption (Drug B): When administered at the approved weight-based recommended dosage, the exposure to sutimlimab increases proportionately with increasing dosage. Steady-state concentrations are achieved by week 7 of therapy. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): At steady-state, the volume of distribution of sutimlimab in patients with cold agglutinin disease was approximately 5.8 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic proteins, sutimlimab likely undergoes catabolism to smaller peptides and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): At the approved recommended dosage, the terminal elimination half-life of sutimlimab is 21 days. The half-life of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •Clearance (Drug A): No clearance available •Clearance (Drug B): At the approved recommended dosage, the clearance of sutimlimab is 0.14 L/day. The clearance of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Enjaymo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sutimlimab •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sutimlimab is a monoclonal antibody directed towards complement subunit C1s used to reduce the need for blood transfusion due to hemolysis in patients with cold agglutinin disease.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Sutimlimab interact? Information: •Drug A: Abciximab •Drug B: Sutimlimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Sutimlimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Sutimlimab is indicated to treat hemolysis in adults with cold agglutinin disease (CAD) and decrease the need for red blood cell transfusion in these patients. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Following a single sutimlimab injection, >90% inhibition of the complement pathway was observed, and this inhibition was sustained when concentrations of sutimlimab were ≥100 mcg/mL. As sutimlimab can impair the complement-mediated immune response, patients requiring therapy should receive all appropriate vaccinations against encapsulated bacteria at least 2 weeks prior to its initiation. Patients undergoing treatment with sutimlimab are at a higher risk of serious infections, especially those caused by encapsulated bacteria such as Neisseria meningitides or Streptococcus pneumoniae, and should be monitored closely throughout therapy for evidence of developing or ongoing infections. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Hemolysis associated with cold agglutinin disease is driven by the activation of the complement system. Cold agglutinins transiently bind erythrocytes as they circulate through cooler parts of the body (e.g. the extremities) - as they circulate back to warmer areas, C1q esterase activates C4 and C2, which generates C3 convertase, an enzyme which cleaves C3 into C3a and C3b. At this stage, the erythrocytes tagged with C3b can be sequestered by macrophages in the reticuloendothelial system, ultimately leading to extravascular hemolysis. Alternatively, C3b may be further cleaved into C3c and C3d - if complement activation continues past the C3 step, the membrane attack complex with C5b-C9 may form, which causes intravascular hemolysis. Sutimlimab is a humanized IgG4 monoclonal antibody targeted at the complement C1s subunit, a serine protease responsible for the activation of the classic complement pathway. By inhibiting the complement cascade at the level of C1s, sutimlimab prevents the deposition of complement opsinins on erythrocytes, thus preventing their eventual hemolysis. •Absorption (Drug A): No absorption available •Absorption (Drug B): When administered at the approved weight-based recommended dosage, the exposure to sutimlimab increases proportionately with increasing dosage. Steady-state concentrations are achieved by week 7 of therapy. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): At steady-state, the volume of distribution of sutimlimab in patients with cold agglutinin disease was approximately 5.8 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic proteins, sutimlimab likely undergoes catabolism to smaller peptides and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): At the approved recommended dosage, the terminal elimination half-life of sutimlimab is 21 days. The half-life of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •Clearance (Drug A): No clearance available •Clearance (Drug B): At the approved recommended dosage, the clearance of sutimlimab is 0.14 L/day. The clearance of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Enjaymo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sutimlimab •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Sutimlimab is a monoclonal antibody directed towards complement subunit C1s used to reduce the need for blood transfusion due to hemolysis in patients with cold agglutinin disease. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Synthetic Conjugated Estrogens, A interact?

•Drug A: Abciximab •Drug B: Synthetic Conjugated Estrogens, A •Severity: MODERATE •Description: Synthetic Conjugated Estrogens, A may decrease the anticoagulant activities of Abciximab. •Extended Description: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of moderate to severe vasomotor symptoms due to menopause and for treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •Absorption (Drug A): No absorption available •Absorption (Drug B): Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several hours •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of baseline-corrected estrone and equilin was found to be 10.6 hr and 9.7 hr, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Cenestin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Synthetic Conjugated Estrogens, A is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal atrophy and dyspareunia.

Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. The severity of the interaction is moderate.

Question: Does Abciximab and Synthetic Conjugated Estrogens, A interact? Information: •Drug A: Abciximab •Drug B: Synthetic Conjugated Estrogens, A •Severity: MODERATE •Description: Synthetic Conjugated Estrogens, A may decrease the anticoagulant activities of Abciximab. •Extended Description: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of moderate to severe vasomotor symptoms due to menopause and for treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •Absorption (Drug A): No absorption available •Absorption (Drug B): Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several hours •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of baseline-corrected estrone and equilin was found to be 10.6 hr and 9.7 hr, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Cenestin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Synthetic Conjugated Estrogens, A is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal atrophy and dyspareunia. Output: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. The severity of the interaction is moderate.

Does Abciximab and Synthetic Conjugated Estrogens, B interact?

•Drug A: Abciximab •Drug B: Synthetic Conjugated Estrogens, B •Severity: MODERATE •Description: Synthetic Conjugated Estrogens, B may decrease the anticoagulant activities of Abciximab. •Extended Description: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of moderate to severe vasomotor symptoms due to menopause and for the treatment of moderate to severe vaginal dryness, pain with intercourse, and symptoms of vulvar and vaginal atrophy due to menopause. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •Absorption (Drug A): No absorption available •Absorption (Drug B): Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The tablets release synthetic conjugated estrogens, B slowly over a period of several hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of baseline-corrected estrone and equilin was found to be 23.46 hr and 15.09 hr, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Enjuvia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Synthetic Conjugated Estrogens, B is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal dryness.

Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. The severity of the interaction is moderate.

Question: Does Abciximab and Synthetic Conjugated Estrogens, B interact? Information: •Drug A: Abciximab •Drug B: Synthetic Conjugated Estrogens, B •Severity: MODERATE •Description: Synthetic Conjugated Estrogens, B may decrease the anticoagulant activities of Abciximab. •Extended Description: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of moderate to severe vasomotor symptoms due to menopause and for the treatment of moderate to severe vaginal dryness, pain with intercourse, and symptoms of vulvar and vaginal atrophy due to menopause. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •Absorption (Drug A): No absorption available •Absorption (Drug B): Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The tablets release synthetic conjugated estrogens, B slowly over a period of several hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of baseline-corrected estrone and equilin was found to be 23.46 hr and 15.09 hr, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Enjuvia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Synthetic Conjugated Estrogens, B is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal dryness. Output: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. The severity of the interaction is moderate.

Does Abciximab and Tacrolimus interact?

•Drug A: Abciximab •Drug B: Tacrolimus •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tacrolimus. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants, and may be used in patients converted from immediate-release formulations. Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable. Both available strengths are indicated in adult patients, while only the lower strength (0.03%) formulation is indicated in pediatric patients between 2 and 15 years of age. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 2.6 ± 2.1 L/kg [pediatric liver transplant patients] 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.040 L/hr/kg [healthy subjects, IV] 0.172 ± 0.088 L/hr/kg [healthy subjects, oral] 0.083 L/hr/kg [adult kidney transplant patients, IV] 0.053 L/hr/kg [adult liver transplant patients, IV] 0.051 L/hr/kg [adult heart transplant patients, IV] 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients] 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients] 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD 50 =134-194 mg/kg (rat). •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Advagraf, Astagraf, Envarsus, Modigraf, Prograf, Protopic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tacrolimus •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tacrolimus is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Tacrolimus interact? Information: •Drug A: Abciximab •Drug B: Tacrolimus •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tacrolimus. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants, and may be used in patients converted from immediate-release formulations. Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable. Both available strengths are indicated in adult patients, while only the lower strength (0.03%) formulation is indicated in pediatric patients between 2 and 15 years of age. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 2.6 ± 2.1 L/kg [pediatric liver transplant patients] 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.040 L/hr/kg [healthy subjects, IV] 0.172 ± 0.088 L/hr/kg [healthy subjects, oral] 0.083 L/hr/kg [adult kidney transplant patients, IV] 0.053 L/hr/kg [adult liver transplant patients, IV] 0.051 L/hr/kg [adult heart transplant patients, IV] 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients] 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients] 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD 50 =134-194 mg/kg (rat). •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Advagraf, Astagraf, Envarsus, Modigraf, Prograf, Protopic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tacrolimus •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tacrolimus is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tafasitamab interact?

•Drug A: Abciximab •Drug B: Tafasitamab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tafasitamab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tafasitamab is indicated, in combination with lenalidomide, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified whom are ineligible for autologous stem cell transplant (ASCT). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tafasitamab induces a reduction in circulating B-cell counts by binding to a surface antigen, CD19, which is important for their survival. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) experienced a 97% reduction in peripheral blood B-cell counts following 8 days of treatment, with a 100% reduction reached within 16 weeks of treatment. Tafasitamab can cause infusion-related reactions, particularly during the initial cycles of therapy. Symptoms may include chills, flushing, dyspnea, and hypertension. Patients may be administered premedications (such as acetaminophen, antihistamines, or glucocorticoids) 0.5 - 2 hours prior to infusion to minimize infusion-related reactions. Tafasitamab may also cause significant myelosuppression, and subsequent infection, due to its mechanism of action - patients should undergo monitoring throughout therapy for signs of myelosuppression and/or infection. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The CD19 surface antigen is a protein expressed on the surface of pre-B and mature B-lymphocytes that appears to play a role in enhancing B-cell receptor signaling and is considered integral to their survival. These surface proteins are also highly expressed on several B-cell malignancies, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and diffuse large B-cell lymphoma (DLBCL). Tafasitamab is a CD19-directed cytolytic monoclonal antibody that, upon binding and blocking the activity of CD19, causes lysis of B-cells. This process is mediated through both direct apoptosis and immune-mediated effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). •Absorption (Drug A): No absorption available •Absorption (Drug B): Following intravenous administration of tafasitamab 12 mg/kg on Days 1, 8, 15, and 22 in cycle(s) 1-3 (with an additional dose on Day 4 of cycle 1), mean trough concentrations were 179 (± 53) μg/mL. From cycle 4 onwards, which involve the administration of tafasitamab 12 mg/kg on Days 1 and 15, mean trough concentrations were 153 (± 68) μg/mL. The overall maximum tafasitamab serum concentrations reached were 483 (± 109) μg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The total volume of distribution of tafasitamab following intravenous injection is approximately 9.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The biotransformation of tafasitamab has not been elucidated. Most monoclonal antibodies undergo intracellular catabolism via lysosomal degradation to smaller amino acids and peptides. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal elimination half-life of tafasitamab is approximately 17 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tafasitamab is approximately 0.41 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Data regarding overdose of tafasitamab are unavailable. Symptoms of overdosage are likely to be consistent with its adverse effect profile, and may therefore involve significant infusion-related reactions and/or myelosuppression. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Monjuvi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tafasitamab is a CD19-directed cytolytic monoclonal antibody used in the treatment of B-cell malignancies.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tafasitamab interact? Information: •Drug A: Abciximab •Drug B: Tafasitamab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tafasitamab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tafasitamab is indicated, in combination with lenalidomide, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified whom are ineligible for autologous stem cell transplant (ASCT). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tafasitamab induces a reduction in circulating B-cell counts by binding to a surface antigen, CD19, which is important for their survival. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) experienced a 97% reduction in peripheral blood B-cell counts following 8 days of treatment, with a 100% reduction reached within 16 weeks of treatment. Tafasitamab can cause infusion-related reactions, particularly during the initial cycles of therapy. Symptoms may include chills, flushing, dyspnea, and hypertension. Patients may be administered premedications (such as acetaminophen, antihistamines, or glucocorticoids) 0.5 - 2 hours prior to infusion to minimize infusion-related reactions. Tafasitamab may also cause significant myelosuppression, and subsequent infection, due to its mechanism of action - patients should undergo monitoring throughout therapy for signs of myelosuppression and/or infection. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The CD19 surface antigen is a protein expressed on the surface of pre-B and mature B-lymphocytes that appears to play a role in enhancing B-cell receptor signaling and is considered integral to their survival. These surface proteins are also highly expressed on several B-cell malignancies, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and diffuse large B-cell lymphoma (DLBCL). Tafasitamab is a CD19-directed cytolytic monoclonal antibody that, upon binding and blocking the activity of CD19, causes lysis of B-cells. This process is mediated through both direct apoptosis and immune-mediated effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). •Absorption (Drug A): No absorption available •Absorption (Drug B): Following intravenous administration of tafasitamab 12 mg/kg on Days 1, 8, 15, and 22 in cycle(s) 1-3 (with an additional dose on Day 4 of cycle 1), mean trough concentrations were 179 (± 53) μg/mL. From cycle 4 onwards, which involve the administration of tafasitamab 12 mg/kg on Days 1 and 15, mean trough concentrations were 153 (± 68) μg/mL. The overall maximum tafasitamab serum concentrations reached were 483 (± 109) μg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The total volume of distribution of tafasitamab following intravenous injection is approximately 9.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The biotransformation of tafasitamab has not been elucidated. Most monoclonal antibodies undergo intracellular catabolism via lysosomal degradation to smaller amino acids and peptides. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal elimination half-life of tafasitamab is approximately 17 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tafasitamab is approximately 0.41 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Data regarding overdose of tafasitamab are unavailable. Symptoms of overdosage are likely to be consistent with its adverse effect profile, and may therefore involve significant infusion-related reactions and/or myelosuppression. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Monjuvi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tafasitamab is a CD19-directed cytolytic monoclonal antibody used in the treatment of B-cell malignancies. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tamoxifen interact?

•Drug A: Abciximab •Drug B: Tamoxifen •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Tamoxifen is combined with Abciximab. •Extended Description: Coadministration of tamoxifen with anticoagulant drugs has been shown to produce an increase in the anticoagulant effect producing cases of bleeding. However, this combination of drugs is concomitantly prescribed as tamoxifen increases the risk of venous thromboembolism. The mechanism of action has not been fully elucidated. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth. Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β. •Absorption (Drug A): No absorption available •Absorption (Drug B): An oral dose of 20mg reaches a C max of 40ng/mL with a T max of 5 hours. The metabolite N-desmethyltamoxifen reaches a C max of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a C ss of 120ng/mL and a C ss of 336ng/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tamoxifen is approximately 50-60L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of tamoxifen in plasma is over 98% and mostly to serum albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Soltamox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tamoxifen Tamoxifène Tamoxifene Tamoxifeno Tamoxifenum trans-Tamoxifen •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tamoxifen is a selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women.

Coadministration of tamoxifen with anticoagulant drugs has been shown to produce an increase in the anticoagulant effect producing cases of bleeding. However, this combination of drugs is concomitantly prescribed as tamoxifen increases the risk of venous thromboembolism. The mechanism of action has not been fully elucidated. The severity of the interaction is moderate.

Question: Does Abciximab and Tamoxifen interact? Information: •Drug A: Abciximab •Drug B: Tamoxifen •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Tamoxifen is combined with Abciximab. •Extended Description: Coadministration of tamoxifen with anticoagulant drugs has been shown to produce an increase in the anticoagulant effect producing cases of bleeding. However, this combination of drugs is concomitantly prescribed as tamoxifen increases the risk of venous thromboembolism. The mechanism of action has not been fully elucidated. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth. Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β. •Absorption (Drug A): No absorption available •Absorption (Drug B): An oral dose of 20mg reaches a C max of 40ng/mL with a T max of 5 hours. The metabolite N-desmethyltamoxifen reaches a C max of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a C ss of 120ng/mL and a C ss of 336ng/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tamoxifen is approximately 50-60L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of tamoxifen in plasma is over 98% and mostly to serum albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Soltamox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tamoxifen Tamoxifène Tamoxifene Tamoxifeno Tamoxifenum trans-Tamoxifen •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tamoxifen is a selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women. Output: Coadministration of tamoxifen with anticoagulant drugs has been shown to produce an increase in the anticoagulant effect producing cases of bleeding. However, this combination of drugs is concomitantly prescribed as tamoxifen increases the risk of venous thromboembolism. The mechanism of action has not been fully elucidated. The severity of the interaction is moderate.

Does Abciximab and Tauroursodeoxycholic acid interact?

•Drug A: Abciximab •Drug B: Tauroursodeoxycholic acid •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tauroursodeoxycholic acid. •Extended Description: Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tauroursodeoxycholic acid is used to prevent and treat gallstone formation. Tauroursodeoxycholic acid is used in combination with phenylbutyric acid to treat amyotrophic lateral sclerosis (ALS) in adults. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tauroursodeoxycholic acid works to decrease bile acid and cholesterol levels. It reduces the cholesterol content and increases the bile acid content in gallbladder bile to prevent the formation of cholesterol gallstones. Tauroursodeoxycholic acid possesses anti-apoptotic and anti-inflammatory properties. These findings provoked the investigations of tauroursodeoxycholic acid as a potential therapeutic agent for neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Other studies also suggest that tauroursodeoxycholic acid can promote angiogenesis and suppress adipogenesis of adipose-derived mesenchymal stem cells (MSCs). Anti-osteoporotic effects of tauroursodeoxycholic acid have also been documented, as it was shown to enhance osteogenic differentiation of bone marrow-derived MSCs. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): About 90% of gallstones are formed by cholesterol, which may be caused by altered gut microbiota from a high-fat diet and other factors. The gut microbiota regulates bile acid metabolism; thus, altered composition in gut microbiota may significantly change the bile acid pool and alter cholesterol secretion. While the exact mechanism of action of tauroursodeoxycholic acid in reducing and preventing gallstone formation is unclear, tauroursodeoxycholic acid may achieve this effect in a number of ways. A recent mouse study suggests that tauroursodeoxycholic acid inhibits intestinal cholesterol absorption and lowers liver cholesterol levels by upregulating the bile acid excretion from the liver to the gallbladder. Tauroursodeoxycholic acid lowers the bile cholesterol saturation in the gallbladder, thereby increasing the solubility of cholesterol in bile. It can also maintain a specific gut microbiota composition to promote the synthesis of bile acids and reduce liver inflammation caused by the lipopolysaccharide in the blood. Ultimately, tauroursodeoxycholic acid enhances the synthesis of bile acids in the liver and reduces cholesterol in the serum and liver. Tauroursodeoxycholic acid inhibits cell apoptosis by disrupting the mitochondrial pathway of cell death. It works by inhibiting oxygen-radical production, ameliorating endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response. Other anti-apoptotic processes mediated by tauroursodeoxycholic acid include cytochrome c release, caspase activation, DNA and nuclear fragmentation, and inhibition of p53 transactivation. It is believed that tauroursodeoxycholic acid works on multiple cellular targets to inhibit apoptosis and upregulate survival pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): There is evidence that tauroursodeoxycholic acid crosses the blood brain barrier in humans. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): There is little biotransformation of tauroursodeoxycholic acid. It is partially deconjugated by intestinal microflora to form unconjugated bile acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information available regarding the LD 50 and overdose of tauroursodeoxycholic acid. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Relyvrio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tauroursodeoxycholic acid is the taurine conjugate of ursodeoxycholic acid with antiapoptotic and ER stress response dampening effects used in some countries to treat gallstones. It is also being investigated for a wide variety of other conditions.

Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Tauroursodeoxycholic acid interact? Information: •Drug A: Abciximab •Drug B: Tauroursodeoxycholic acid •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tauroursodeoxycholic acid. •Extended Description: Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tauroursodeoxycholic acid is used to prevent and treat gallstone formation. Tauroursodeoxycholic acid is used in combination with phenylbutyric acid to treat amyotrophic lateral sclerosis (ALS) in adults. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tauroursodeoxycholic acid works to decrease bile acid and cholesterol levels. It reduces the cholesterol content and increases the bile acid content in gallbladder bile to prevent the formation of cholesterol gallstones. Tauroursodeoxycholic acid possesses anti-apoptotic and anti-inflammatory properties. These findings provoked the investigations of tauroursodeoxycholic acid as a potential therapeutic agent for neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Other studies also suggest that tauroursodeoxycholic acid can promote angiogenesis and suppress adipogenesis of adipose-derived mesenchymal stem cells (MSCs). Anti-osteoporotic effects of tauroursodeoxycholic acid have also been documented, as it was shown to enhance osteogenic differentiation of bone marrow-derived MSCs. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): About 90% of gallstones are formed by cholesterol, which may be caused by altered gut microbiota from a high-fat diet and other factors. The gut microbiota regulates bile acid metabolism; thus, altered composition in gut microbiota may significantly change the bile acid pool and alter cholesterol secretion. While the exact mechanism of action of tauroursodeoxycholic acid in reducing and preventing gallstone formation is unclear, tauroursodeoxycholic acid may achieve this effect in a number of ways. A recent mouse study suggests that tauroursodeoxycholic acid inhibits intestinal cholesterol absorption and lowers liver cholesterol levels by upregulating the bile acid excretion from the liver to the gallbladder. Tauroursodeoxycholic acid lowers the bile cholesterol saturation in the gallbladder, thereby increasing the solubility of cholesterol in bile. It can also maintain a specific gut microbiota composition to promote the synthesis of bile acids and reduce liver inflammation caused by the lipopolysaccharide in the blood. Ultimately, tauroursodeoxycholic acid enhances the synthesis of bile acids in the liver and reduces cholesterol in the serum and liver. Tauroursodeoxycholic acid inhibits cell apoptosis by disrupting the mitochondrial pathway of cell death. It works by inhibiting oxygen-radical production, ameliorating endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response. Other anti-apoptotic processes mediated by tauroursodeoxycholic acid include cytochrome c release, caspase activation, DNA and nuclear fragmentation, and inhibition of p53 transactivation. It is believed that tauroursodeoxycholic acid works on multiple cellular targets to inhibit apoptosis and upregulate survival pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): There is evidence that tauroursodeoxycholic acid crosses the blood brain barrier in humans. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): There is little biotransformation of tauroursodeoxycholic acid. It is partially deconjugated by intestinal microflora to form unconjugated bile acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information available regarding the LD 50 and overdose of tauroursodeoxycholic acid. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Relyvrio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tauroursodeoxycholic acid is the taurine conjugate of ursodeoxycholic acid with antiapoptotic and ER stress response dampening effects used in some countries to treat gallstones. It is also being investigated for a wide variety of other conditions. Output: Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. The severity of the interaction is moderate.

Does Abciximab and Tazobactam interact?

•Drug A: Abciximab •Drug B: Tazobactam •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Tazobactam is combined with Abciximab. •Extended Description: Tazobactam is frequently coadministered in a single agent (piperacillin-tazobactam), which may increase the risk of bleeding. When coadministered with anticoagulants or other drugs that increase the risk of bleeding, hemorrhage may result, especially at higher doses of agents that predispose to bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tazobactam is used in combination with piperacillin or ceftolozane to broaden the spectrum of piperacillin antibacterial action, treating susceptible infections. As with any other antibiotic, tazobactam should only be used for infections that are either proven or strongly suspected to be susceptible to the tazobactam containing drug. Tazobactam-piperacillin When combined with piperacillin, it is used to treat a variety of infections, including those caused by aerobic and facultative gram-positive and gram-negative bacteria, in addition to gram-positive and gram-negative anaerobes. Some examples of infections treated with piperacillin-tazobactam include cellulitis, diabetic foot infections, appendicitis, and postpartum endometritis infections. Certain gram-negative bacilli infections with beta-lactamase producing organisms cannot be treated with piperacillin-tazobactam, due to a gene mutation conferring antibiotic resistance. Tazobactam-ceftolozane Tazobactam is used in combination with ceftolozane for the treatment of infections caused by designated susceptible microorganisms in adult and pediatric patients: Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole Complicated Urinary Tract Infections (cUTI), including pyelonephritis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tazobactam inhibits the action of bacterial beta-lactamase producing organisms, which are normally resistant to beta-lactam antibiotics. This augments the effects of antibiotics which would otherwise not be effective in treating certain infections. These antibiotics contain a beta-lactam ring in their chemical structure, which is destroyed by beta-lactam resistant organisms. When combined with other antibiotics, a variety of infections, including serious and life-threatening infections may be treated. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tazobactam broadens the spectrum of piperacillin and ceftolozane by making them effective against organisms that express beta-lactamase and would normally degrade them. This occurs through the irreversible inhibition of beta-lactamase enzymes. In addition, tazobactam may bind covalently to plasmid-mediated and chromosome-mediated beta-lactamase enzymes. Tazobactam is predominantly effective against the OHIO-1, SHV-1, and TEM groups of beta-lactamases, but may also inhibit other beta-lactamases. Tazobactam shows little antibacterial activity by itself, and for this reason, is generally not administered alone. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tazobactam is coadministered with piperacillin or ceftolozane, pharmacokinetic information will be provided for these combinations. Piperacillin-tazobactam Peak plasma concentrations occur immediately after the completion of intravenous infusion. Following several doses of piperacillin-tazobactam infusions every 6 hours, peak concentrations were similar to those that were measured after the initial dose. Ceftolozane-piperacillin AUC: 24.4-25 mcg•h/mL Peak concentrations are reached on day 1 after the first dose and range from 18 to 18.4 mcg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 18.2 L when given with piperacillin 13.5-18.2 L when given with ceftolozane Piperacillin-tazobactam is widely distributed in body tissues and fluids. These may include but are not limited to the intestine, gallbladder, lung, female reproductive organs, and the bile. Meningeal distribution of piperacillin-tazobactam increases with inflammation, but is otherwise low. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tazobactam is bout 30% bound to plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tazobactam is mainly metabolized to M1, an inactive metabolite. Hydrolysis occurs on the beta-lactam ring to form M1 (the inactive metabolite). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Tazobactam and its metabolite are mainly eliminated by the kidneys with about 80% of the administered dose eliminated as unchanged drug. The remaining drug is excreted as a single metabolite. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Piperacillin-tazobactam After a single dose in healthy volunteers, the plasma half-life of piperacillin and tazobactam was in the range of 0.7 to 1.2 hours. Ceftolozane-tazobactam 0.91-1.03 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Because tazobactam is cleared by the kidneys and is a substrate of the transporters OAT1 and OAT3, inhibitors of these transporters should be avoided to ensure efficacy. Dosage adjustments of piperacillin-tazobactam and ceftolozane-tazobactam must be made for patients with impaired renal clearance. The mean clearance rate of tazobactam was found to be 48.3-83.6 mL/min in patients admitted to the intensive care unit who were given renal replacement therapy and receiving intravenous piperacillin-tazobactam. The clearance of tazobactam is dependent on renal function, as determined by renal clearance. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Overdose Post-marketing reports have been made of overdose cases with piperacillin/tazobactam. Nausea, vomiting, and diarrhea are frequent manifestations of an overdose. Neuromuscular excitability or seizures may also occur with high intravenous doses or renal failure. There is no specific antidote. Provide supportive measures in case of an overdose. Anticonvulsive agents may be indicated when neuromuscular excitability or seizures occur. If anaphylaxis occurs, traditional measures should be taken to manage hypersensitivity (for example, adrenaline, antihistamines, corticosteroids, and oxygen/airway maintenance). Similar measures should be taken after a ceftolozane-tazobactam overdose. Hemodialysis can be used to remove the drug from the circulation. A note on nephrotoxicity Cases of life-threatening nephrotoxicity have been seen in critically ill patients receiving piperacillin-tazobactam. Alternative therapy and/or renal monitoring should be considered in critically ill patients. Carcinogenesis/Mutagenesis Tazobactam tested negative for genotoxic effects in the Ames assay, an after in vitro chromosomal aberration and point mutation assay in the Chinese hamster, an various other assays. Use in pregnancy Tazobactam has been found cross the placenta in rats. No data on human studies are available, however, rat studies have shown no teratogenetic effects at doses 6-14 times the equivalent maximum recommended human dose. Use in lactation There are no data on the presence of tazobactam in human breastmilk. No data are currently available on the effects of tazobactam on the infant, or how it affects milk production. Use clinical judgement and consider the maternal need for the drug and the benefits of breastfeeding the infant before administration during lactation. Small concentrations of piperacillin-tazobactam have been found in the breastmilk and can lead to hypersensitivity in a breastfeeding infant. In some cases, breastfeeding may have to be discontinued temporarily. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zerbaxa, Zosyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tazobactam is a beta lactamase inhibitor administered with antibiotics such as piperacillin and ceftolozane to prevent their degradation, resulting in increased efficacy.

Tazobactam is frequently coadministered in a single agent (piperacillin-tazobactam), which may increase the risk of bleeding. When coadministered with anticoagulants or other drugs that increase the risk of bleeding, hemorrhage may result, especially at higher doses of agents that predispose to bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Tazobactam interact? Information: •Drug A: Abciximab •Drug B: Tazobactam •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Tazobactam is combined with Abciximab. •Extended Description: Tazobactam is frequently coadministered in a single agent (piperacillin-tazobactam), which may increase the risk of bleeding. When coadministered with anticoagulants or other drugs that increase the risk of bleeding, hemorrhage may result, especially at higher doses of agents that predispose to bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tazobactam is used in combination with piperacillin or ceftolozane to broaden the spectrum of piperacillin antibacterial action, treating susceptible infections. As with any other antibiotic, tazobactam should only be used for infections that are either proven or strongly suspected to be susceptible to the tazobactam containing drug. Tazobactam-piperacillin When combined with piperacillin, it is used to treat a variety of infections, including those caused by aerobic and facultative gram-positive and gram-negative bacteria, in addition to gram-positive and gram-negative anaerobes. Some examples of infections treated with piperacillin-tazobactam include cellulitis, diabetic foot infections, appendicitis, and postpartum endometritis infections. Certain gram-negative bacilli infections with beta-lactamase producing organisms cannot be treated with piperacillin-tazobactam, due to a gene mutation conferring antibiotic resistance. Tazobactam-ceftolozane Tazobactam is used in combination with ceftolozane for the treatment of infections caused by designated susceptible microorganisms in adult and pediatric patients: Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole Complicated Urinary Tract Infections (cUTI), including pyelonephritis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tazobactam inhibits the action of bacterial beta-lactamase producing organisms, which are normally resistant to beta-lactam antibiotics. This augments the effects of antibiotics which would otherwise not be effective in treating certain infections. These antibiotics contain a beta-lactam ring in their chemical structure, which is destroyed by beta-lactam resistant organisms. When combined with other antibiotics, a variety of infections, including serious and life-threatening infections may be treated. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tazobactam broadens the spectrum of piperacillin and ceftolozane by making them effective against organisms that express beta-lactamase and would normally degrade them. This occurs through the irreversible inhibition of beta-lactamase enzymes. In addition, tazobactam may bind covalently to plasmid-mediated and chromosome-mediated beta-lactamase enzymes. Tazobactam is predominantly effective against the OHIO-1, SHV-1, and TEM groups of beta-lactamases, but may also inhibit other beta-lactamases. Tazobactam shows little antibacterial activity by itself, and for this reason, is generally not administered alone. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tazobactam is coadministered with piperacillin or ceftolozane, pharmacokinetic information will be provided for these combinations. Piperacillin-tazobactam Peak plasma concentrations occur immediately after the completion of intravenous infusion. Following several doses of piperacillin-tazobactam infusions every 6 hours, peak concentrations were similar to those that were measured after the initial dose. Ceftolozane-piperacillin AUC: 24.4-25 mcg•h/mL Peak concentrations are reached on day 1 after the first dose and range from 18 to 18.4 mcg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 18.2 L when given with piperacillin 13.5-18.2 L when given with ceftolozane Piperacillin-tazobactam is widely distributed in body tissues and fluids. These may include but are not limited to the intestine, gallbladder, lung, female reproductive organs, and the bile. Meningeal distribution of piperacillin-tazobactam increases with inflammation, but is otherwise low. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tazobactam is bout 30% bound to plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tazobactam is mainly metabolized to M1, an inactive metabolite. Hydrolysis occurs on the beta-lactam ring to form M1 (the inactive metabolite). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Tazobactam and its metabolite are mainly eliminated by the kidneys with about 80% of the administered dose eliminated as unchanged drug. The remaining drug is excreted as a single metabolite. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Piperacillin-tazobactam After a single dose in healthy volunteers, the plasma half-life of piperacillin and tazobactam was in the range of 0.7 to 1.2 hours. Ceftolozane-tazobactam 0.91-1.03 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Because tazobactam is cleared by the kidneys and is a substrate of the transporters OAT1 and OAT3, inhibitors of these transporters should be avoided to ensure efficacy. Dosage adjustments of piperacillin-tazobactam and ceftolozane-tazobactam must be made for patients with impaired renal clearance. The mean clearance rate of tazobactam was found to be 48.3-83.6 mL/min in patients admitted to the intensive care unit who were given renal replacement therapy and receiving intravenous piperacillin-tazobactam. The clearance of tazobactam is dependent on renal function, as determined by renal clearance. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Overdose Post-marketing reports have been made of overdose cases with piperacillin/tazobactam. Nausea, vomiting, and diarrhea are frequent manifestations of an overdose. Neuromuscular excitability or seizures may also occur with high intravenous doses or renal failure. There is no specific antidote. Provide supportive measures in case of an overdose. Anticonvulsive agents may be indicated when neuromuscular excitability or seizures occur. If anaphylaxis occurs, traditional measures should be taken to manage hypersensitivity (for example, adrenaline, antihistamines, corticosteroids, and oxygen/airway maintenance). Similar measures should be taken after a ceftolozane-tazobactam overdose. Hemodialysis can be used to remove the drug from the circulation. A note on nephrotoxicity Cases of life-threatening nephrotoxicity have been seen in critically ill patients receiving piperacillin-tazobactam. Alternative therapy and/or renal monitoring should be considered in critically ill patients. Carcinogenesis/Mutagenesis Tazobactam tested negative for genotoxic effects in the Ames assay, an after in vitro chromosomal aberration and point mutation assay in the Chinese hamster, an various other assays. Use in pregnancy Tazobactam has been found cross the placenta in rats. No data on human studies are available, however, rat studies have shown no teratogenetic effects at doses 6-14 times the equivalent maximum recommended human dose. Use in lactation There are no data on the presence of tazobactam in human breastmilk. No data are currently available on the effects of tazobactam on the infant, or how it affects milk production. Use clinical judgement and consider the maternal need for the drug and the benefits of breastfeeding the infant before administration during lactation. Small concentrations of piperacillin-tazobactam have been found in the breastmilk and can lead to hypersensitivity in a breastfeeding infant. In some cases, breastfeeding may have to be discontinued temporarily. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zerbaxa, Zosyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tazobactam is a beta lactamase inhibitor administered with antibiotics such as piperacillin and ceftolozane to prevent their degradation, resulting in increased efficacy. Output: Tazobactam is frequently coadministered in a single agent (piperacillin-tazobactam), which may increase the risk of bleeding. When coadministered with anticoagulants or other drugs that increase the risk of bleeding, hemorrhage may result, especially at higher doses of agents that predispose to bleeding. The severity of the interaction is moderate.

Does Abciximab and Tedizolid phosphate interact?

•Drug A: Abciximab •Drug B: Tedizolid phosphate •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tedizolid phosphate. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tedizolid is indicated for the treatment of acute bacterial infections of the skin and skin structure (ABSSSI). To prevent drug resistance, tedizolid should only be used for infections that are caused by susceptible bacteria. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tedizolid is an oxazolidinone antibiotic that works by inhibiting protein synthesis by bacterial ribosomes. However, oxazolidinone antibiotics can also bind to human mitochondrial, but not cytoplasmic, ribosomes. Mitochondrial protein synthesis inhibition is associated with adverse patient effects such as neurological, hematological, and gastrointestinal toxicity, although tedizolid is tolerated better than the related linezolid. Alternative therapies should be considered when treating neutropenic patients with ABSSSI. Clostridium difficile -associated diarrhea has been reported in patients treated with tedizolid. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Despite renewed efforts to combat the spread of antimicrobial resistance, multidrug-resistant organisms, including gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, remain a threat. Oxazolidinones represent a relatively new class of antibacterials inhibiting protein synthesis that is generally capable of overcoming resistance to other bacterial protein synthesis inhibitors. Protein synthesis involves the action of ribosomes, multi-subunit complexes composed of both protein and ribosomal RNA (rRNA) substituents. Translocation along the length of a messenger RNA and concomitant protein synthesis involves the action of the A, P, and E sites of the peptidyltransferase centre (PTC), which accepts charged aminoacyl-tRNAs and catalyzes the formation of peptide bonds between them. The bacterial 70S ribosome comprises a small (30S) and a large (50S) subunit. Early studies into the mechanism of action of oxazolidinone antibiotics suggested that they inhibit a step in the initiation of protein synthesis. However, this mechanism was inconsistent with mapped resistance mutations, and later studies involving cross-linking and direct structural determination of the binding site revealed that oxazolidinones, including both linezolid and tedizolid, bind in the A site of the PTC by interacting with the 23S rRNA component. The structural studies also revealed that oxazolidinone binding alters the conformation of a conserved nucleotide in the 23S rRNA (U2585 in Escherichia coli ), which renders the PTC non-productive for peptide bond formation. Hence, tedizolid exerts its effect through inhibiting bacterial protein synthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tedizolid reaches peak plasma concentrations within three hours for oral administration and within one hour following intravenous administration; the absolute oral bioavailability is approximately 91%. Food has no effect on absorption. When given once daily, either orally or intravenously, tedizolid reaches steady-state concentrations in approximately three days. The C max for tedizolid after a single dose/at steady-state is 2.0 ± 0.7/2.2 ± 0.6 mcg/mL for oral administration, and 2.3 ± 0.6/3.0 ± 0.7 mcg/mL for intravenous administration, respectively. Similarly, the T max has a median (range) of 2.5 (1.0 - 8.0)/3.5 (1.0 - 6.0) hrs for the oral route and 1.1 (0.9 - 1.5)/1.2 (0.9 - 1.5) hrs when given intravenous. The AUC is 23.8 ± 6.8/25.6 ± 8.4 mcg*hr/mL for oral and 26.6 ± 5.2/29.2 ± 6.2 mcg*hr/mL for intravenous. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution for tedizolid following a single intravenous dose of 200 mg is between 67 and 80 L. In a study involving oral administration of 200 mg tedizolid to steady-state, the volume of distribution was 108 ± 21 L, while a single 600 mg oral dose resulted in an apparent volume of distribution of 113.3 ± 19.3 L. Tedizolid has been observed to penetrate the interstitial space of both adipose and skeletal muscle tissue and is also found in the epithelial lining fluid as well as in alveolar macrophages. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 70 to 90% of tedizolid is bound to human plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tedizolid is administered as a phosphate prodrug that is converted to tedizolid (the circulating active moiety). Prior to excretion, the majority of tedizolid is converted to an inactive sulphate conjugate in the liver, though this is unlikely to involve the action of cytochrome P450-family enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): When given as a single oral dose, approximately 82% of tedizolid is excreted via the feces and 18% in urine. The majority is found as the inactive sulphate conjugate, with only 3% recovered unchanged. Over 85% of the elimination occurs within 96 hours. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Tedizolid has a half-life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Tedizolid has an apparent oral clearance of 6.9 ± 1.7 L/hr for a single dose and 8.4 ± 2.1 L/hr at steady-state. The systemic clearance is 6.4 ± 1.2 L/hr for a single dose and 5.9 ± 1.4 L/hr at steady-state. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Toxicity information regarding tedizolid is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nausea, headache, dizziness, diarrhea, and vomiting. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Sivextro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tedizolid phosphate Torezolid phosphate •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tedizolid phosphate is an oxazolidinone class antibiotic that inhibits bacterial protein synthesis and is proven to be effective in the treatment of certain Gram-positive bacterial infections.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Tedizolid phosphate interact? Information: •Drug A: Abciximab •Drug B: Tedizolid phosphate •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tedizolid phosphate. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tedizolid is indicated for the treatment of acute bacterial infections of the skin and skin structure (ABSSSI). To prevent drug resistance, tedizolid should only be used for infections that are caused by susceptible bacteria. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tedizolid is an oxazolidinone antibiotic that works by inhibiting protein synthesis by bacterial ribosomes. However, oxazolidinone antibiotics can also bind to human mitochondrial, but not cytoplasmic, ribosomes. Mitochondrial protein synthesis inhibition is associated with adverse patient effects such as neurological, hematological, and gastrointestinal toxicity, although tedizolid is tolerated better than the related linezolid. Alternative therapies should be considered when treating neutropenic patients with ABSSSI. Clostridium difficile -associated diarrhea has been reported in patients treated with tedizolid. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Despite renewed efforts to combat the spread of antimicrobial resistance, multidrug-resistant organisms, including gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, remain a threat. Oxazolidinones represent a relatively new class of antibacterials inhibiting protein synthesis that is generally capable of overcoming resistance to other bacterial protein synthesis inhibitors. Protein synthesis involves the action of ribosomes, multi-subunit complexes composed of both protein and ribosomal RNA (rRNA) substituents. Translocation along the length of a messenger RNA and concomitant protein synthesis involves the action of the A, P, and E sites of the peptidyltransferase centre (PTC), which accepts charged aminoacyl-tRNAs and catalyzes the formation of peptide bonds between them. The bacterial 70S ribosome comprises a small (30S) and a large (50S) subunit. Early studies into the mechanism of action of oxazolidinone antibiotics suggested that they inhibit a step in the initiation of protein synthesis. However, this mechanism was inconsistent with mapped resistance mutations, and later studies involving cross-linking and direct structural determination of the binding site revealed that oxazolidinones, including both linezolid and tedizolid, bind in the A site of the PTC by interacting with the 23S rRNA component. The structural studies also revealed that oxazolidinone binding alters the conformation of a conserved nucleotide in the 23S rRNA (U2585 in Escherichia coli ), which renders the PTC non-productive for peptide bond formation. Hence, tedizolid exerts its effect through inhibiting bacterial protein synthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tedizolid reaches peak plasma concentrations within three hours for oral administration and within one hour following intravenous administration; the absolute oral bioavailability is approximately 91%. Food has no effect on absorption. When given once daily, either orally or intravenously, tedizolid reaches steady-state concentrations in approximately three days. The C max for tedizolid after a single dose/at steady-state is 2.0 ± 0.7/2.2 ± 0.6 mcg/mL for oral administration, and 2.3 ± 0.6/3.0 ± 0.7 mcg/mL for intravenous administration, respectively. Similarly, the T max has a median (range) of 2.5 (1.0 - 8.0)/3.5 (1.0 - 6.0) hrs for the oral route and 1.1 (0.9 - 1.5)/1.2 (0.9 - 1.5) hrs when given intravenous. The AUC is 23.8 ± 6.8/25.6 ± 8.4 mcg*hr/mL for oral and 26.6 ± 5.2/29.2 ± 6.2 mcg*hr/mL for intravenous. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution for tedizolid following a single intravenous dose of 200 mg is between 67 and 80 L. In a study involving oral administration of 200 mg tedizolid to steady-state, the volume of distribution was 108 ± 21 L, while a single 600 mg oral dose resulted in an apparent volume of distribution of 113.3 ± 19.3 L. Tedizolid has been observed to penetrate the interstitial space of both adipose and skeletal muscle tissue and is also found in the epithelial lining fluid as well as in alveolar macrophages. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 70 to 90% of tedizolid is bound to human plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tedizolid is administered as a phosphate prodrug that is converted to tedizolid (the circulating active moiety). Prior to excretion, the majority of tedizolid is converted to an inactive sulphate conjugate in the liver, though this is unlikely to involve the action of cytochrome P450-family enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): When given as a single oral dose, approximately 82% of tedizolid is excreted via the feces and 18% in urine. The majority is found as the inactive sulphate conjugate, with only 3% recovered unchanged. Over 85% of the elimination occurs within 96 hours. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Tedizolid has a half-life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Tedizolid has an apparent oral clearance of 6.9 ± 1.7 L/hr for a single dose and 8.4 ± 2.1 L/hr at steady-state. The systemic clearance is 6.4 ± 1.2 L/hr for a single dose and 5.9 ± 1.4 L/hr at steady-state. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Toxicity information regarding tedizolid is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nausea, headache, dizziness, diarrhea, and vomiting. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Sivextro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tedizolid phosphate Torezolid phosphate •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tedizolid phosphate is an oxazolidinone class antibiotic that inhibits bacterial protein synthesis and is proven to be effective in the treatment of certain Gram-positive bacterial infections. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Temozolomide interact?

•Drug A: Abciximab •Drug B: Temozolomide •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Temozolomide. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10 /L and a platelet count of ≥100 x 10 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future. •Absorption (Drug A): No absorption available •Absorption (Drug B): Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T max of one hour. Following a single oral dose of 150 mg/m, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m /day. The median T max is 1 hour Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 hours). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours). •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Temozolomide has a mean elimination half-life of 1.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Temozolomide has a clearance of approximately 5.5 L/hr/m. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Temodar, Temomedac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-perillyl alcohol temozolomide Methazolastone Temozolodida Temozolomid Temozolomida Témozolomide Temozolomide Temozolomidum TMZ •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Temozolomide is an alkylating agent used to treat glioblastoma multiforme and refractory anaplastic astrocytoma.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Temozolomide interact? Information: •Drug A: Abciximab •Drug B: Temozolomide •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Temozolomide. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10 /L and a platelet count of ≥100 x 10 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future. •Absorption (Drug A): No absorption available •Absorption (Drug B): Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T max of one hour. Following a single oral dose of 150 mg/m, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m /day. The median T max is 1 hour Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 hours). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours). •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Temozolomide has a mean elimination half-life of 1.8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Temozolomide has a clearance of approximately 5.5 L/hr/m. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Temodar, Temomedac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-perillyl alcohol temozolomide Methazolastone Temozolodida Temozolomid Temozolomida Témozolomide Temozolomide Temozolomidum TMZ •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Temozolomide is an alkylating agent used to treat glioblastoma multiforme and refractory anaplastic astrocytoma. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Temsirolimus interact?

•Drug A: Abciximab •Drug B: Temsirolimus •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Temsirolimus. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor. •Absorption (Drug A): No absorption available •Absorption (Drug B): Infused intravenous over 30 - 60 minutes. C max is typically observed at the end of infusion •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 87% bound to plasma proteins in vitro at a concentration of 100 ng/ml •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): 16.2 L/h (22%) •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Torisel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Temsirolimus is a antineoplastic agent used in the treatment of renal cell carcinoma (RCC) that works by inhibiting mTOR.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Temsirolimus interact? Information: •Drug A: Abciximab •Drug B: Temsirolimus •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Temsirolimus. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor. •Absorption (Drug A): No absorption available •Absorption (Drug B): Infused intravenous over 30 - 60 minutes. C max is typically observed at the end of infusion •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 87% bound to plasma proteins in vitro at a concentration of 100 ng/ml •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): 16.2 L/h (22%) •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Torisel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Temsirolimus is a antineoplastic agent used in the treatment of renal cell carcinoma (RCC) that works by inhibiting mTOR. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tenecteplase interact?

•Drug A: Abciximab •Drug B: Tenecteplase •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tenecteplase. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For treatment of myocardial infarction and lysis of intracoronary emboli •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tenecteplase is a fibrin-specific tissue-plasminogen activator. It binds to fibrin rich clots and cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tenecteplase binds to fibrin rich clots via the fibronectin finger-like domain and the Kringle 2 domain. The protease domain then cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.9 hours (mammalian reticulocytes, in vitro) >20 hours (yeast, in vivo) >10 hours (Escherichia coli, in vivo) •Clearance (Drug A): No clearance available •Clearance (Drug B): 99 - 119 mL/min [acute myocardial infarction patients] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Metalyse, Tnkase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tenecteplase is a modified form of recombinant human tissue plasminogen activator used in the emergency treatment of myocardial infarction and pulmonary emboli.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Tenecteplase interact? Information: •Drug A: Abciximab •Drug B: Tenecteplase •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tenecteplase. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For treatment of myocardial infarction and lysis of intracoronary emboli •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tenecteplase is a fibrin-specific tissue-plasminogen activator. It binds to fibrin rich clots and cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tenecteplase binds to fibrin rich clots via the fibronectin finger-like domain and the Kringle 2 domain. The protease domain then cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.9 hours (mammalian reticulocytes, in vitro) >20 hours (yeast, in vivo) >10 hours (Escherichia coli, in vivo) •Clearance (Drug A): No clearance available •Clearance (Drug B): 99 - 119 mL/min [acute myocardial infarction patients] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Metalyse, Tnkase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tenecteplase is a modified form of recombinant human tissue plasminogen activator used in the emergency treatment of myocardial infarction and pulmonary emboli. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Teniposide interact?

•Drug A: Abciximab •Drug B: Teniposide •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Teniposide. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 10.3 mL/min/m2 •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epidophyllotoxin Teniposid Téniposide Teniposide Teniposido Teniposidum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Teniposide is a cytotoxic drug used as an adjunct for chemotherapy induction in the treatment of refractory childhood acute lymphoblastic leukemia.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Teniposide interact? Information: •Drug A: Abciximab •Drug B: Teniposide •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Teniposide. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 10.3 mL/min/m2 •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epidophyllotoxin Teniposid Téniposide Teniposide Teniposido Teniposidum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Teniposide is a cytotoxic drug used as an adjunct for chemotherapy induction in the treatment of refractory childhood acute lymphoblastic leukemia. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tenoxicam interact?

•Drug A: Abciximab •Drug B: Tenoxicam •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tenoxicam is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, backache, and pain. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tenoxicam, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The antiinflammatory effects of tenoxicam may result from the inhibition of the enzyme cycooxygenase and the subsequent peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, their inhibition accounts for the peripheral analgesic effects of tenoxicam. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •Absorption (Drug A): No absorption available •Absorption (Drug B): Oral absorption of tenoxicam is rapid and complete (absolute bioavailability 100%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tenoxicam is metabolized in the liver to several pharmacologically inactive metabolites (mainly 5'-hydroxy-tenoxicam). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 72 hours (range 59 to 74 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tenoxicam is an anti inflammatory analgesic used to treat mild to moderate pain as well as the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Tenoxicam interact? Information: •Drug A: Abciximab •Drug B: Tenoxicam •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tenoxicam is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, backache, and pain. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tenoxicam, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The antiinflammatory effects of tenoxicam may result from the inhibition of the enzyme cycooxygenase and the subsequent peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, their inhibition accounts for the peripheral analgesic effects of tenoxicam. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •Absorption (Drug A): No absorption available •Absorption (Drug B): Oral absorption of tenoxicam is rapid and complete (absolute bioavailability 100%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tenoxicam is metabolized in the liver to several pharmacologically inactive metabolites (mainly 5'-hydroxy-tenoxicam). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 72 hours (range 59 to 74 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tenoxicam is an anti inflammatory analgesic used to treat mild to moderate pain as well as the signs and symptoms of rheumatoid arthritis and osteoarthritis. Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Teplizumab interact?

•Drug A: Abciximab •Drug B: Teplizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Teplizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Teplizumab is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Teplizumab is a monoclonal antibody that binds to CD3 molecules on the surface of CD4+ and CD8+ T cells, both involved in the destruction of pancreatic β cells. Several studies have detected an increase in C-peptide levels in early-onset type 1 diabetes (T1D) patients treated with teplizumab, suggesting an improved β cell function. The exposure-response relationship and the safety and effectiveness pharmacodynamic time-response of teplizumab have not been fully elucidated. In the absence of T cell depletion, the use of teplizumab in a 14-day course of treatment can lead to the development of lymphopenia. Cytokine release syndrome (CRS) has also been detected in patients treated with teplizumab. The main manifestations of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these manifestations occurred in the first 5 days of treatment. In addition, the use of teplizumab may lead to the development of serious infections and hypersensitivity reactions. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms. The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition. Combined with other observations from animal and human studies, it is clear that T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions. The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response. Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 and inhibits T cell activation through steric inhibition of antigen recognition. Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D. However, the exact mechanism underlying this effect remains clear. One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further β cell destruction. Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8 central memory (CD8CM) T cells. It is clear, however, that treatment is most effective in patients who have not yet progressed to Stage 3 and who have an active immune response. •Absorption (Drug A): No absorption available •Absorption (Drug B): During the 14-day treatment course of teplizumab, steady-state concentrations are not expected to be achieved. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In a 60 kg subject, teplizumab has a central volume of distribution (Vd) of 2.27 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As a monoclonal antibody, teplizumab is expected to be metabolized into small peptides by proteases throughout the body. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Teplizumab showed saturable binding and elimination. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In a 60 kg subject, teplizumab has a mean terminal elimination half-life of 4.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): In a 60 kg subject, teplizumab has a clearance of 2.7 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Toxicity information regarding teplizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious infections, lymphopenia and cytokine release syndrome. Symptomatic and supportive measures are recommended. The mutagenic and carcinogenic potential of teplizumab has not been evaluated. As an antibody, teplizumab is not expected to interact directly with DNA. In female and male mice, teplizumab did not have significant effects in fertility and reproductive performance when administered subcutaneously at doses up to 20 mg/kg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tzield •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Teplizumab is a CD3-directed monoclonal antibody indicated to delay the onset of Stage 3 type 1 diabetes in patients with Stage 2 type 1 diabetes.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Teplizumab interact? Information: •Drug A: Abciximab •Drug B: Teplizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Teplizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Teplizumab is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Teplizumab is a monoclonal antibody that binds to CD3 molecules on the surface of CD4+ and CD8+ T cells, both involved in the destruction of pancreatic β cells. Several studies have detected an increase in C-peptide levels in early-onset type 1 diabetes (T1D) patients treated with teplizumab, suggesting an improved β cell function. The exposure-response relationship and the safety and effectiveness pharmacodynamic time-response of teplizumab have not been fully elucidated. In the absence of T cell depletion, the use of teplizumab in a 14-day course of treatment can lead to the development of lymphopenia. Cytokine release syndrome (CRS) has also been detected in patients treated with teplizumab. The main manifestations of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these manifestations occurred in the first 5 days of treatment. In addition, the use of teplizumab may lead to the development of serious infections and hypersensitivity reactions. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms. The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition. Combined with other observations from animal and human studies, it is clear that T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions. The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response. Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 and inhibits T cell activation through steric inhibition of antigen recognition. Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D. However, the exact mechanism underlying this effect remains clear. One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further β cell destruction. Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8 central memory (CD8CM) T cells. It is clear, however, that treatment is most effective in patients who have not yet progressed to Stage 3 and who have an active immune response. •Absorption (Drug A): No absorption available •Absorption (Drug B): During the 14-day treatment course of teplizumab, steady-state concentrations are not expected to be achieved. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In a 60 kg subject, teplizumab has a central volume of distribution (Vd) of 2.27 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As a monoclonal antibody, teplizumab is expected to be metabolized into small peptides by proteases throughout the body. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Teplizumab showed saturable binding and elimination. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In a 60 kg subject, teplizumab has a mean terminal elimination half-life of 4.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): In a 60 kg subject, teplizumab has a clearance of 2.7 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Toxicity information regarding teplizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious infections, lymphopenia and cytokine release syndrome. Symptomatic and supportive measures are recommended. The mutagenic and carcinogenic potential of teplizumab has not been evaluated. As an antibody, teplizumab is not expected to interact directly with DNA. In female and male mice, teplizumab did not have significant effects in fertility and reproductive performance when administered subcutaneously at doses up to 20 mg/kg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tzield •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Teplizumab is a CD3-directed monoclonal antibody indicated to delay the onset of Stage 3 type 1 diabetes in patients with Stage 2 type 1 diabetes. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Testosterone cypionate interact?

•Drug A: Abciximab •Drug B: Testosterone cypionate •Severity: MODERATE •Description: Testosterone cypionate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone cypionate is used in males that present conditions derived from a deficiency or absence of endogenous testosterone. These conditions are 1) primary hypogonadism, defined as the testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; and 2) hypogonadotropic hypogonadism characterized by idiopathic gonadotropin, LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma or radiation. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone cypionate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. The continuous variation in plasma testosterone after intramuscular administration of testosterone cypionate results in fluctuations in mood and libido as well as some local inflammation. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): No absorption available •Absorption (Drug B): Testosterone cypionate is an esterified anabolic which allows it to present a greater degree of solubility in fats and thus, the release and absorption occur in a slow rate compare to homologous molecules. Intramuscular administration of 200 mg of testosterone cypionate produced a mean supratherapeutic Cmax of 1122 ng/dl which occurred 4-5 days post-injection. After the fifth day, the levels of testosterone cypionate in plasma went down reaching an average of 400 ng/dl. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone cypionate, following conversion into testosterone, is approximately 98% protein-bound to sex hormone-binding globulin in plasma. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): To start its activity, testosterone cypionate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the cypionate ester moiety and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life of testosterone cypionate is one of the longest, being approximately of 8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone cypionate presents a lower clearance rate after intramuscular administration compared to other analogs of testosterone. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Preclinical studies with testosterone implants induced cervical-uterine tumors in mice which metastasized in some cases. Some reports indicate that administration of testosterone cypionate in females can augment the susceptibility to hepatoma as well as increase the number of tumors. Clinical studies have reported cases of hepatocellular carcinoma in long-term high-dose therapy. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Depo-testosterone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosterone cipionate Testosterone cyclopentanepropionate Testosterone cyclopentylpropionate Testosterone cypionate •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone cypionate is an androgen used to treat low or absent testosterone.

Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Testosterone cypionate interact? Information: •Drug A: Abciximab •Drug B: Testosterone cypionate •Severity: MODERATE •Description: Testosterone cypionate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone cypionate is used in males that present conditions derived from a deficiency or absence of endogenous testosterone. These conditions are 1) primary hypogonadism, defined as the testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; and 2) hypogonadotropic hypogonadism characterized by idiopathic gonadotropin, LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma or radiation. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone cypionate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. The continuous variation in plasma testosterone after intramuscular administration of testosterone cypionate results in fluctuations in mood and libido as well as some local inflammation. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): No absorption available •Absorption (Drug B): Testosterone cypionate is an esterified anabolic which allows it to present a greater degree of solubility in fats and thus, the release and absorption occur in a slow rate compare to homologous molecules. Intramuscular administration of 200 mg of testosterone cypionate produced a mean supratherapeutic Cmax of 1122 ng/dl which occurred 4-5 days post-injection. After the fifth day, the levels of testosterone cypionate in plasma went down reaching an average of 400 ng/dl. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone cypionate, following conversion into testosterone, is approximately 98% protein-bound to sex hormone-binding globulin in plasma. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): To start its activity, testosterone cypionate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the cypionate ester moiety and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life of testosterone cypionate is one of the longest, being approximately of 8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone cypionate presents a lower clearance rate after intramuscular administration compared to other analogs of testosterone. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Preclinical studies with testosterone implants induced cervical-uterine tumors in mice which metastasized in some cases. Some reports indicate that administration of testosterone cypionate in females can augment the susceptibility to hepatoma as well as increase the number of tumors. Clinical studies have reported cases of hepatocellular carcinoma in long-term high-dose therapy. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Depo-testosterone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosterone cipionate Testosterone cyclopentanepropionate Testosterone cyclopentylpropionate Testosterone cypionate •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone cypionate is an androgen used to treat low or absent testosterone. Output: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Does Abciximab and Testosterone enanthate interact?

•Drug A: Abciximab •Drug B: Testosterone enanthate •Severity: MODERATE •Description: Testosterone enanthate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone enanthate in males is indicated as a replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Some of the treated conditions are 1) primary hypogonadism, defined as testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; 2) hypogonadotropic hypogonadism due to an idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or due to a pituitary-hypothalamic injury from tumors, trauma or radiation, in this case it is important to accompany the treatment with adrenal cortical and thyroid hormone replacement therapy; 3) to stimulate puberty in patients with delayed puberty not secondary to a pathological disorder. If the conditions 1 and 2 occur prior to puberty, the androgen replacement therapy will be needed during adolescent years for the development of secondary sexual characteristics and prolonged androgen treatment might be needed it to maintain sexual characteristics after puberty. In females, testosterone enanthate is indicated to be used secondarily in presence of advanced inoperable metastatic mammary cancer in women who are from one to five years postmenopausal. It has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Testosterone enanthate injections that are currently formulated for subcutaneous use are specifically indicated only for primary hypogonadism and hypogonadotropic hypogonadism. The use of such formulations is limited because the safety and efficacy of these subcutaneous products in adult males with late-onset hypogonadism and males less than 18 years old have not yet been established. Moreover, subcutaneously administered testosterone enanthate is indicated only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies, considering the medication could cause blood pressure increases that can raise the risk of major adverse cardiovascular events like non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone enanthate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. Continuous administration of testosterone enanthate shows a significant suppression of dihydrotestosterone, serum PSA, HDL and FSH, as well as a slight increase in serum estradiol. The levels of dihydrotestosterone and FSH can remain suppressed even 14 days after treatment termination. There are no changes in mood and sexual activity by the presence of testosterone enanthate. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing androgen effects. Such activities are useful as endogenous androgens like testosterone and dihydrotestosterone are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). •Absorption (Drug A): No absorption available •Absorption (Drug B): The pharmacokinetic profile of testosterone enanthate was studied in a regime of multiple dosing and the testosterone level was reported to present a Cmax above 1200 ng/dl after 24 hours of the last dose. The concentration decreased sequentially until it reached 600 ng/dl after one week. The pharmacokinetic profile of testosterone enanthate presented differences depending on the administered dose in which the tmax was shifted to a range of 36-48 hours. The plasma testosterone level plateaued below the therapeutic range after 3-4 weeks. This reports showed that the different formulation of testosterone enanthate and testosterone cypionate generates a different profile and thus, they are not therapeutically equivalent. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 98% of testosterone in plasma is bound to SHBG while 2% remains unbound (i.e. free). •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): To start its activity, testosterone enanthate has to be processed by enzymes in the bloodstream. These enzymes will catalyze the molecule at the ester location of the moiety. Once processed in this manner, the testosterone enanthate molecule is metabolized to various 17-keto steroids through two different pathways. Subsequently, the major active metabolites are estradiol and DHTd. Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. The inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Testosterone enanthate presents a long half-life in the range of 7-9 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Testosterone enanthate has been tested in preclinical carcinogenesis trials. In this studies, it is suggested that the exposure to this drug may increase the susceptibility to hematoma as well as the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver. Testosterone enanthate is not indicated for use in females and is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action. During treatment with large doses of exogenous androgens, including testosterone enanthate, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis. Reduced fertility is observed in some men taking testosterone replacement therapy and the impact on fertility may be irreversible. Safety and effectiveness of testosterone enanthate in pediatric patients less than 18 years old have not been established. Improper use may result in the acceleration of bone age and premature closure of epiphyses. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of Benign Prostatic Hyperplasia. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Delatestryl, Xyosted •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone enanthate is an androgen used to treat low or absent testosterone.

Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Testosterone enanthate interact? Information: •Drug A: Abciximab •Drug B: Testosterone enanthate •Severity: MODERATE •Description: Testosterone enanthate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone enanthate in males is indicated as a replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Some of the treated conditions are 1) primary hypogonadism, defined as testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; 2) hypogonadotropic hypogonadism due to an idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or due to a pituitary-hypothalamic injury from tumors, trauma or radiation, in this case it is important to accompany the treatment with adrenal cortical and thyroid hormone replacement therapy; 3) to stimulate puberty in patients with delayed puberty not secondary to a pathological disorder. If the conditions 1 and 2 occur prior to puberty, the androgen replacement therapy will be needed during adolescent years for the development of secondary sexual characteristics and prolonged androgen treatment might be needed it to maintain sexual characteristics after puberty. In females, testosterone enanthate is indicated to be used secondarily in presence of advanced inoperable metastatic mammary cancer in women who are from one to five years postmenopausal. It has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Testosterone enanthate injections that are currently formulated for subcutaneous use are specifically indicated only for primary hypogonadism and hypogonadotropic hypogonadism. The use of such formulations is limited because the safety and efficacy of these subcutaneous products in adult males with late-onset hypogonadism and males less than 18 years old have not yet been established. Moreover, subcutaneously administered testosterone enanthate is indicated only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies, considering the medication could cause blood pressure increases that can raise the risk of major adverse cardiovascular events like non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Administration of ester derivatives of testosterone as testosterone enanthate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. Continuous administration of testosterone enanthate shows a significant suppression of dihydrotestosterone, serum PSA, HDL and FSH, as well as a slight increase in serum estradiol. The levels of dihydrotestosterone and FSH can remain suppressed even 14 days after treatment termination. There are no changes in mood and sexual activity by the presence of testosterone enanthate. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing androgen effects. Such activities are useful as endogenous androgens like testosterone and dihydrotestosterone are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). •Absorption (Drug A): No absorption available •Absorption (Drug B): The pharmacokinetic profile of testosterone enanthate was studied in a regime of multiple dosing and the testosterone level was reported to present a Cmax above 1200 ng/dl after 24 hours of the last dose. The concentration decreased sequentially until it reached 600 ng/dl after one week. The pharmacokinetic profile of testosterone enanthate presented differences depending on the administered dose in which the tmax was shifted to a range of 36-48 hours. The plasma testosterone level plateaued below the therapeutic range after 3-4 weeks. This reports showed that the different formulation of testosterone enanthate and testosterone cypionate generates a different profile and thus, they are not therapeutically equivalent. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 98% of testosterone in plasma is bound to SHBG while 2% remains unbound (i.e. free). •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): To start its activity, testosterone enanthate has to be processed by enzymes in the bloodstream. These enzymes will catalyze the molecule at the ester location of the moiety. Once processed in this manner, the testosterone enanthate molecule is metabolized to various 17-keto steroids through two different pathways. Subsequently, the major active metabolites are estradiol and DHTd. Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. The inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Testosterone enanthate presents a long half-life in the range of 7-9 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Testosterone enanthate has been tested in preclinical carcinogenesis trials. In this studies, it is suggested that the exposure to this drug may increase the susceptibility to hematoma as well as the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver. Testosterone enanthate is not indicated for use in females and is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action. During treatment with large doses of exogenous androgens, including testosterone enanthate, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis. Reduced fertility is observed in some men taking testosterone replacement therapy and the impact on fertility may be irreversible. Safety and effectiveness of testosterone enanthate in pediatric patients less than 18 years old have not been established. Improper use may result in the acceleration of bone age and premature closure of epiphyses. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of Benign Prostatic Hyperplasia. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Delatestryl, Xyosted •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone enanthate is an androgen used to treat low or absent testosterone. Output: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Does Abciximab and Testosterone propionate interact?

•Drug A: Abciximab •Drug B: Testosterone propionate •Severity: MODERATE •Description: Testosterone propionate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone propionate is used in veterinary practice in heifers in order to stimulate maximal growth. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The administration of testosterone propionate can induce production of proteins related to male sexual development. Clinical trials have shown a decrease in plasma LH after the administration of testosterone propionate. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5alpha-reductase. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): No absorption available •Absorption (Drug B): Testosterone propionate presents a slow absorption from the intramuscular site of administration. This slow absorption is due to the presence of the less polar ester group. The absorption rate of testosterone propionate generates a frequent injection requirement when compared with testosterone enanthate or testosterone cypionate. It presents absorption parameters of AUC and residence time of 180-210 ng h/ml and 40-60 h, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The registered volume of distribution for testosterone propionate is in the range of 75-120 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Even 98% of testosterone in plasma is bound to sex hormone-binding globulin and 2% remains unbound or bound to albumin and other proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As all testosterone esters, testosterone propionate is rapidly hydrolysed into free testosterone in plasma. Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. From the rest of the dose, approximately 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Testosterone propionate possesses a relatively short half-life compared with other testosterone esters at approximately 4.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone propionate has a reduced clearance rate compared to testosterone. The reported clearance rate is of approximately 2000 ml/min. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Reports have showed a potential stimulation of cancerous tissue growth. The potential testosterone propionate accumulation in the body produces a high risk of edema secondaryh to water and sodium retention. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone propionate is a slow-release anabolic steroid no longer used commonly for the treatment of androgen deficiency or promotion of anabolic effects on muscles.

Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Testosterone propionate interact? Information: •Drug A: Abciximab •Drug B: Testosterone propionate •Severity: MODERATE •Description: Testosterone propionate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone propionate is used in veterinary practice in heifers in order to stimulate maximal growth. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The administration of testosterone propionate can induce production of proteins related to male sexual development. Clinical trials have shown a decrease in plasma LH after the administration of testosterone propionate. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5alpha-reductase. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. •Absorption (Drug A): No absorption available •Absorption (Drug B): Testosterone propionate presents a slow absorption from the intramuscular site of administration. This slow absorption is due to the presence of the less polar ester group. The absorption rate of testosterone propionate generates a frequent injection requirement when compared with testosterone enanthate or testosterone cypionate. It presents absorption parameters of AUC and residence time of 180-210 ng h/ml and 40-60 h, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The registered volume of distribution for testosterone propionate is in the range of 75-120 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Even 98% of testosterone in plasma is bound to sex hormone-binding globulin and 2% remains unbound or bound to albumin and other proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As all testosterone esters, testosterone propionate is rapidly hydrolysed into free testosterone in plasma. Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. From the rest of the dose, approximately 6% of a dose is excreted in the feces, mostly in the unconjugated form. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Testosterone propionate possesses a relatively short half-life compared with other testosterone esters at approximately 4.5 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Testosterone propionate has a reduced clearance rate compared to testosterone. The reported clearance rate is of approximately 2000 ml/min. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Reports have showed a potential stimulation of cancerous tissue growth. The potential testosterone propionate accumulation in the body produces a high risk of edema secondaryh to water and sodium retention. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone propionate is a slow-release anabolic steroid no longer used commonly for the treatment of androgen deficiency or promotion of anabolic effects on muscles. Output: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Does Abciximab and Testosterone undecanoate interact?

•Drug A: Abciximab •Drug B: Testosterone undecanoate •Severity: MODERATE •Description: Testosterone undecanoate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone undecanoate is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. These conditions include: Congenital or acquired primary hypogonadism: testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone FSH, luteinizing hormone LH ) above the normal range. Congenital or acquired hypogonadotropic hypogonadism: gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Testosterone undecanoate is not used to treat age-related hypogonadism. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Once in circulation, testosterone undecanoate is cleaved to release testosterone, which mediates a range of biological actions. Testosterone is an endogenous male hormone that plays a key role in male sexual differentiation: it is involved in the regulation of hematopoiesis, body composition, and bone metabolism. As a hormone replacement therapy, testosterone undecanoate is an exogenous source of testosterone in males with hypogonadism. Testosterone therapy aims to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, and loss of muscle and bone mass. Testosterone has a controlled substance in the US due to the abuse potential by athletes and bodybuilders. The use of testosterone at higher doses than recommended can lead to withdrawal symptoms lasting for weeks or months. Withdrawal symptoms include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism. Testosterone can cause hirsutism, virilization, deepening of the voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities when administered to women. The use in adolescents can lead to the premature closure of bony epiphyses with termination of growth and precocious puberty. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Testosterone is a critical male sex hormone that is responsible for the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics, such as the growth and maturation of male sex organs, the development of male hair distribution, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, resulting from insufficient testosterone secretion, has two main etiologies: primary hypogonadism is caused by defects in the gonads, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH and LH). In the circulation, testosterone undecanoate is cleaved by endogenous non-specific esterases to release testosterone, the active component of the compound. The undecanoate side chain is pharmacologically inactive. Testosterone can be further converted by 5α reductase to its more biologically active form, dihydrotestosterone (DHT). The actions of testosterone and DHT are mediated via androgen receptor, which is widely expressed in many tissues, including the bone, muscle, prostate, and adipose tissue. Testosterone binds to androgen receptors with high affinity and regulates target gene transcription involved in the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics. Testosterone can cause improved sexual function, increased lean body mass, bone density, erythropoiesis, prostate size, and changes in lipid profiles. •Absorption (Drug A): No absorption available •Absorption (Drug B): Testosterone undecanoate is a lipophilic molecule that is absorbed into the intestinal lymphatic system after oral administration. It is then released into the general blood circulation by the thoracic duct, thereby bypassing the portal circulation and first-pass metabolism in the liver, unlike endogenous testosterone. Following oral administration of 237 mg twice per day in males with hypogonadism, the mean (SD) C max was 1008 (581) ng/dL. T max is about five hours following oral administration. Decreased testosterone exposure was observed when administered without food. Following intramuscular administration of 750 mg testosterone undecanoate, serum testosterone concentrations reached a maximum after a median of seven days (range of four to 42 days), which then slowly declined. The mean (SD) C max was about 90.9 (68.8) ng/dL on the fourth day following injection of testosterone undecanoate. Steady-state serum testosterone concentration was achieved with the third injection at 14 weeks. At 42 days following the injection, testosterone undecanoate was nearly undetectable. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): There is no information available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 40% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) and about 2% of the drug remains unbound to plasma proteins. The rest is loosely bound to albumin and other plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Testosterone undecanoate can be reduced to dihydrotestosterone undecanoate via 5α-reductase. In the circulation, the ester bond linking testosterone to the undecanoic acid is cleaved by endogenous non-specific esterases. Like all fatty acids, the undecanoic side chain undergoes β-oxidation to form acetyl coenzyme A (CoA) and, finally, propionyl CoA. Testosterone is metabolized to various 17-keto steroids through two different pathways to form major active metabolites, estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life of testosterone undecanoate is approximately two hours. Once testosterone is formed from testosterone undecanoate, the half life of testosterone can vary and the reported values in the literature remain inconsistent, ranging from 10 to to 100 minutes. Testosterone undecanoate in castor oil for intramuscular injection had a half life of 33.9 days, allowing it to maintain serum levels in the normal range for over 6 weeks.[A176954] •Clearance (Drug A): No clearance available •Clearance (Drug B): While there is limited information available, an earlier study reports a metabolic clearance rate of 24.5 mL/min/kg for testosterone following oral administration of 25 mg testosterone and 40 mg testosterone undecanoate in women. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD 50 is 4000 mg/kg in mice and rats. The subcutaneous LD 50 is 2880 mg/kg in mice and rats. There is limited information on testosterone undecanoate overdose. There was one report of acute overdose from an approved injectable testosterone product, which resulted in increased serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. There was one case of overdose following administration of oral testosterone undecanoate capsules: this patient inadvertently took a 20% higher dose than the maximum recommended dose but did not report any adverse reactions. Overdose should be managed with discontinuation of the drug in combination with appropriate symptomatic and supportive care. The abuse of anabolic androgenic steroids can result in serious adverse reactions, such as cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility, and aggression. Men receiving testosterone have experienced transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Aveed, Jatenzo, Kyzatrex, Tlando •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone undecanoate is an androgen indicated for testosterone replacement therapy in adult males with primary hypogonadism and hypogonadotropic hypogonadism.

Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Testosterone undecanoate interact? Information: •Drug A: Abciximab •Drug B: Testosterone undecanoate •Severity: MODERATE •Description: Testosterone undecanoate may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone undecanoate is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. These conditions include: Congenital or acquired primary hypogonadism: testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone FSH, luteinizing hormone LH ) above the normal range. Congenital or acquired hypogonadotropic hypogonadism: gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Testosterone undecanoate is not used to treat age-related hypogonadism. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Once in circulation, testosterone undecanoate is cleaved to release testosterone, which mediates a range of biological actions. Testosterone is an endogenous male hormone that plays a key role in male sexual differentiation: it is involved in the regulation of hematopoiesis, body composition, and bone metabolism. As a hormone replacement therapy, testosterone undecanoate is an exogenous source of testosterone in males with hypogonadism. Testosterone therapy aims to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, and loss of muscle and bone mass. Testosterone has a controlled substance in the US due to the abuse potential by athletes and bodybuilders. The use of testosterone at higher doses than recommended can lead to withdrawal symptoms lasting for weeks or months. Withdrawal symptoms include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism. Testosterone can cause hirsutism, virilization, deepening of the voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities when administered to women. The use in adolescents can lead to the premature closure of bony epiphyses with termination of growth and precocious puberty. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Testosterone is a critical male sex hormone that is responsible for the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics, such as the growth and maturation of male sex organs, the development of male hair distribution, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, resulting from insufficient testosterone secretion, has two main etiologies: primary hypogonadism is caused by defects in the gonads, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH and LH). In the circulation, testosterone undecanoate is cleaved by endogenous non-specific esterases to release testosterone, the active component of the compound. The undecanoate side chain is pharmacologically inactive. Testosterone can be further converted by 5α reductase to its more biologically active form, dihydrotestosterone (DHT). The actions of testosterone and DHT are mediated via androgen receptor, which is widely expressed in many tissues, including the bone, muscle, prostate, and adipose tissue. Testosterone binds to androgen receptors with high affinity and regulates target gene transcription involved in the normal growth and development of the male sex organs and the maintenance of secondary sex characteristics. Testosterone can cause improved sexual function, increased lean body mass, bone density, erythropoiesis, prostate size, and changes in lipid profiles. •Absorption (Drug A): No absorption available •Absorption (Drug B): Testosterone undecanoate is a lipophilic molecule that is absorbed into the intestinal lymphatic system after oral administration. It is then released into the general blood circulation by the thoracic duct, thereby bypassing the portal circulation and first-pass metabolism in the liver, unlike endogenous testosterone. Following oral administration of 237 mg twice per day in males with hypogonadism, the mean (SD) C max was 1008 (581) ng/dL. T max is about five hours following oral administration. Decreased testosterone exposure was observed when administered without food. Following intramuscular administration of 750 mg testosterone undecanoate, serum testosterone concentrations reached a maximum after a median of seven days (range of four to 42 days), which then slowly declined. The mean (SD) C max was about 90.9 (68.8) ng/dL on the fourth day following injection of testosterone undecanoate. Steady-state serum testosterone concentration was achieved with the third injection at 14 weeks. At 42 days following the injection, testosterone undecanoate was nearly undetectable. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): There is no information available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 40% of circulating testosterone is bound to sex hormone-binding globulin (SHBG) and about 2% of the drug remains unbound to plasma proteins. The rest is loosely bound to albumin and other plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Testosterone undecanoate can be reduced to dihydrotestosterone undecanoate via 5α-reductase. In the circulation, the ester bond linking testosterone to the undecanoic acid is cleaved by endogenous non-specific esterases. Like all fatty acids, the undecanoic side chain undergoes β-oxidation to form acetyl coenzyme A (CoA) and, finally, propionyl CoA. Testosterone is metabolized to various 17-keto steroids through two different pathways to form major active metabolites, estradiol and dihydrotestosterone (DHT). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): About 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life of testosterone undecanoate is approximately two hours. Once testosterone is formed from testosterone undecanoate, the half life of testosterone can vary and the reported values in the literature remain inconsistent, ranging from 10 to to 100 minutes. Testosterone undecanoate in castor oil for intramuscular injection had a half life of 33.9 days, allowing it to maintain serum levels in the normal range for over 6 weeks.[A176954] •Clearance (Drug A): No clearance available •Clearance (Drug B): While there is limited information available, an earlier study reports a metabolic clearance rate of 24.5 mL/min/kg for testosterone following oral administration of 25 mg testosterone and 40 mg testosterone undecanoate in women. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD 50 is 4000 mg/kg in mice and rats. The subcutaneous LD 50 is 2880 mg/kg in mice and rats. There is limited information on testosterone undecanoate overdose. There was one report of acute overdose from an approved injectable testosterone product, which resulted in increased serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. There was one case of overdose following administration of oral testosterone undecanoate capsules: this patient inadvertently took a 20% higher dose than the maximum recommended dose but did not report any adverse reactions. Overdose should be managed with discontinuation of the drug in combination with appropriate symptomatic and supportive care. The abuse of anabolic androgenic steroids can result in serious adverse reactions, such as cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility, and aggression. Men receiving testosterone have experienced transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Aveed, Jatenzo, Kyzatrex, Tlando •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone undecanoate is an androgen indicated for testosterone replacement therapy in adult males with primary hypogonadism and hypogonadotropic hypogonadism. Output: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Does Abciximab and Testosterone interact?

•Drug A: Abciximab •Drug B: Testosterone •Severity: MODERATE •Description: Testosterone may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone is indicated to treat primary hypogonadism and hypogonadotropic hypogonadism. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics. The duration of action of testosterone is variable from patient to patient with a half life of 10-100 minutes. The therapeutic index is wide considering the normal testosterone levels in an adult man range from 300-1000ng/dL. Counsel patients regarding the risk of secondary exposure of testosterone topical products to children. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes. Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum. Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution. •Absorption (Drug A): No absorption available •Absorption (Drug B): A single 100mg topical dose of testosterone has an AUC of 10425±5521ng*h/dL and a C max of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of testosterone in elderly men is 80.36±24.51L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone is 40% bound to sex hormone binding globulin, 2% unbound, and the remainder is bound to albumin and other proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): 90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated metabolites. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of testosterone is highly variable, ranging from 10-100 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean metabolic clearance in middle aged men is 812±64L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Data regarding an overdose with a topical testosterone product is not readily available. In the case of overdose with an injectable product, patients may present with a cerebrovascular event. Treat overdoses by stopping testosterone products, washing off any topical products with soap and water, and initiating symptomatic and supportive treatments. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Testopel, Vogelxo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosteron Testosterona Testostérone Testosterone Testosteronum Virosterone •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone is a hormone used to treat hypogonadism, breast carcinoma in women, or the vasomotor symptoms of menopause.

Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Testosterone interact? Information: •Drug A: Abciximab •Drug B: Testosterone •Severity: MODERATE •Description: Testosterone may increase the anticoagulant activities of Abciximab. •Extended Description: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Testosterone is indicated to treat primary hypogonadism and hypogonadotropic hypogonadism. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics. The duration of action of testosterone is variable from patient to patient with a half life of 10-100 minutes. The therapeutic index is wide considering the normal testosterone levels in an adult man range from 300-1000ng/dL. Counsel patients regarding the risk of secondary exposure of testosterone topical products to children. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes. Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum. Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution. •Absorption (Drug A): No absorption available •Absorption (Drug B): A single 100mg topical dose of testosterone has an AUC of 10425±5521ng*h/dL and a C max of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of testosterone in elderly men is 80.36±24.51L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone is 40% bound to sex hormone binding globulin, 2% unbound, and the remainder is bound to albumin and other proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): 90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated metabolites. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of testosterone is highly variable, ranging from 10-100 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean metabolic clearance in middle aged men is 812±64L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Data regarding an overdose with a topical testosterone product is not readily available. In the case of overdose with an injectable product, patients may present with a cerebrovascular event. Treat overdoses by stopping testosterone products, washing off any topical products with soap and water, and initiating symptomatic and supportive treatments. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Testopel, Vogelxo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosteron Testosterona Testostérone Testosterone Testosteronum Virosterone •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Testosterone is a hormone used to treat hypogonadism, breast carcinoma in women, or the vasomotor symptoms of menopause. Output: Testosterone and derivatives may increase sensitivity to oral anticoagulants, increasing the risk of bleeding; however, the mechanism has not been fully elucidated. Although product labeling and various studies support that testosterone may potentiate anticoagulant effects, certain studies suggest that testosterone may increase the risk of venous thromboembolism (VTE). Despite the above findings, it is generally accepted that testosterone potentiates the anticoagulant effects of other drugs. The severity of the interaction is moderate.

Does Abciximab and Tetanus immune globulin, human interact?

•Drug A: Abciximab •Drug B: Tetanus immune globulin, human •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tetanus immune globulin, human. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Absorption (Drug A): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Route of elimination (Drug A): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Clearance (Drug A): No clearance available •Toxicity (Drug A): No toxicity available •Brand Names (Drug A): No brand names available •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Summary not found

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tetanus immune globulin, human interact? Information: •Drug A: Abciximab •Drug B: Tetanus immune globulin, human •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tetanus immune globulin, human. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Absorption (Drug A): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Route of elimination (Drug A): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Clearance (Drug A): No clearance available •Toxicity (Drug A): No toxicity available •Brand Names (Drug A): No brand names available •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Summary not found Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tezepelumab interact?

•Drug A: Abciximab •Drug B: Tezepelumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tezepelumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tezepelumab is indicated as an add-on maintenance treatment for patients aged 12 years and older with severe asthma. In Europe, it is reserved for patients who are inadequately controlled despite maintenance treatment with high-dose inhaled corticosteroids plus another drug. Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tezepelumab is a human monoclonal IgG2λ antibody blocking thymic stromal lymphopoietin (TSLP). Tezepelumab treatment in asthmatic patients improves disease markers, including blood and airway submucosal eosinophils and IgE, FeNO, IL-5, and IL-13 levels. Despite an excellent safety profile, tezepelumab may be associated with hypersensitivity reactions and increased risk of infection, especially by parasitic helminths. Patients receiving tezepelumab should not discontinue systemic or inhaled corticosteroids, and any reduction in these drugs should be performed cautiously. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Asthma is a heterogeneous chronic obstructive respiratory disease characterized by reduced airflow, chronic inflammation, and airway remodelling. Generally, asthma can be divided into "type 2" (T2, including allergic and eosinophilic presentations) and T2-low (including neutrophilic and paucigranulocytic presentations) endotypes, each driven by distinct underlying pathways. Thymic stromal lymphopoietin (TSLP) is an innate pleiotropic IL-2-family cytokine distantly related to IL-7; two forms of TSLP exist, with a short isoform (sfTSLP, 60 amino acids long) and a long isoform (lfTSLP, 159 amino acids long). The short isoform appears to be constitutively expressed, especially by lung and gut epithelial cells, while lfTSLP is upregulated in response to proinflammatory stimuli. While the role of sfTSLP is still unclear, lfTSLP has emerged as an upstream alarmin central to the pathophysiology of inflammatory disorders including asthma, atopic rhinitis, chronic obstructive pulmonary disease, eosinophilic esophagitis, and atopic dermatitis. Under normal conditions, lfTSLP interacts with its cognate receptor TSLPR, and IL-7Rα in a ternary complex with three contact sites labelled site I (TSLP:TSLPR), site II (TSLP:IL-7Rα), and site III (TSLPR:IL-7Rα). The assembly of the ternary complex is stepwise, as TSLP does not interact appreciably with IL-7Rα until after it has bound TSLPR. Complementary electrostatic surfaces on TSLP and TSLPR mediate initial high affinity formation of a TSLP:TSLPR complex ( K D of 32 nM and k a of 1.7 x 10 M s ). This initial binding induces a restructuring of the π-helical turn in the TSLP αA helix and structuring of the AB loop to facilitate binding of TSLP to a hydrophobic patch on IL-7Rα to form the ternary complex ( K D of 29 nM and k a of 1.23 x 10 M s ). The complete ternary complex is stabilized by additional interactions between TSLPR and IL-7Rα at site III near the transmembrane domain of each receptor. Formation of the ternary complex activates JAK1/2, which, through downstream pathways involving STAT3/5, NF-κB, PI3K, and MAPK, induces the expression of Th2 cytokines including IL-4, IL-5, IL-9, and IL-13. TSLP can induce Th2 cytokine production by stimulating dendritic cells and ILC2 cells (primarily in T2 asthma). Furthermore, TSLP has been implicated in steroid resistance of ILC2 cells. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of Th17 cells, which secrete IL-17A to recruit neutrophils and drive inflammation. In paucigranulocytic asthma, TSLP mediates cross-talk between mast cells, smooth muscle cells, and fibroblasts. Hence, despite different underlying pathways, TSLP appears to function as a critical upstream driver across asthma endotypes. Tezepelumab is a human monoclonal IgG2λ antibody that binds to TSLP with a dissociation constant of 15.8 pM. Specifically, the variable heavy chain domain (V H ) complementarity determining regions (CDRs) of tezepelumab bind TSLP at the AB -loop region and C-terminal region of the αD helix, obstructing the TSLPR binding region while leaving the IL-7Rα binding region unobstructed. As TSLP is incapable of binding IL-7Rα prior to its inclusion in the TSLP:TSLPR dimer, tezepelumab effectively blocks the assembly of the ternary complex and resulting downstream signalling. Furthermore, unlike existing therapies that act on specific downstream effector molecules, targeting TSLP ensures effective upstream blockade and is expected to be efficacious against multiple asthma endotypes. •Absorption (Drug A): No absorption available •Absorption (Drug B): When administered subcutaneously, tezepelumab reaches C max in approximately 3-10 days with an estimated absolute bioavailability of 77%, regardless of injection site choice. Tezepelumab displays dose-proportional pharmacokinetics over a range of 2.1-420 mg (0.01-2 times the recommended dose) following a single subcutaneous dose. With a 4-week dosing schedule, tezepelumab achieves steady-state kinetics after 12 weeks with a 1.86-fold C trough accumulation ratio. There are no clinically meaningful changes expected for tezepelumab pharmacokinetics in patients across patient populations, including those with renal or hepatic impairment. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Tezepelumab has a central V d of 3.9 L and a peripheral V d of 2.2 L (for a 70 kg individual). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As a human monoclonal antibody, tezepelumab is expected to be degraded by various proteolytic enzymes throughout the body. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As a human monoclonal antibody, tezepelumab is eliminated primarily through catabolism; there is no evidence of target-mediated clearance at the therapeutic dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Tezepelumab has an elimination half-life of ~26 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Tezepelumab has an estimated clearance of 0.17 L/d (for a 70 kg individual). •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Toxicity information regarding tezepelumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as opportunistic infections and other conditions related to immunosuppression. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tezspire •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tezepelumab is a human monoclonal IgG2λ thymic stromal lymphopoietin (TSLP)-blocking antibody for add-on maintenance therapy in severe asthma.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tezepelumab interact? Information: •Drug A: Abciximab •Drug B: Tezepelumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tezepelumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tezepelumab is indicated as an add-on maintenance treatment for patients aged 12 years and older with severe asthma. In Europe, it is reserved for patients who are inadequately controlled despite maintenance treatment with high-dose inhaled corticosteroids plus another drug. Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tezepelumab is a human monoclonal IgG2λ antibody blocking thymic stromal lymphopoietin (TSLP). Tezepelumab treatment in asthmatic patients improves disease markers, including blood and airway submucosal eosinophils and IgE, FeNO, IL-5, and IL-13 levels. Despite an excellent safety profile, tezepelumab may be associated with hypersensitivity reactions and increased risk of infection, especially by parasitic helminths. Patients receiving tezepelumab should not discontinue systemic or inhaled corticosteroids, and any reduction in these drugs should be performed cautiously. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Asthma is a heterogeneous chronic obstructive respiratory disease characterized by reduced airflow, chronic inflammation, and airway remodelling. Generally, asthma can be divided into "type 2" (T2, including allergic and eosinophilic presentations) and T2-low (including neutrophilic and paucigranulocytic presentations) endotypes, each driven by distinct underlying pathways. Thymic stromal lymphopoietin (TSLP) is an innate pleiotropic IL-2-family cytokine distantly related to IL-7; two forms of TSLP exist, with a short isoform (sfTSLP, 60 amino acids long) and a long isoform (lfTSLP, 159 amino acids long). The short isoform appears to be constitutively expressed, especially by lung and gut epithelial cells, while lfTSLP is upregulated in response to proinflammatory stimuli. While the role of sfTSLP is still unclear, lfTSLP has emerged as an upstream alarmin central to the pathophysiology of inflammatory disorders including asthma, atopic rhinitis, chronic obstructive pulmonary disease, eosinophilic esophagitis, and atopic dermatitis. Under normal conditions, lfTSLP interacts with its cognate receptor TSLPR, and IL-7Rα in a ternary complex with three contact sites labelled site I (TSLP:TSLPR), site II (TSLP:IL-7Rα), and site III (TSLPR:IL-7Rα). The assembly of the ternary complex is stepwise, as TSLP does not interact appreciably with IL-7Rα until after it has bound TSLPR. Complementary electrostatic surfaces on TSLP and TSLPR mediate initial high affinity formation of a TSLP:TSLPR complex ( K D of 32 nM and k a of 1.7 x 10 M s ). This initial binding induces a restructuring of the π-helical turn in the TSLP αA helix and structuring of the AB loop to facilitate binding of TSLP to a hydrophobic patch on IL-7Rα to form the ternary complex ( K D of 29 nM and k a of 1.23 x 10 M s ). The complete ternary complex is stabilized by additional interactions between TSLPR and IL-7Rα at site III near the transmembrane domain of each receptor. Formation of the ternary complex activates JAK1/2, which, through downstream pathways involving STAT3/5, NF-κB, PI3K, and MAPK, induces the expression of Th2 cytokines including IL-4, IL-5, IL-9, and IL-13. TSLP can induce Th2 cytokine production by stimulating dendritic cells and ILC2 cells (primarily in T2 asthma). Furthermore, TSLP has been implicated in steroid resistance of ILC2 cells. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of Th17 cells, which secrete IL-17A to recruit neutrophils and drive inflammation. In paucigranulocytic asthma, TSLP mediates cross-talk between mast cells, smooth muscle cells, and fibroblasts. Hence, despite different underlying pathways, TSLP appears to function as a critical upstream driver across asthma endotypes. Tezepelumab is a human monoclonal IgG2λ antibody that binds to TSLP with a dissociation constant of 15.8 pM. Specifically, the variable heavy chain domain (V H ) complementarity determining regions (CDRs) of tezepelumab bind TSLP at the AB -loop region and C-terminal region of the αD helix, obstructing the TSLPR binding region while leaving the IL-7Rα binding region unobstructed. As TSLP is incapable of binding IL-7Rα prior to its inclusion in the TSLP:TSLPR dimer, tezepelumab effectively blocks the assembly of the ternary complex and resulting downstream signalling. Furthermore, unlike existing therapies that act on specific downstream effector molecules, targeting TSLP ensures effective upstream blockade and is expected to be efficacious against multiple asthma endotypes. •Absorption (Drug A): No absorption available •Absorption (Drug B): When administered subcutaneously, tezepelumab reaches C max in approximately 3-10 days with an estimated absolute bioavailability of 77%, regardless of injection site choice. Tezepelumab displays dose-proportional pharmacokinetics over a range of 2.1-420 mg (0.01-2 times the recommended dose) following a single subcutaneous dose. With a 4-week dosing schedule, tezepelumab achieves steady-state kinetics after 12 weeks with a 1.86-fold C trough accumulation ratio. There are no clinically meaningful changes expected for tezepelumab pharmacokinetics in patients across patient populations, including those with renal or hepatic impairment. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Tezepelumab has a central V d of 3.9 L and a peripheral V d of 2.2 L (for a 70 kg individual). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As a human monoclonal antibody, tezepelumab is expected to be degraded by various proteolytic enzymes throughout the body. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As a human monoclonal antibody, tezepelumab is eliminated primarily through catabolism; there is no evidence of target-mediated clearance at the therapeutic dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Tezepelumab has an elimination half-life of ~26 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Tezepelumab has an estimated clearance of 0.17 L/d (for a 70 kg individual). •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Toxicity information regarding tezepelumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as opportunistic infections and other conditions related to immunosuppression. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tezspire •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tezepelumab is a human monoclonal IgG2λ thymic stromal lymphopoietin (TSLP)-blocking antibody for add-on maintenance therapy in severe asthma. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Thalidomide interact?

•Drug A: Abciximab •Drug B: Thalidomide •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Thalidomide. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •Absorption (Drug A): No absorption available •Absorption (Drug B): The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral clearance of thalidomide is 10.50 ± 2.10 L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Talidomida Thalidomide Thalidomidum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Thalidomide interact? Information: •Drug A: Abciximab •Drug B: Thalidomide •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Thalidomide. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •Absorption (Drug A): No absorption available •Absorption (Drug B): The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The oral clearance of thalidomide is 10.50 ± 2.10 L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Talidomida Thalidomide Thalidomidum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Thiotepa interact?

•Drug A: Abciximab •Drug B: Thiotepa •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Thiotepa. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Urinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.5 to 4.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tepadina •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Thiotepa interact? Information: •Drug A: Abciximab •Drug B: Thiotepa •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Thiotepa. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric patients. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Urinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.5 to 4.1 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tepadina •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tiaprofenic acid interact?

•Drug A: Abciximab •Drug B: Tiaprofenic acid •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tiaprofenic acid is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tiaprofenic acid is used to treat pain, especially arthritic pain. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tiaprofenic acid is a non-steroidal anti-inflammatory drug of the arylpropionic acid (profen) class, used to treat pain, especially arthritic pain. The typical adult dose is 300mg twice daily. This drug is not recommended for use in the pediatric population. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tiaprofenic acid belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). It works by blocking the production of a chemical (prostaglandin) which the body produces in response to injury or certain diseases. This prostaglandin would otherwise go on to cause swelling, pain and inflammation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Bioavailability is 90% following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic (10%). Sparingly metabolised in the liver to two inactive metabolites. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.5-2.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide tiaprofenique Acido tiaprofenico Acidum tiaprofenicum Tiaprofenic acid Tiaprofensäure •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tiaprofenic acid is a nonsteroidal anti-inflammatory (NSAID) used to manage inflammation and analgesia associated with rheumatoid arthritis and osteoarthritis.

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Tiaprofenic acid interact? Information: •Drug A: Abciximab •Drug B: Tiaprofenic acid •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tiaprofenic acid is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tiaprofenic acid is used to treat pain, especially arthritic pain. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tiaprofenic acid is a non-steroidal anti-inflammatory drug of the arylpropionic acid (profen) class, used to treat pain, especially arthritic pain. The typical adult dose is 300mg twice daily. This drug is not recommended for use in the pediatric population. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tiaprofenic acid belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). It works by blocking the production of a chemical (prostaglandin) which the body produces in response to injury or certain diseases. This prostaglandin would otherwise go on to cause swelling, pain and inflammation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Bioavailability is 90% following oral administration. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic (10%). Sparingly metabolised in the liver to two inactive metabolites. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.5-2.5 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide tiaprofenique Acido tiaprofenico Acidum tiaprofenicum Tiaprofenic acid Tiaprofensäure •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tiaprofenic acid is a nonsteroidal anti-inflammatory (NSAID) used to manage inflammation and analgesia associated with rheumatoid arthritis and osteoarthritis. Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Tibolone interact?

•Drug A: Abciximab •Drug B: Tibolone •Severity: MINOR •Description: Tibolone may increase the anticoagulant activities of Abciximab. •Extended Description: Tibolone has the tendency to increase blood fibrinolytic activity, leading to lower fibrinogen levels, higher antithrombin III, plasminogen and fibrinolytic activity values. Co-administration of tibolone with anticoagulant agents may lead to enhanced therapeutic action and anticoagulant effect of those drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the relief of post-menopausal symptoms and for the prevention of osteoporosis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator. Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): This drug's effects are owed to the activity of its metabolites in various tissues. Upon ingestion, tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body. The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens. In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner. Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences. The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process. In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway. The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tibolone is 96% bound to plasma proteins, most likely albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites in feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life is approximately 45 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Elimination of tibolone is not dependent renal function. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): >2000 mg/kg The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations. Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage. Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): tibolona Tibolone tibolonum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): No summary available

Tibolone has the tendency to increase blood fibrinolytic activity, leading to lower fibrinogen levels, higher antithrombin III, plasminogen and fibrinolytic activity values. Co-administration of tibolone with anticoagulant agents may lead to enhanced therapeutic action and anticoagulant effect of those drugs. The severity of the interaction is minor.

Question: Does Abciximab and Tibolone interact? Information: •Drug A: Abciximab •Drug B: Tibolone •Severity: MINOR •Description: Tibolone may increase the anticoagulant activities of Abciximab. •Extended Description: Tibolone has the tendency to increase blood fibrinolytic activity, leading to lower fibrinogen levels, higher antithrombin III, plasminogen and fibrinolytic activity values. Co-administration of tibolone with anticoagulant agents may lead to enhanced therapeutic action and anticoagulant effect of those drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the relief of post-menopausal symptoms and for the prevention of osteoporosis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator. Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): This drug's effects are owed to the activity of its metabolites in various tissues. Upon ingestion, tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body. The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens. In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner. Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences. The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process. In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway. The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tibolone is 96% bound to plasma proteins, most likely albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites in feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The elimination half-life is approximately 45 h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Elimination of tibolone is not dependent renal function. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): >2000 mg/kg The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations. Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage. Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): tibolona Tibolone tibolonum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): No summary available Output: Tibolone has the tendency to increase blood fibrinolytic activity, leading to lower fibrinogen levels, higher antithrombin III, plasminogen and fibrinolytic activity values. Co-administration of tibolone with anticoagulant agents may lead to enhanced therapeutic action and anticoagulant effect of those drugs. The severity of the interaction is minor.

Does Abciximab and Ticagrelor interact?

•Drug A: Abciximab •Drug B: Ticagrelor •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Ticagrelor. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ticagrelor is a P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Ticagrelor is a P2Y 12 receptor antagonist. The P2Y 12 receptor couples with Gα i2 and other G i proteins which inhibit adenylyl cyclase. G i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y 12 receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke. •Absorption (Drug A): No absorption available •Absorption (Drug B): Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The steady state volume of distribution of ticagrelor is 88 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of ticagrelor is 0.00584L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Patients experiencing an overdose may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Brilinta, Brilique •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ticagrelor •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke and cardiovascular death.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Ticagrelor interact? Information: •Drug A: Abciximab •Drug B: Ticagrelor •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Ticagrelor. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ticagrelor is a P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Ticagrelor is a P2Y 12 receptor antagonist. The P2Y 12 receptor couples with Gα i2 and other G i proteins which inhibit adenylyl cyclase. G i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y 12 receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke. •Absorption (Drug A): No absorption available •Absorption (Drug B): Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The steady state volume of distribution of ticagrelor is 88 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 12 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): The renal clearance of ticagrelor is 0.00584L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Patients experiencing an overdose may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Brilinta, Brilique •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ticagrelor •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke and cardiovascular death. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Ticlopidine interact?

•Drug A: Abciximab •Drug B: Ticlopidine •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Ticlopidine is combined with Abciximab. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption is greater than 80%. Food increases absorption by approximately 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution was not quantified. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less). •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ticlopidine clearance was not quantified, but clearance decreases with age. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA).

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Ticlopidine interact? Information: •Drug A: Abciximab •Drug B: Ticlopidine •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Ticlopidine is combined with Abciximab. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption is greater than 80%. Food increases absorption by approximately 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution was not quantified. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less). •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age. •Clearance (Drug A): No clearance available •Clearance (Drug B): Ticlopidine clearance was not quantified, but clearance decreases with age. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA). Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Tildrakizumab interact?

•Drug A: Abciximab •Drug B: Tildrakizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tildrakizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Moderate-severe plaque psoriasis,. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tildrakuzimab is a targeted immunomodulator that decreases inflammation by inhibiting the action of various cytokines associated with plaque psoriasis, thus relieving its symptom of scaly plaques,. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): This drug selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function IL-23 regulates Th17 cells and is a powerful activator of keratinocyte proliferation. Targeting IL-23p19 alone has been found to be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis. Upon administration, downregulation of Th17 and Th22 cell responses occur. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines. •Absorption (Drug A): No absorption available •Absorption (Drug B): The mean (± SD) steady-state trough concentrations at 16 weeks post initiation of treatment ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%). The absolute bioavailability of tildrakizumab is estimated to be about 73-80% after subcutaneous administration. The peak concentration (Cmax) is reached by approximately 6 days. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The geometric mean (CV%) volume of distribution is 10.8 L (24%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life is approximately 23 days (23%). •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean (CV%) systemic clearance is 0.32 L/day (38%). •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): It is advised to evaluate patients for tuberculosis infection prior to initiating treatment with ILUMYA. This drug may increase the risk of infection. It is advisable to perform tests for current tuberculosis status, as this drug may lead to reactivation of latent infection. A common issue for monoclonal antibody drugs is the development of antibodies to the drugs, thus rendering them less effective or completely ineffective. A clinical trial was done to assess antibody development to this drug,. Up until week 64, approximately 6.5% of subjects treated with ILUMYA 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all patients receiving ILUMYA) had antibodies that were considered neutralizing. The development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and decreased efficacy. Most common (≥ 1% and at a higher rate than placebo) adverse reactions associated with ILUMYA treatment are upper respiratory infections, injection site reactions, and diarrhea. Cases of angioedema and urticaria occurred in ILUMYA treated subjects in various clinical trials. If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy should be initiated. In an embryo-fetal study, subcutaneous doses up to 300 mg/kg tildrakizumab were given to pregnant cynomolgus monkeys once every two weeks during organogenesis to 118 days gestation (22 days from parturition). No maternal or embryo-fetal toxicities were seen at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Ilumya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tildrakizumab is an interleukin-23 antagonist used to treat moderate to severe plaque psoriasis.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tildrakizumab interact? Information: •Drug A: Abciximab •Drug B: Tildrakizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tildrakizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Moderate-severe plaque psoriasis,. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tildrakuzimab is a targeted immunomodulator that decreases inflammation by inhibiting the action of various cytokines associated with plaque psoriasis, thus relieving its symptom of scaly plaques,. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): This drug selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function IL-23 regulates Th17 cells and is a powerful activator of keratinocyte proliferation. Targeting IL-23p19 alone has been found to be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis. Upon administration, downregulation of Th17 and Th22 cell responses occur. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines. •Absorption (Drug A): No absorption available •Absorption (Drug B): The mean (± SD) steady-state trough concentrations at 16 weeks post initiation of treatment ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%). The absolute bioavailability of tildrakizumab is estimated to be about 73-80% after subcutaneous administration. The peak concentration (Cmax) is reached by approximately 6 days. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The geometric mean (CV%) volume of distribution is 10.8 L (24%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life is approximately 23 days (23%). •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean (CV%) systemic clearance is 0.32 L/day (38%). •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): It is advised to evaluate patients for tuberculosis infection prior to initiating treatment with ILUMYA. This drug may increase the risk of infection. It is advisable to perform tests for current tuberculosis status, as this drug may lead to reactivation of latent infection. A common issue for monoclonal antibody drugs is the development of antibodies to the drugs, thus rendering them less effective or completely ineffective. A clinical trial was done to assess antibody development to this drug,. Up until week 64, approximately 6.5% of subjects treated with ILUMYA 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all patients receiving ILUMYA) had antibodies that were considered neutralizing. The development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and decreased efficacy. Most common (≥ 1% and at a higher rate than placebo) adverse reactions associated with ILUMYA treatment are upper respiratory infections, injection site reactions, and diarrhea. Cases of angioedema and urticaria occurred in ILUMYA treated subjects in various clinical trials. If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy should be initiated. In an embryo-fetal study, subcutaneous doses up to 300 mg/kg tildrakizumab were given to pregnant cynomolgus monkeys once every two weeks during organogenesis to 118 days gestation (22 days from parturition). No maternal or embryo-fetal toxicities were seen at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Ilumya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tildrakizumab is an interleukin-23 antagonist used to treat moderate to severe plaque psoriasis. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tinzaparin interact?

•Drug A: Abciximab •Drug B: Tinzaparin •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tinzaparin. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tinzaparin is used for the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism. It is also used for the treatment of deep vein thrombosis and/or pulmonary embolism. It is indicated for use in preventing clot formation in indwelling intravenous lines for hemodialysis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tinzaparin, like other LMWHs, have a higher anti-Xa activity than anti-IIa activity. The anti-Xa activity of tinzaparin is 2.0 +/- 0.5 times greater than its to anti-IIa activity. Heparin exhibits approximately equal inhibitory activity against Xa and IIa. Tinzaparin is an anticoagulant that blocks the formation of thrombi. Like all LMWHs, tinzaparin only causes activated partial thromboplastin time (aPTT) prolongation at higher doses and routine monitoring is not recommended. However, anti-factor Xa levels may be monitored in some conditions such as pregnancy and renal dysfunction. Its use should be avoided in patients with a creatinine clearance less than 20 mL/min. In these patients, unfractionated heparin should be used. Tinzaparin can be used in patients who have a creatinine clearance between 20-30 mL/min, giving it the highest safety threshold for use in renal failure patients compared to all the LMWHs. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tinzaparin binds to the plasma protein antithrombin III, forming a complex with then accelerates the inhibition of factor Xa. Its affinity for factor Xa is 2-4 times greater than that of unbound ATIII. The inactivation of factor Xa in turn will exponentially generation of thrombin (factor IIa) molecules, which is needed to activate fibrinogen to fibrin. The coagulation cascade is inhibited because fibrin cannot be formed in the presence of tinzaparin. Like all LMWH, it cannot be given intramuscularly due to increased risk of hematoma. •Absorption (Drug A): No absorption available •Absorption (Drug B): Subcutaneous injection - about 90% when measured as anti-Xa activity versus 67% for anti-IIa activity. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Anti-Xa activity is 4 L. Anti-IIa activity is 10.9 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Low protein binding compared to unfractionated heparin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sulfation and polymerization occurs in the liver. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Linear elimination through kidneys •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Anti-Xa activity is 82 minutes. Anti-IIa activity is 71 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance is dose-dependant. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Osteoporosis with increasing duration of use, bleeding, alopecia, heparin induced thrombocytopenia (HIT). All of these adverse drug reactions occur less with LMWH compared to unfractionated heparin. Tinzaparin showed no toxic effects at doses up to 5 mg/kg in mice, rats, or dogs in standard acute, subacute, and chronic toxicity studies. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Innohep •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tinzaparin is a low molecular weight heparin used for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Tinzaparin interact? Information: •Drug A: Abciximab •Drug B: Tinzaparin •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tinzaparin. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tinzaparin is used for the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism. It is also used for the treatment of deep vein thrombosis and/or pulmonary embolism. It is indicated for use in preventing clot formation in indwelling intravenous lines for hemodialysis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tinzaparin, like other LMWHs, have a higher anti-Xa activity than anti-IIa activity. The anti-Xa activity of tinzaparin is 2.0 +/- 0.5 times greater than its to anti-IIa activity. Heparin exhibits approximately equal inhibitory activity against Xa and IIa. Tinzaparin is an anticoagulant that blocks the formation of thrombi. Like all LMWHs, tinzaparin only causes activated partial thromboplastin time (aPTT) prolongation at higher doses and routine monitoring is not recommended. However, anti-factor Xa levels may be monitored in some conditions such as pregnancy and renal dysfunction. Its use should be avoided in patients with a creatinine clearance less than 20 mL/min. In these patients, unfractionated heparin should be used. Tinzaparin can be used in patients who have a creatinine clearance between 20-30 mL/min, giving it the highest safety threshold for use in renal failure patients compared to all the LMWHs. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tinzaparin binds to the plasma protein antithrombin III, forming a complex with then accelerates the inhibition of factor Xa. Its affinity for factor Xa is 2-4 times greater than that of unbound ATIII. The inactivation of factor Xa in turn will exponentially generation of thrombin (factor IIa) molecules, which is needed to activate fibrinogen to fibrin. The coagulation cascade is inhibited because fibrin cannot be formed in the presence of tinzaparin. Like all LMWH, it cannot be given intramuscularly due to increased risk of hematoma. •Absorption (Drug A): No absorption available •Absorption (Drug B): Subcutaneous injection - about 90% when measured as anti-Xa activity versus 67% for anti-IIa activity. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Anti-Xa activity is 4 L. Anti-IIa activity is 10.9 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Low protein binding compared to unfractionated heparin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Sulfation and polymerization occurs in the liver. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Linear elimination through kidneys •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Anti-Xa activity is 82 minutes. Anti-IIa activity is 71 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance is dose-dependant. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Osteoporosis with increasing duration of use, bleeding, alopecia, heparin induced thrombocytopenia (HIT). All of these adverse drug reactions occur less with LMWH compared to unfractionated heparin. Tinzaparin showed no toxic effects at doses up to 5 mg/kg in mice, rats, or dogs in standard acute, subacute, and chronic toxicity studies. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Innohep •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tinzaparin is a low molecular weight heparin used for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Tioguanine interact?

•Drug A: Abciximab •Drug B: Tioguanine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tioguanine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 minutes) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral, mouse: LD 50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Lanvis, Tabloid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Amino 6MP 6-Mercaptoguanine 6-TG 6-Thioguanine Thioguanine Tioguanin Tioguanina Tioguanine Tioguaninum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tioguanine is a purine analogue antineoplastic agent used for the induction of remission, and for remission consolidation in patients with acute nonlymphocytic anemias.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Tioguanine interact? Information: •Drug A: Abciximab •Drug B: Tioguanine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tioguanine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%) •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 minutes) •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral, mouse: LD 50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Lanvis, Tabloid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Amino 6MP 6-Mercaptoguanine 6-TG 6-Thioguanine Thioguanine Tioguanin Tioguanina Tioguanine Tioguaninum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tioguanine is a purine analogue antineoplastic agent used for the induction of remission, and for remission consolidation in patients with acute nonlymphocytic anemias. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tipranavir interact?

•Drug A: Abciximab •Drug B: Tipranavir •Severity: MODERATE •Description: Tipranavir may increase the antiplatelet activities of Abciximab. •Extended Description: In vitro experiments have demonstrated that tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving ritonavir. In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding incidents and death. Therefore, the bleeding risk of antiplatelet agents may be increased with the concomitant use of tipranavir. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. 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): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption is limited, although no absolute quantification of absorption is available. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5-6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral LD 50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Aptivus •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tipranavir is a protease inhibitor used to treat HIV-1 resistant to more than 1 protease inhibitor.

In vitro experiments have demonstrated that tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving ritonavir. In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding incidents and death. Therefore, the bleeding risk of antiplatelet agents may be increased with the concomitant use of tipranavir. The severity of the interaction is moderate.

Question: Does Abciximab and Tipranavir interact? Information: •Drug A: Abciximab •Drug B: Tipranavir •Severity: MODERATE •Description: Tipranavir may increase the antiplatelet activities of Abciximab. •Extended Description: In vitro experiments have demonstrated that tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving ritonavir. In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding incidents and death. Therefore, the bleeding risk of antiplatelet agents may be increased with the concomitant use of tipranavir. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. 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): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorption is limited, although no absolute quantification of absorption is available. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5-6 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral LD 50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Aptivus •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tipranavir is a protease inhibitor used to treat HIV-1 resistant to more than 1 protease inhibitor. Output: In vitro experiments have demonstrated that tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving ritonavir. In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding incidents and death. Therefore, the bleeding risk of antiplatelet agents may be increased with the concomitant use of tipranavir. The severity of the interaction is moderate.

Does Abciximab and Tirofiban interact?

•Drug A: Abciximab •Drug B: Tirofiban •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Tirofiban is combined with Abciximab. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For treatment, in combination with heparin, of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation. When administered intravenously, tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Tirofiban has been recently shown in patients with unstable angina to reduce ischemic events at 48 hours following infusion when compared to standard heparin therapy. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Platelet aggregation inhibition is reversible following cessation of the infusion of tirofiban. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 22 to 42 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 65% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Metabolism appears to be limited. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 213 - 314 mL/min [Healthy subjects] 152 - 267 mL/min [patients with coronary artery disease] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Aggrastat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tirofiban Tirofibán Tirofibanum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tirofiban is a platelet aggregation inhibitor used to prevent thrombotic events in non-ST elevated acute coronary syndrome.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Tirofiban interact? Information: •Drug A: Abciximab •Drug B: Tirofiban •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Tirofiban is combined with Abciximab. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For treatment, in combination with heparin, of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation. When administered intravenously, tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Tirofiban has been recently shown in patients with unstable angina to reduce ischemic events at 48 hours following infusion when compared to standard heparin therapy. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Platelet aggregation inhibition is reversible following cessation of the infusion of tirofiban. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 22 to 42 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 65% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Metabolism appears to be limited. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): 213 - 314 mL/min [Healthy subjects] 152 - 267 mL/min [patients with coronary artery disease] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Aggrastat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tirofiban Tirofibán Tirofibanum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tirofiban is a platelet aggregation inhibitor used to prevent thrombotic events in non-ST elevated acute coronary syndrome. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Tislelizumab interact?

•Drug A: Abciximab •Drug B: Tislelizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tislelizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tislelizumab is indicated as monotherapy for the treatment of unresectable, locally advanced, or metastatic esophageal squamous cell carcinoma in adults after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor, such as platinum-based chemotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tislelizumab decreased tumour growth in xenograft models and a human PD-1 transgenic mouse model. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1 and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in T cells in in vitro cell-based assays. •Absorption (Drug A): No absorption available •Absorption (Drug B): The pharmacokinetics (PK) of tislelizumab were characterized using population PK analysis with concentration data from 2 596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every 2 weeks, 2.0 and 5.0 mg/kg every 3 weeks, and 200 mg every 3 weeks. The time to reach 90% steady-state level is approximately 84 days (12 weeks) after 200 mg doses once every 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately 2-fold. Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A population pharmacokinetic analysis indicates that the steady-state volume of distribution is 6.42 L, which is typical of monoclonal antibodies with limited distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available on the protein binding of tislelizumab. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Based on population PK analysis, the geometrical mean terminal half-life of tislelizumab was approximately 23.8 days with a coefficient variation (CV) of 31%. •Clearance (Drug A): No clearance available •Clearance (Drug B): Based on population PK analysis, the clearance of tislelizumab was 0.153 l/day with an interindividual variability of 26.3%. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There are no available data on the use of tislelizumab in pregnant women. Based on its mechanism of action, tislelizumab can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signaling has been shown to disrupt tolerance to the fetus and result in increased fetal loss. Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing fetus. Women should be advised of the potential risk to a fetus. Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab. No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10, or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations). There is no information on overdose with tislelizumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse drug reactions, and appropriate symptomatic treatment should be instituted immediately. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tevimbra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tislelizumab is an IgG4 variant monoclonal antibody against PD-1 indicated for the treatment of unresectable, locally advanced or metastatic esophageal squamous cell carcinoma

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tislelizumab interact? Information: •Drug A: Abciximab •Drug B: Tislelizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tislelizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tislelizumab is indicated as monotherapy for the treatment of unresectable, locally advanced, or metastatic esophageal squamous cell carcinoma in adults after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor, such as platinum-based chemotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tislelizumab decreased tumour growth in xenograft models and a human PD-1 transgenic mouse model. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1 and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in T cells in in vitro cell-based assays. •Absorption (Drug A): No absorption available •Absorption (Drug B): The pharmacokinetics (PK) of tislelizumab were characterized using population PK analysis with concentration data from 2 596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every 2 weeks, 2.0 and 5.0 mg/kg every 3 weeks, and 200 mg every 3 weeks. The time to reach 90% steady-state level is approximately 84 days (12 weeks) after 200 mg doses once every 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately 2-fold. Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A population pharmacokinetic analysis indicates that the steady-state volume of distribution is 6.42 L, which is typical of monoclonal antibodies with limited distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available on the protein binding of tislelizumab. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Based on population PK analysis, the geometrical mean terminal half-life of tislelizumab was approximately 23.8 days with a coefficient variation (CV) of 31%. •Clearance (Drug A): No clearance available •Clearance (Drug B): Based on population PK analysis, the clearance of tislelizumab was 0.153 l/day with an interindividual variability of 26.3%. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There are no available data on the use of tislelizumab in pregnant women. Based on its mechanism of action, tislelizumab can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signaling has been shown to disrupt tolerance to the fetus and result in increased fetal loss. Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing fetus. Women should be advised of the potential risk to a fetus. Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab. No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10, or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations). There is no information on overdose with tislelizumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse drug reactions, and appropriate symptomatic treatment should be instituted immediately. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tevimbra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tislelizumab is an IgG4 variant monoclonal antibody against PD-1 indicated for the treatment of unresectable, locally advanced or metastatic esophageal squamous cell carcinoma Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tisotumab vedotin interact?

•Drug A: Abciximab •Drug B: Tisotumab vedotin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tisotumab vedotin. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to in vitro studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fcγ receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant activity. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) C max of tisotumab vedotin-tftv was 40.8 (8.12) μg/mL and the mean (± SD) AUC was 57.5 (13.4) day x μg/mL. The mean (± SD) C max of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The C max of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of MMAE ranged from 68% to 82% in vitro. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized by CYP3A4 in vitro. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information on the LD 50 values and overdose profile of tisotumab vedotin. Tisotumab vedotin is associated with a risk for ocular toxicity. In clinical trials, ocular adverse reactions occurred in 60% of patients with cervical cancer. The most common reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). More severe reactions included ulcerative keratitis, ulcerative keratitis with perforation requiring corneal transplantation, and symblepharon in patients with other tumor types. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tivdak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tisotumab vedotin is a tissue factor-directed antibody drug conjugate that is used to treat adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tisotumab vedotin interact? Information: •Drug A: Abciximab •Drug B: Tisotumab vedotin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tisotumab vedotin. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to in vitro studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fcγ receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant activity. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) C max of tisotumab vedotin-tftv was 40.8 (8.12) μg/mL and the mean (± SD) AUC was 57.5 (13.4) day x μg/mL. The mean (± SD) C max of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The C max of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of MMAE ranged from 68% to 82% in vitro. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized by CYP3A4 in vitro. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no information on the LD 50 values and overdose profile of tisotumab vedotin. Tisotumab vedotin is associated with a risk for ocular toxicity. In clinical trials, ocular adverse reactions occurred in 60% of patients with cervical cancer. The most common reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). More severe reactions included ulcerative keratitis, ulcerative keratitis with perforation requiring corneal transplantation, and symblepharon in patients with other tumor types. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Tivdak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tisotumab vedotin is a tissue factor-directed antibody drug conjugate that is used to treat adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tocilizumab interact?

•Drug A: Abciximab •Drug B: Tocilizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tocilizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. •Absorption (Drug A): No absorption available •Absorption (Drug B): A 162mg subcutaneous dose given weekly has a C max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C max of 154±42µg/mL and an AUC of 39216±14304µg*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the serum protein binding of tocilizumab is not readily available. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Data regarding the exact route of elimination of monoclonal antibodies is not readily available. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher doses. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Actemra, RoActemra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA).

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tocilizumab interact? Information: •Drug A: Abciximab •Drug B: Tocilizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tocilizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. •Absorption (Drug A): No absorption available •Absorption (Drug B): A 162mg subcutaneous dose given weekly has a C max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C max of 154±42µg/mL and an AUC of 39216±14304µg*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the serum protein binding of tocilizumab is not readily available. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Data regarding the exact route of elimination of monoclonal antibodies is not readily available. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher doses. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Actemra, RoActemra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA). Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tofacitinib interact?

•Drug A: Abciximab •Drug B: Tofacitinib •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tofacitinib. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tofacitinib is indicated for the treatment of adult patients with moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers. It is also indicated as an oral solution in patients ≥2 years of age for the treatment of polyarticular course juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Tofacitinib is not recommended to be used in combination with other biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressive agents such as azathioprine or cyclosporine. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well. •Absorption (Drug A): No absorption available •Absorption (Drug B): 74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max ) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vd= 87L after intravenous administration. Distribution is equal between red blood cells and plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 40%, mostly bound to albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): 70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated as unchanged drug. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): ~3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking. Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. Role of JAK inhibition in the development of gastrointestinal perforation is not known. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Xeljanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tofacitinib is a Janus kinase (JAK) inhibitor used to treat rheumatic conditions, such as rheumatoid arthritis and ankylosing spondylitis, and ulcerative colitis.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Tofacitinib interact? Information: •Drug A: Abciximab •Drug B: Tofacitinib •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Tofacitinib. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tofacitinib is indicated for the treatment of adult patients with moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers. It is also indicated as an oral solution in patients ≥2 years of age for the treatment of polyarticular course juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Tofacitinib is not recommended to be used in combination with other biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressive agents such as azathioprine or cyclosporine. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well. •Absorption (Drug A): No absorption available •Absorption (Drug B): 74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max ) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vd= 87L after intravenous administration. Distribution is equal between red blood cells and plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 40%, mostly bound to albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): 70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated as unchanged drug. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): ~3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking. Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. Role of JAK inhibition in the development of gastrointestinal perforation is not known. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Xeljanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tofacitinib is a Janus kinase (JAK) inhibitor used to treat rheumatic conditions, such as rheumatoid arthritis and ankylosing spondylitis, and ulcerative colitis. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tolfenamic acid interact?

•Drug A: Abciximab •Drug B: Tolfenamic acid •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tolfenamic acid is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In the information for tolfenamic acid, it is stated that this drug, being an NSAID, is effective in treating the pain associated with the acute attack of migraines in adults. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Studies have shown that tolfenamic acid presents a non-dose dependent partial inhibition of irritant-induced temperature rise as well as a dose-dependent inhibition of skin edema. By studying its NSAID properties more closely, it was noted a dose-related inhibition of serum thromboxane which indicated the inhibition of COX-1. In the same line, there was noted a inhibition of prostaglandin E2 synthesis which marks a related COX-2 inhibition. The maximal inhibition of thromboxane was greater than 80% as well as is proven to be a potent prostaglandin E inhibitor. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors. As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h. It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively. The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml. The bioavailability of tolfenamic acid is around 75%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution is of 1.79-3.2 L/kg. When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose. Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The first pass metabolism accounts for 20% of the administered dose of tolfenamic acid. Urine metabolite studies have demonstrated the identification of five metabolites from which three of them are monohydroxylated, one is monohydroxylated and hydroxylated and one last metabolite that presented and oxidized methyl group to form a carboxyl group. Two of these hydroxylated metabolites are N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates. Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The estimated half-life of tolfenamic acid is 8.01-13.50 hours. When tested intravenously, the reported half-life was 6.1h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg. When tested intravenously, the reported clearance rate was 72.4 ml.h/kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): No summary available

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Tolfenamic acid interact? Information: •Drug A: Abciximab •Drug B: Tolfenamic acid •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tolfenamic acid is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In the information for tolfenamic acid, it is stated that this drug, being an NSAID, is effective in treating the pain associated with the acute attack of migraines in adults. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Studies have shown that tolfenamic acid presents a non-dose dependent partial inhibition of irritant-induced temperature rise as well as a dose-dependent inhibition of skin edema. By studying its NSAID properties more closely, it was noted a dose-related inhibition of serum thromboxane which indicated the inhibition of COX-1. In the same line, there was noted a inhibition of prostaglandin E2 synthesis which marks a related COX-2 inhibition. The maximal inhibition of thromboxane was greater than 80% as well as is proven to be a potent prostaglandin E inhibitor. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors. As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h. It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively. The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml. The bioavailability of tolfenamic acid is around 75%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution is of 1.79-3.2 L/kg. When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose. Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The first pass metabolism accounts for 20% of the administered dose of tolfenamic acid. Urine metabolite studies have demonstrated the identification of five metabolites from which three of them are monohydroxylated, one is monohydroxylated and hydroxylated and one last metabolite that presented and oxidized methyl group to form a carboxyl group. Two of these hydroxylated metabolites are N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates. Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The estimated half-life of tolfenamic acid is 8.01-13.50 hours. When tested intravenously, the reported half-life was 6.1h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg. When tested intravenously, the reported clearance rate was 72.4 ml.h/kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): No summary available Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Tolmetin interact?

•Drug A: Abciximab •Drug B: Tolmetin •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tolmetin is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, including the treatment of acute flares long-term management. Also for treatment of juvenile rheumatoid arthritis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tolmetin is a nonsteroidal anti-inflammatory agent. Studies in animals have shown tolmetin to possess anti-inflammatory, analgesic and antipyretic activity. In the rat, tolmetin prevents the development of experimentally induced polyarthritis and also decreases established inflammation. In patients with either rheumatoid arthritis or osteaoarthritis, tolmetin is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetin is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. tolmetin has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mode of action of tolmetin is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation. Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin does not appear to alter the course of the underlying disease in man. •Absorption (Drug A): No absorption available •Absorption (Drug B): Rapidly and almost completely absorbed with peak plasma levels being reached within 30-60 minutes after an oral therapeutic dose. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Biphasic elimination from the plasma consisting of a rapid phase with a half-life of one to 2 hours followed by a slower phase with a half-life of about 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolmetin Tolmetina Tolmétine Tolmetino Tolmetinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tolmetin is an NSAID used to treat acute flares of various painful conditions and used for the long term management of osteoarthritis, rheumatoid arthritis, and juvenile arthritis.

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Tolmetin interact? Information: •Drug A: Abciximab •Drug B: Tolmetin •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tolmetin is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, including the treatment of acute flares long-term management. Also for treatment of juvenile rheumatoid arthritis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tolmetin is a nonsteroidal anti-inflammatory agent. Studies in animals have shown tolmetin to possess anti-inflammatory, analgesic and antipyretic activity. In the rat, tolmetin prevents the development of experimentally induced polyarthritis and also decreases established inflammation. In patients with either rheumatoid arthritis or osteaoarthritis, tolmetin is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetin is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. tolmetin has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mode of action of tolmetin is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation. Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin does not appear to alter the course of the underlying disease in man. •Absorption (Drug A): No absorption available •Absorption (Drug B): Rapidly and almost completely absorbed with peak plasma levels being reached within 30-60 minutes after an oral therapeutic dose. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Biphasic elimination from the plasma consisting of a rapid phase with a half-life of one to 2 hours followed by a slower phase with a half-life of about 5 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolmetin Tolmetina Tolmétine Tolmetino Tolmetinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tolmetin is an NSAID used to treat acute flares of various painful conditions and used for the long term management of osteoarthritis, rheumatoid arthritis, and juvenile arthritis. Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Topotecan interact?

•Drug A: Abciximab •Drug B: Topotecan •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Topotecan. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 35% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 2-3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The primary anticipated complication of overdosage would consist of bone marrow suppression. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Hycamtin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Topotecan Topotecane Topotecanum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Topotecan interact? Information: •Drug A: Abciximab •Drug B: Topotecan •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Topotecan. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 35% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 2-3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The primary anticipated complication of overdosage would consist of bone marrow suppression. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Hycamtin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Topotecan Topotecane Topotecanum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Toremifene interact?

•Drug A: Abciximab •Drug B: Toremifene •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Toremifene is combined with Abciximab. •Extended Description: Toremifene has been reported to produce vaginal bleeding as a common effect. This effect is mainly observed when toremifene is given in high doses. Hence, concomitant administration of toremifene and anticoagulants should be done cautiously as there is a potential increase in the risk and severity of bleeding events. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Toremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors. •Absorption (Drug A): No absorption available •Absorption (Drug B): Well absorbed •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 580 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Toremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5 days •Clearance (Drug A): No clearance available •Clearance (Drug B): 5 L/h •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Fareston •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Toremifene is a first generation nonsteroidal selective estrogen receptor modulator used to treat certain breast cancers.

Toremifene has been reported to produce vaginal bleeding as a common effect. This effect is mainly observed when toremifene is given in high doses. Hence, concomitant administration of toremifene and anticoagulants should be done cautiously as there is a potential increase in the risk and severity of bleeding events. The severity of the interaction is minor.

Question: Does Abciximab and Toremifene interact? Information: •Drug A: Abciximab •Drug B: Toremifene •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Toremifene is combined with Abciximab. •Extended Description: Toremifene has been reported to produce vaginal bleeding as a common effect. This effect is mainly observed when toremifene is given in high doses. Hence, concomitant administration of toremifene and anticoagulants should be done cautiously as there is a potential increase in the risk and severity of bleeding events. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Toremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors. •Absorption (Drug A): No absorption available •Absorption (Drug B): Well absorbed •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 580 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Toremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 5 days •Clearance (Drug A): No clearance available •Clearance (Drug B): 5 L/h •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Fareston •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Toremifene is a first generation nonsteroidal selective estrogen receptor modulator used to treat certain breast cancers. Output: Toremifene has been reported to produce vaginal bleeding as a common effect. This effect is mainly observed when toremifene is given in high doses. Hence, concomitant administration of toremifene and anticoagulants should be done cautiously as there is a potential increase in the risk and severity of bleeding events. The severity of the interaction is minor.

Does Abciximab and Toripalimab interact?

•Drug A: Abciximab •Drug B: Toripalimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Toripalimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Toripalimab is indicated in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma (NPC). It is also indicated as a second-line monotherapy for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after platinum-containing chemotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The exposure-response relationships and time course of pharmacodynamic response for toripalimab have not been fully characterized. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The binding of programmed death ligands 1 and 2 (PD-L1 and PD-L2) to the PD-1 receptor on T-cells results in the inhibition of T-cell proliferation and cytokine production - this pathway therefore plays a vital role in immune inhibition and self-tolerance. In some cancers, PD-1 ligands may be overexpressed and result in the inhibition of tumor surveillance. Toripalimab is a monoclonal antibody directed against the PD-1 receptor. It blocks the PD-L1/PD-1 pathway, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. •Absorption (Drug A): No absorption available •Absorption (Drug B): Steady-state concentrations of toripalimab were reached by week 7 when administered every two weeks. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): At steady-state, the mean volume of distribution was 3.7 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic proteins, toripalimab is likely degraded via catabolic processes into smaller peptides and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean terminal elimination half-life after one dose of toripalimab was 10 ± 1.5 days. The mean terminal elimination half-life of toripalimab at steady-state was 18 ± 9.4 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance after one dose of toripalimab was 14.9 mL/h. The mean clearance of toripalimab at steady-state was 9.5 mL/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Loqtorzi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Toripalimab is a PD-1 blocking monoclonal antibody used for the treatment of metastatic and recurrent nasopharyngeal carcinomas.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Toripalimab interact? Information: •Drug A: Abciximab •Drug B: Toripalimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Toripalimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Toripalimab is indicated in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma (NPC). It is also indicated as a second-line monotherapy for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after platinum-containing chemotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): The exposure-response relationships and time course of pharmacodynamic response for toripalimab have not been fully characterized. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The binding of programmed death ligands 1 and 2 (PD-L1 and PD-L2) to the PD-1 receptor on T-cells results in the inhibition of T-cell proliferation and cytokine production - this pathway therefore plays a vital role in immune inhibition and self-tolerance. In some cancers, PD-1 ligands may be overexpressed and result in the inhibition of tumor surveillance. Toripalimab is a monoclonal antibody directed against the PD-1 receptor. It blocks the PD-L1/PD-1 pathway, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. •Absorption (Drug A): No absorption available •Absorption (Drug B): Steady-state concentrations of toripalimab were reached by week 7 when administered every two weeks. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): At steady-state, the mean volume of distribution was 3.7 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic proteins, toripalimab is likely degraded via catabolic processes into smaller peptides and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean terminal elimination half-life after one dose of toripalimab was 10 ± 1.5 days. The mean terminal elimination half-life of toripalimab at steady-state was 18 ± 9.4 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance after one dose of toripalimab was 14.9 mL/h. The mean clearance of toripalimab at steady-state was 9.5 mL/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Loqtorzi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Toripalimab is a PD-1 blocking monoclonal antibody used for the treatment of metastatic and recurrent nasopharyngeal carcinomas. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Trabectedin interact?

•Drug A: Abciximab •Drug B: Trabectedin •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Trabectedin. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. •Absorption (Drug A): No absorption available •Absorption (Drug B): Administered intravenously. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 94 to 98% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 33-50 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Yondelis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma).

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Trabectedin interact? Information: •Drug A: Abciximab •Drug B: Trabectedin •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Trabectedin. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. •Absorption (Drug A): No absorption available •Absorption (Drug B): Administered intravenously. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 94 to 98% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 33-50 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Yondelis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma). Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Tralokinumab interact?

•Drug A: Abciximab •Drug B: Tralokinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tralokinumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tralokinumab is indicated in Canada, the US, and the EU for the treatment of moderate-to-severe atopic dermatitis in patients who are candidates for systemic therapy and are inadequately controlled with topical interventions. In Canada, tralokinumab is only approved for adults, while in the US and Europe, it is approved for use in patients 12 years of age and older. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tralokinumab exerts its therapeutic effects by inhibiting the inflammatory cytokine (IL-13) primarily responsible for the pathogenesis of atopic dermatitis. It is administered subcutaneously with a loading dose of 600mg followed by a maintenance dose of 300mg every two weeks. In clinical studies, tralokinumab treatment decreased the concentrations of a number of Th2 and Th22 immunity biomarkers in the blood, including periostin, IL-22, serum IgE. It also reduced epidermal thickness and decreased the expression of Keratin 16 and Ki-67 in skin affected by atopic dermatitis. Hypersensitivity reactions, including anaphylaxis, have been reported following the use of tralokinumab. Patients experiencing a systemic hypersensitivity reaction should discontinue treatment and initiate immediate therapy as clinically indicated. Tralokinumab should not be used in patients with pre-existing helminth infections, as the influence of tralokinumab on the immune response against helminth infections is unclear. Patients with helminth infections should be treated prior to therapy with tralokinumab. Patients becoming infected during the course of therapy may be treated with anti-helminth medications, but should discontinue tralokinumab if the infection fails to resolve. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin-13 (IL-13) is a pro-inflammatory cytokine that has been implicated as the primary driver of atopic dermatitis (AD). IL-13 binds with high affinity to both a heterodimeric form of IL-13Rα1 - complexed with IL-4Rα - and to IL-13Rα2, both of which are expressed on keratinocytes and fibroblasts. While IL-13Rα2 does not appear to act as a signal mediator, the binding of IL-13 to heterodimeric IL-4Rα and IL-13Rα1 activates downstream Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) pathways which proceed to activate various signal transducer and activator of transcription (STAT) pathways. STAT signalling induces the expression of periostin, an extracellular matrix protein which serves a number of physiological functions in addition to its pathogenic role in skin fibrosis and chronic allergic inflammation. IL-13 also appears to contribute to skin barrier dysfunction via an indirect downregulation of filaggrin (FLG), a structural protein essential for correct skin barrier functioning. Tralokinumab is a monoclonal antibody targeted against IL-13. It neutralizes the activity of IL-13 by blocking its interaction with both the IL-13Rα1/IL-4Rα receptor complex and IL-13Rα2 receptors. •Absorption (Drug A): No absorption available •Absorption (Drug B): The absolute bioavailability of tralokinumab following subcutaneous administration is 76%, with a median T max of 5-8 days. In clinical trials, steady-state serum concentrations were achieved by week 16 of treatment, with trough concentrations ranging from 98.0±41.1 mcg/mL to 101.4±42.7 mcg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tralokinumab as estimated by population pharmacokinetic analysis was 4.2 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available for the protein binding of tralokinumab. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic and endogenous proteins, the metabolism of tralokinumab is likely to occur via catabolism to smaller peptides and amino acids and has not been studied directly. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The elimination of tralokinumab occurs through a non-saturable proteolytic pathway. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life of tralokinumab is approximately 22 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tralokinumab following subcutaneous administration was estimated to be 0.149 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There are no data regarding overdosage with tralokinumab. In clinical trials, intravenous doses up to 30 mg/kg and subcutaneous doses of 600mg every two weeks for 3 months were found to be well-tolerated. In the event of a suspected overdose, patients should be administered supportive care as clinically indicated. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Adbry •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tralokinumab is a monoclonal antibody directed against interleukin-13 which is used in the treatment of moderate-to-severe atopic dermatitis in patients requiring systemic therapy.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tralokinumab interact? Information: •Drug A: Abciximab •Drug B: Tralokinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tralokinumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tralokinumab is indicated in Canada, the US, and the EU for the treatment of moderate-to-severe atopic dermatitis in patients who are candidates for systemic therapy and are inadequately controlled with topical interventions. In Canada, tralokinumab is only approved for adults, while in the US and Europe, it is approved for use in patients 12 years of age and older. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tralokinumab exerts its therapeutic effects by inhibiting the inflammatory cytokine (IL-13) primarily responsible for the pathogenesis of atopic dermatitis. It is administered subcutaneously with a loading dose of 600mg followed by a maintenance dose of 300mg every two weeks. In clinical studies, tralokinumab treatment decreased the concentrations of a number of Th2 and Th22 immunity biomarkers in the blood, including periostin, IL-22, serum IgE. It also reduced epidermal thickness and decreased the expression of Keratin 16 and Ki-67 in skin affected by atopic dermatitis. Hypersensitivity reactions, including anaphylaxis, have been reported following the use of tralokinumab. Patients experiencing a systemic hypersensitivity reaction should discontinue treatment and initiate immediate therapy as clinically indicated. Tralokinumab should not be used in patients with pre-existing helminth infections, as the influence of tralokinumab on the immune response against helminth infections is unclear. Patients with helminth infections should be treated prior to therapy with tralokinumab. Patients becoming infected during the course of therapy may be treated with anti-helminth medications, but should discontinue tralokinumab if the infection fails to resolve. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin-13 (IL-13) is a pro-inflammatory cytokine that has been implicated as the primary driver of atopic dermatitis (AD). IL-13 binds with high affinity to both a heterodimeric form of IL-13Rα1 - complexed with IL-4Rα - and to IL-13Rα2, both of which are expressed on keratinocytes and fibroblasts. While IL-13Rα2 does not appear to act as a signal mediator, the binding of IL-13 to heterodimeric IL-4Rα and IL-13Rα1 activates downstream Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) pathways which proceed to activate various signal transducer and activator of transcription (STAT) pathways. STAT signalling induces the expression of periostin, an extracellular matrix protein which serves a number of physiological functions in addition to its pathogenic role in skin fibrosis and chronic allergic inflammation. IL-13 also appears to contribute to skin barrier dysfunction via an indirect downregulation of filaggrin (FLG), a structural protein essential for correct skin barrier functioning. Tralokinumab is a monoclonal antibody targeted against IL-13. It neutralizes the activity of IL-13 by blocking its interaction with both the IL-13Rα1/IL-4Rα receptor complex and IL-13Rα2 receptors. •Absorption (Drug A): No absorption available •Absorption (Drug B): The absolute bioavailability of tralokinumab following subcutaneous administration is 76%, with a median T max of 5-8 days. In clinical trials, steady-state serum concentrations were achieved by week 16 of treatment, with trough concentrations ranging from 98.0±41.1 mcg/mL to 101.4±42.7 mcg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of tralokinumab as estimated by population pharmacokinetic analysis was 4.2 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available for the protein binding of tralokinumab. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic and endogenous proteins, the metabolism of tralokinumab is likely to occur via catabolism to smaller peptides and amino acids and has not been studied directly. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The elimination of tralokinumab occurs through a non-saturable proteolytic pathway. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half-life of tralokinumab is approximately 22 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of tralokinumab following subcutaneous administration was estimated to be 0.149 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There are no data regarding overdosage with tralokinumab. In clinical trials, intravenous doses up to 30 mg/kg and subcutaneous doses of 600mg every two weeks for 3 months were found to be well-tolerated. In the event of a suspected overdose, patients should be administered supportive care as clinically indicated. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Adbry •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tralokinumab is a monoclonal antibody directed against interleukin-13 which is used in the treatment of moderate-to-severe atopic dermatitis in patients requiring systemic therapy. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Tranylcypromine interact?

•Drug A: Abciximab •Drug B: Tranylcypromine •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tranylcypromine is combined with Abciximab. •Extended Description: It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of major depressive episode without melancholia. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tranylcypromine belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOIs). Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. MAO is an enzyme that catalyzes the oxidative deamination of a number of amines, including serotonin, norepinephrine, epinephrine, and dopamine. Two isoforms of MAO, A and B, are found in the body. MAO-A is mainly found within cells located in the periphery and catalyzes the breakdown of serotonin, norepinephrine, epinephrine, dopamine and tyramine. MAO-B acts on phenylethylamine, norepinephrine, epinephrine, dopamine and tyramine, is localized extracellularly and is found predominantly in the brain. While the mechanism of MAOIs is still unclear, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. It has been postulated that depression is caused by low levels of serotonin and/or norepinephrine and that increasing serotonergic and norepinephrinergic neurotransmission results in relief of depressive symptoms. MAO A inhibition is thought to be more relevant to antidepressant activity than MAO B inhibition. Selective MAO B inhibitors, such as selegiline, have no antidepressant effects. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tranylcypromine irreversibly and nonselectively inhibits monoamine oxidase (MAO). Within neurons, MAO appears to regulate the levels of monoamines released upon synaptic firing. Since depression is associated with low levels of monoamines, the inhibition of MAO serves to ease depressive symptoms, as this results in an increase in the concentrations of these amines within the CNS. •Absorption (Drug A): No absorption available •Absorption (Drug B): Interindividual variability in absorption. May be biphasic in some individuals. Peak plasma concentrations occur in one hour following oral administration with a secondary peak occurring within 2-3 hours. Biphasic absorption may represent different rates of absorption of the stereoisomers of the drug, though additional studies are required to confirm this. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.1-5.7 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.5-3.2 hours in patients with normal renal and hepatic function •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): In overdosage, some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Parnate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): dl-tranylcypromine Racemic Tranylcypromine Tranilcipromina Transamine Tranylcypromin Tranylcypromine Tranylcyprominum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tranylcypromine is a monoamine oxidase inhibitor used to treat major depressive disorder.

It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. The severity of the interaction is moderate.

Question: Does Abciximab and Tranylcypromine interact? Information: •Drug A: Abciximab •Drug B: Tranylcypromine •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Tranylcypromine is combined with Abciximab. •Extended Description: It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of major depressive episode without melancholia. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tranylcypromine belongs to a class of antidepressants called monoamine oxidase inhibitors (MAOIs). Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. MAO is an enzyme that catalyzes the oxidative deamination of a number of amines, including serotonin, norepinephrine, epinephrine, and dopamine. Two isoforms of MAO, A and B, are found in the body. MAO-A is mainly found within cells located in the periphery and catalyzes the breakdown of serotonin, norepinephrine, epinephrine, dopamine and tyramine. MAO-B acts on phenylethylamine, norepinephrine, epinephrine, dopamine and tyramine, is localized extracellularly and is found predominantly in the brain. While the mechanism of MAOIs is still unclear, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. It has been postulated that depression is caused by low levels of serotonin and/or norepinephrine and that increasing serotonergic and norepinephrinergic neurotransmission results in relief of depressive symptoms. MAO A inhibition is thought to be more relevant to antidepressant activity than MAO B inhibition. Selective MAO B inhibitors, such as selegiline, have no antidepressant effects. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Tranylcypromine irreversibly and nonselectively inhibits monoamine oxidase (MAO). Within neurons, MAO appears to regulate the levels of monoamines released upon synaptic firing. Since depression is associated with low levels of monoamines, the inhibition of MAO serves to ease depressive symptoms, as this results in an increase in the concentrations of these amines within the CNS. •Absorption (Drug A): No absorption available •Absorption (Drug B): Interindividual variability in absorption. May be biphasic in some individuals. Peak plasma concentrations occur in one hour following oral administration with a secondary peak occurring within 2-3 hours. Biphasic absorption may represent different rates of absorption of the stereoisomers of the drug, though additional studies are required to confirm this. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 1.1-5.7 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 1.5-3.2 hours in patients with normal renal and hepatic function •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): In overdosage, some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Parnate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): dl-tranylcypromine Racemic Tranylcypromine Tranilcipromina Transamine Tranylcypromin Tranylcypromine Tranylcyprominum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tranylcypromine is a monoamine oxidase inhibitor used to treat major depressive disorder. Output: It has been reported that concomitant administration of antiplatelet agents and monoamine oxidase inhibitor antidepressants that increase the levels of serotonin are associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. The severity of the interaction is moderate.

Does Abciximab and Trastuzumab deruxtecan interact?

•Drug A: Abciximab •Drug B: Trastuzumab deruxtecan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab deruxtecan. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In the US, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. In Canada, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously been treated with trastuzumab emtansine, or who have received at least one prior anti-HER2-based regimen either in the metastatic setting or in the adjuvant/neoadjuvant setting who have experienced disease recurrence during or within 6 months of adjuvant/neoadjuvant therapy. Trastuzumab deruxtecan is also indicated in Canada for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. In Europe, trastuzumab deruxtecan is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens and unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. It is also indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. It is also indicated as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer whose tumors have an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy. By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors. The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor. It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes. Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase. •Absorption (Drug A): No absorption available •Absorption (Drug B): The Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study. Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The Dxd portion of the drug has a plasma protein binding estimated at 97%. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG. Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody. In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces. Unmetabolized DXd was found in the urine during a pharmacokinetic study. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Trastuzumab deruxtecan is rapidly cleared from systemic circulation. Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Enhertu •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast cancer.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Trastuzumab deruxtecan interact? Information: •Drug A: Abciximab •Drug B: Trastuzumab deruxtecan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab deruxtecan. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In the US, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. In Canada, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously been treated with trastuzumab emtansine, or who have received at least one prior anti-HER2-based regimen either in the metastatic setting or in the adjuvant/neoadjuvant setting who have experienced disease recurrence during or within 6 months of adjuvant/neoadjuvant therapy. Trastuzumab deruxtecan is also indicated in Canada for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. In Europe, trastuzumab deruxtecan is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens and unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. It is also indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. It is also indicated as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer whose tumors have an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy. By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors. The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor. It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes. Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase. •Absorption (Drug A): No absorption available •Absorption (Drug B): The Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study. Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The Dxd portion of the drug has a plasma protein binding estimated at 97%. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG. Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody. In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces. Unmetabolized DXd was found in the urine during a pharmacokinetic study. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Trastuzumab deruxtecan is rapidly cleared from systemic circulation. Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Enhertu •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast cancer. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Trastuzumab emtansine interact?

•Drug A: Abciximab •Drug B: Trastuzumab emtansine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Trastuzumab emtansine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trastuzumab emtansine is a HER2 antibody-drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis. Trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by trastuzumab emtansine. •Absorption (Drug A): No absorption available •Absorption (Drug B): The absorption/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of trastuzumab emtansine is about 3.13 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): DM1 has a plasma protein binding value of 93%. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The route of elimination has not yet been fully elucidated. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Trastuzumab emtansine has a long half life of about 4 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): After IV infusion, trastuzumab emtansine has a clearance of 0.68 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Kadcyla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing breast cancer.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Trastuzumab emtansine interact? Information: •Drug A: Abciximab •Drug B: Trastuzumab emtansine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Trastuzumab emtansine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trastuzumab emtansine is a HER2 antibody-drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis. Trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by trastuzumab emtansine. •Absorption (Drug A): No absorption available •Absorption (Drug B): The absorption/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of trastuzumab emtansine is about 3.13 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): DM1 has a plasma protein binding value of 93%. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The route of elimination has not yet been fully elucidated. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Trastuzumab emtansine has a long half life of about 4 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): After IV infusion, trastuzumab emtansine has a clearance of 0.68 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Kadcyla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing breast cancer. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Trastuzumab interact?

•Drug A: Abciximab •Drug B: Trastuzumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the adjuvant treatment of HER2-overexpressing breast cancer, trastuzumab is indicated in several clinical settings: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as monotherapy following multi-modality anthracycline-based therapy. Trastuzumab is indicated as a first-line treatment, in combination with paclitaxel, for metastatic HER2-overexpressing breast cancer, and as monotherapy in patients who have previously received one or more chemotherapy regimens in the metastatic setting. In Europe, trastuzumab can also be used in combination with paclitaxel or docetaxel for the treatment of metastatic HER2-positive breast cancer in adult patients and with an aromatase inhibitor in postmenopausal patients. For HER2-positive early breast cancer, the EMA approved trastuzumab as monotherapy following surgery, chemotherapy (neoadjuvant or adjuvant), and radiation or following adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel. It can also be used in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin or with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy for locally advanced (including inflammatory) disease or tumors > 2 cm in diameter. Trastuzumab is also indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease by the FDA and EMA. Trastuzumab is indicated for subcutaneous administration - in combination with either hyaluronidase or both hyaluronidase and pertuzumab - for the treatment of adults with HER2-positive breast cancers. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells in vivo. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation, and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction. Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor. •Absorption (Drug A): No absorption available •Absorption (Drug B): Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 mcg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): After it binds to HER2, trastuzumab is metabolized intracellularly into smaller peptides and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very low. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Herceptin, Herceptin Hylecta, Herzuma, Kanjinti, Ontruzant, Perjeta-Herceptin, Phesgo, Trazimera •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trastuzumab is a monoclonal anti-human epidermal growth factor receptor 2 protein antibody used to treat HER2-positive breast, gastroesophageal, and gastric cancers.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Trastuzumab interact? Information: •Drug A: Abciximab •Drug B: Trastuzumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the adjuvant treatment of HER2-overexpressing breast cancer, trastuzumab is indicated in several clinical settings: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as monotherapy following multi-modality anthracycline-based therapy. Trastuzumab is indicated as a first-line treatment, in combination with paclitaxel, for metastatic HER2-overexpressing breast cancer, and as monotherapy in patients who have previously received one or more chemotherapy regimens in the metastatic setting. In Europe, trastuzumab can also be used in combination with paclitaxel or docetaxel for the treatment of metastatic HER2-positive breast cancer in adult patients and with an aromatase inhibitor in postmenopausal patients. For HER2-positive early breast cancer, the EMA approved trastuzumab as monotherapy following surgery, chemotherapy (neoadjuvant or adjuvant), and radiation or following adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel. It can also be used in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin or with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy for locally advanced (including inflammatory) disease or tumors > 2 cm in diameter. Trastuzumab is also indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease by the FDA and EMA. Trastuzumab is indicated for subcutaneous administration - in combination with either hyaluronidase or both hyaluronidase and pertuzumab - for the treatment of adults with HER2-positive breast cancers. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells in vivo. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation, and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction. Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor. •Absorption (Drug A): No absorption available •Absorption (Drug B): Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 mcg/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): After it binds to HER2, trastuzumab is metabolized intracellularly into smaller peptides and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very low. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, respectively. •Clearance (Drug A): No clearance available •Clearance (Drug B): The predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 L/day. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Herceptin, Herceptin Hylecta, Herzuma, Kanjinti, Ontruzant, Perjeta-Herceptin, Phesgo, Trazimera •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trastuzumab is a monoclonal anti-human epidermal growth factor receptor 2 protein antibody used to treat HER2-positive breast, gastroesophageal, and gastric cancers. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Trazodone interact?

•Drug A: Abciximab •Drug B: Trazodone •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Trazodone is combined with Abciximab. •Extended Description: Platelets normally release serotonin, and this process is essential in homeostasis, stabilizing blood flow.3 Combining an antiplatelet agent or anticoagulant with trazodone may increase the risk of bleeding of antiplatelet agents due to its serotonergic effects, which interfere with platelet release of serotonin. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms. •Absorption (Drug A): No absorption available •Absorption (Drug B): Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of trazodone is 89-95% according to in vitro studies. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD50 of trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Desyrel, Oleptro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trazodona Trazodone Trazodonum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trazodone is a serotonin uptake inhibitor used to treat major depressive disorder.

Platelets normally release serotonin, and this process is essential in homeostasis, stabilizing blood flow.3 Combining an antiplatelet agent or anticoagulant with trazodone may increase the risk of bleeding of antiplatelet agents due to its serotonergic effects, which interfere with platelet release of serotonin. The severity of the interaction is moderate.

Question: Does Abciximab and Trazodone interact? Information: •Drug A: Abciximab •Drug B: Trazodone •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Trazodone is combined with Abciximab. •Extended Description: Platelets normally release serotonin, and this process is essential in homeostasis, stabilizing blood flow.3 Combining an antiplatelet agent or anticoagulant with trazodone may increase the risk of bleeding of antiplatelet agents due to its serotonergic effects, which interfere with platelet release of serotonin. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms. •Absorption (Drug A): No absorption available •Absorption (Drug B): Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of trazodone is 89-95% according to in vitro studies. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD50 of trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Desyrel, Oleptro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trazodona Trazodone Trazodonum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trazodone is a serotonin uptake inhibitor used to treat major depressive disorder. Output: Platelets normally release serotonin, and this process is essential in homeostasis, stabilizing blood flow.3 Combining an antiplatelet agent or anticoagulant with trazodone may increase the risk of bleeding of antiplatelet agents due to its serotonergic effects, which interfere with platelet release of serotonin. The severity of the interaction is moderate.

Does Abciximab and Tremelimumab interact?

•Drug A: Abciximab •Drug B: Tremelimumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tremelimumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab. It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tremelimumab is a cytotoxic agent that works to decrease tumour growth. It binds to its target, human CTLA-4, with high selectivity and subnanomolar affinity. Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells. In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc receptors. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC). This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells. CD80 and CD86 are also referred to together as B7 molecules. In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions. Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4 and CD8 T cell surface. These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription. B7 molecules act as ligands to both of these receptors, and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells. Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity. •Absorption (Drug A): No absorption available •Absorption (Drug B): In patients with solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The geometric mean (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady-state. •Clearance (Drug A): No clearance available •Clearance (Drug B): The geometric mean (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady-state. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is limited information regarding the acute toxicity profile and overdosage of tremelimumab. The maximum tolerated dose in non-human primates was 100 mg/kg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Imjudo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tremelimumab is an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Tremelimumab interact? Information: •Drug A: Abciximab •Drug B: Tremelimumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Tremelimumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab. It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Tremelimumab is a cytotoxic agent that works to decrease tumour growth. It binds to its target, human CTLA-4, with high selectivity and subnanomolar affinity. Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells. In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc receptors. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC). This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells. CD80 and CD86 are also referred to together as B7 molecules. In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions. Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4 and CD8 T cell surface. These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription. B7 molecules act as ligands to both of these receptors, and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells. Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity. •Absorption (Drug A): No absorption available •Absorption (Drug B): In patients with solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The geometric mean (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady-state. •Clearance (Drug A): No clearance available •Clearance (Drug B): The geometric mean (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady-state. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is limited information regarding the acute toxicity profile and overdosage of tremelimumab. The maximum tolerated dose in non-human primates was 100 mg/kg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Imjudo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Tremelimumab is an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Treprostinil interact?

•Drug A: Abciximab •Drug B: Treprostinil •Severity: MODERATE •Description: Treprostinil may increase the antiplatelet activities of Abciximab. •Extended Description: Prostacyclin analogs may interfere with platelet aggregation, further potentiating the bleeding risk of antiplatelet agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol.

Prostacyclin analogs may interfere with platelet aggregation, further potentiating the bleeding risk of antiplatelet agents. The severity of the interaction is moderate.

Question: Does Abciximab and Treprostinil interact? Information: •Drug A: Abciximab •Drug B: Treprostinil •Severity: MODERATE •Description: Treprostinil may increase the antiplatelet activities of Abciximab. •Extended Description: Prostacyclin analogs may interfere with platelet aggregation, further potentiating the bleeding risk of antiplatelet agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol. Output: Prostacyclin analogs may interfere with platelet aggregation, further potentiating the bleeding risk of antiplatelet agents. The severity of the interaction is moderate.

Does Abciximab and Triamcinolone interact?

•Drug A: Abciximab •Drug B: Triamcinolone •Severity: MODERATE •Description: The therapeutic efficacy of Abciximab can be decreased when used in combination with Triamcinolone. •Extended Description: Concomitant use of anticoagulants and triamcinolone can inhibit the effect of anticoagulants.1,2,3,4,5 •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Triamcinolone hexacetonide injections are indicated for intralesional administration in alopecia areata, discoid lupus erythematosus, keloids, and necrobiosis lipoidica diabeticorum. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. Triamcinolone acetonide spray and cream are indicated for the treatment of inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. A triamcinolone acetonide 10mg/mL or 40mg/mL injection is indicated intra-articularly for acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis. The same 10mg/mL injection is indicated by the intralesional route for the treatment of alopecia areata, discoid lupus erythematosus, keloids, necrobiosis lipoidica diabeticorum, and tumors of an aponeurosis or tendon. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. The 40mg/mL injection is indicated intramuscularly for controlling severe allergic conditions such as asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity, perennial or seasonal allergic rhinitis, serum sickness, and transfusion reactions; treatment of bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, Stevens-Johnson syndrome, congenital adrenal hyperplasia, hypercalcemia in cancer, nonsuppurative thyroiditis, autoimmune hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, secondary thrombocytopenia, trichinosis, tuberculous meningitis, acute exacerbations of multiple sclerosis or cerebral edema, sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammation, berylliosis, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis, dermatomyositis, polymyositis, and systemic lupus erythematosus; adjunct treatment of adrenocortical insufficiency, regional enteritis, ulcerative colitis, fulminating or disseminated pulmonary tuberculosis, acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis; palliative management of leukemia and lymphoma; induction of diuresis or remission of proteinuria in idiopathic nephrotic syndrome or lupus erythematosus. A triamcinolone intravitreal injection is indicated for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions. The intravitreal injection is also used for visualization during vitrectomy. An extended release suspension is indicated intra-articularly for management of pain in osteoarthritis of the knee. A triamcinolone acetonide suspension for injection into the suprachoroidal space is indicated for the treatment of macular edema associated with uveitis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Triamcinolone is a corticosteroid with anti-inflammatory properties. These properties are used to treat inflammation in conditions that affect various organs and tissues. Triamcinolone should not be administered as an epidural injection. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Corticosteroids like triamcinolone inhibit phospholipase A2 on cell membranes, preventing the breakdown of lysosomal membranes of leukocytes, which in turn prevent the formation of arachidonic acid, which decrease expression of cyclooxygenase and lipoxygenase, inhibiting synthesis of prostaglandins and leukotrienes. Anti-inflammatory activity occurs via reversal of vascular dilation and reducing permeability, which prevents macrophage and leukocyte migration. Triamcinolone also inhibits nuclear factor kappa-B, which decreases the production of pro-inflammatory signals such as interleukin-6, interleukin-8, and monocyte chemoattractant protein-1. •Absorption (Drug A): No absorption available •Absorption (Drug B): A 16mg oral dose of triamcinolone reaches a C max of 5.23±0.84ng/mL with a T max of 2.24±0.78h and an AUC of 36.0±6.2ng*h/mL. A 2mg intravenous dose of triamcinolone acetonide has an AUC of 57.7ng*h/mL. The bioavailability of 800µg of inhaled triamcinolone acetonide is 25%, with 10.4% coming from pulmonary absorption and the rest being accounted for by deposition on the oral mucosa and other underlying factors. An inhaled dose of triamcinolone acetonide reaches a C max of 0.92ng/mL with a T max of 1.74h and an AUC of 5.12ng*h/mL. The fraction of an inhaled dose that is actually absorbed via the pulmonary route reaches a C max of 0.55ng/mL with a T max of 0.66h and an AUC of 2.15ng*h/mL. A 16mg oral dose of triamcinolone diacetate reaches a C max of 5.33±1.55ng/mL with a T max of 1.86±0.47h and an AUC of 32.7±9.9ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of triamcinolone is 115.2±10L. The mean apparent volume of distribution of triamcinolone acetonide is 1.96L/kg. The apparent volume of distribution of triamcinolone diacetate is 119.7±33.14L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Triamcinolone is mostly bound to corticosteroid-binding globulin or serum albumin. Triamcinolone acetonide is approximately 68% protein bound in plasma. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The major metabolite of triamcinolone is 6-beta-hydroxy-triamcinolone. Data regarding the metabolism of triamcinolone is not readily available. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Approximately 20% of a dose of triamcinolone is recovered in the urine as the unchanged drug, 25% is recovered as 6-beta-hydroxy-triamcinolone, and 5% is recovered as unidentified metabolites. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of triamcinolone is 2.7h. The mean terminal elimination half life following an inhaled dose of triamcinolone acetonide is 2.4h. The half life of triamcinolone diacetate is 2.8h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of triamcinolone is 28.6±5.6L/h. The mean total body clearance of triamcinolone acetonide is 0.57L/h. The clearance of triamcinolone diacetate is 34.4±10.6L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The subcutaneous LD 50 of triamcinolone acetonide in rats is 13,100µg/kg and in mice is 132mg/kg. The oral LD 50 in rats is 1451mg/kg and in mice is 2168mg/kg.[LD 50 ] The intraperitoneal LD 50 in mice is 105mg/kg.[LD 50 ] Patients experiencing an overdose may develop Cushing's syndrome. This overdose may be treated with supportive therapy and mifepristone for its antiglucocorticoid activity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Allernaze, Aristocort, Aristocort R, Juulissa Pharmapak, Kenalog, Kourzeq, Marcaine, Nasacort, Oracort, Oralone, Pediaderm Ta, Triaderm, Trianex, Triderm, Triesence, Triloan Suik, Tritocin, Viaderm Kc, Xipere, Zilretta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxyprednisolone Tiamcinolonum Triamcinolona Triamcinolone Triamcinolonum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues.

Concomitant use of anticoagulants and triamcinolone can inhibit the effect of anticoagulants.1,2,3,4,5 The severity of the interaction is moderate.

Question: Does Abciximab and Triamcinolone interact? Information: •Drug A: Abciximab •Drug B: Triamcinolone •Severity: MODERATE •Description: The therapeutic efficacy of Abciximab can be decreased when used in combination with Triamcinolone. •Extended Description: Concomitant use of anticoagulants and triamcinolone can inhibit the effect of anticoagulants.1,2,3,4,5 •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Triamcinolone hexacetonide injections are indicated for intralesional administration in alopecia areata, discoid lupus erythematosus, keloids, and necrobiosis lipoidica diabeticorum. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. Triamcinolone acetonide spray and cream are indicated for the treatment of inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. A triamcinolone acetonide 10mg/mL or 40mg/mL injection is indicated intra-articularly for acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis. The same 10mg/mL injection is indicated by the intralesional route for the treatment of alopecia areata, discoid lupus erythematosus, keloids, necrobiosis lipoidica diabeticorum, and tumors of an aponeurosis or tendon. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. The 40mg/mL injection is indicated intramuscularly for controlling severe allergic conditions such as asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity, perennial or seasonal allergic rhinitis, serum sickness, and transfusion reactions; treatment of bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, Stevens-Johnson syndrome, congenital adrenal hyperplasia, hypercalcemia in cancer, nonsuppurative thyroiditis, autoimmune hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, secondary thrombocytopenia, trichinosis, tuberculous meningitis, acute exacerbations of multiple sclerosis or cerebral edema, sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammation, berylliosis, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis, dermatomyositis, polymyositis, and systemic lupus erythematosus; adjunct treatment of adrenocortical insufficiency, regional enteritis, ulcerative colitis, fulminating or disseminated pulmonary tuberculosis, acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis; palliative management of leukemia and lymphoma; induction of diuresis or remission of proteinuria in idiopathic nephrotic syndrome or lupus erythematosus. A triamcinolone intravitreal injection is indicated for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions. The intravitreal injection is also used for visualization during vitrectomy. An extended release suspension is indicated intra-articularly for management of pain in osteoarthritis of the knee. A triamcinolone acetonide suspension for injection into the suprachoroidal space is indicated for the treatment of macular edema associated with uveitis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Triamcinolone is a corticosteroid with anti-inflammatory properties. These properties are used to treat inflammation in conditions that affect various organs and tissues. Triamcinolone should not be administered as an epidural injection. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Corticosteroids like triamcinolone inhibit phospholipase A2 on cell membranes, preventing the breakdown of lysosomal membranes of leukocytes, which in turn prevent the formation of arachidonic acid, which decrease expression of cyclooxygenase and lipoxygenase, inhibiting synthesis of prostaglandins and leukotrienes. Anti-inflammatory activity occurs via reversal of vascular dilation and reducing permeability, which prevents macrophage and leukocyte migration. Triamcinolone also inhibits nuclear factor kappa-B, which decreases the production of pro-inflammatory signals such as interleukin-6, interleukin-8, and monocyte chemoattractant protein-1. •Absorption (Drug A): No absorption available •Absorption (Drug B): A 16mg oral dose of triamcinolone reaches a C max of 5.23±0.84ng/mL with a T max of 2.24±0.78h and an AUC of 36.0±6.2ng*h/mL. A 2mg intravenous dose of triamcinolone acetonide has an AUC of 57.7ng*h/mL. The bioavailability of 800µg of inhaled triamcinolone acetonide is 25%, with 10.4% coming from pulmonary absorption and the rest being accounted for by deposition on the oral mucosa and other underlying factors. An inhaled dose of triamcinolone acetonide reaches a C max of 0.92ng/mL with a T max of 1.74h and an AUC of 5.12ng*h/mL. The fraction of an inhaled dose that is actually absorbed via the pulmonary route reaches a C max of 0.55ng/mL with a T max of 0.66h and an AUC of 2.15ng*h/mL. A 16mg oral dose of triamcinolone diacetate reaches a C max of 5.33±1.55ng/mL with a T max of 1.86±0.47h and an AUC of 32.7±9.9ng*h/mL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of triamcinolone is 115.2±10L. The mean apparent volume of distribution of triamcinolone acetonide is 1.96L/kg. The apparent volume of distribution of triamcinolone diacetate is 119.7±33.14L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Triamcinolone is mostly bound to corticosteroid-binding globulin or serum albumin. Triamcinolone acetonide is approximately 68% protein bound in plasma. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The major metabolite of triamcinolone is 6-beta-hydroxy-triamcinolone. Data regarding the metabolism of triamcinolone is not readily available. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Approximately 20% of a dose of triamcinolone is recovered in the urine as the unchanged drug, 25% is recovered as 6-beta-hydroxy-triamcinolone, and 5% is recovered as unidentified metabolites. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The half life of triamcinolone is 2.7h. The mean terminal elimination half life following an inhaled dose of triamcinolone acetonide is 2.4h. The half life of triamcinolone diacetate is 2.8h. •Clearance (Drug A): No clearance available •Clearance (Drug B): The clearance of triamcinolone is 28.6±5.6L/h. The mean total body clearance of triamcinolone acetonide is 0.57L/h. The clearance of triamcinolone diacetate is 34.4±10.6L/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The subcutaneous LD 50 of triamcinolone acetonide in rats is 13,100µg/kg and in mice is 132mg/kg. The oral LD 50 in rats is 1451mg/kg and in mice is 2168mg/kg.[LD 50 ] The intraperitoneal LD 50 in mice is 105mg/kg.[LD 50 ] Patients experiencing an overdose may develop Cushing's syndrome. This overdose may be treated with supportive therapy and mifepristone for its antiglucocorticoid activity. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Allernaze, Aristocort, Aristocort R, Juulissa Pharmapak, Kenalog, Kourzeq, Marcaine, Nasacort, Oracort, Oralone, Pediaderm Ta, Triaderm, Trianex, Triderm, Triesence, Triloan Suik, Tritocin, Viaderm Kc, Xipere, Zilretta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxyprednisolone Tiamcinolonum Triamcinolona Triamcinolone Triamcinolonum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues. Output: Concomitant use of anticoagulants and triamcinolone can inhibit the effect of anticoagulants.1,2,3,4,5 The severity of the interaction is moderate.

Does Abciximab and Triflusal interact?

•Drug A: Abciximab •Drug B: Triflusal •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Triflusal. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Triflusal is indicated as prophylaxis of thromboembolic disorders. It has been registered in Spain and in other countries of Europe, South America and South Korea for the prevention of Stroke and myocardial infarction. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Triflusal is an antithrombotic anticoagulant. It irreversibly inhibits the production of thromboxane-B2 in platelets by acetylating cycloxygenase-1. Triflusal affects many other targets such as NF kappa B, which is a gene expression regulatory factor for cycloxygenase-a and cytokines. Numerous studies comparing the efficacy and safety profile (i.e. systemic hemorrhage) between triflusal and acetylsalsylic acid has shown either no significant difference or a better effacy and safety profile for triflusal. Triflusal has been shown to protect cerebral tissue due to its inhibition of lipid peroxidation resulting from anoxia-reoxygenation. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Triflusal is chemically related to acetylsalicylic acid (ASA) and irreversibly inhibits cycloxygenase-1 (COX-1) in platelets. Acetylation of the active group of COX-1 prevents the formation of thromboxane-B2 in platelets. However, it is unique because it spares the arachidonic acid metabolic pathway in endothelial cells. In addition, it favors the production of nitric oxide, a vasodilator. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorbed in the small intestine with a bioavailability range from 83% to 100%. There is no significant difference between the absorption of the oral solution and capsule formulation. Triflusal displays a Cmax of 11.6 mcg/ml and a tmax of 0.88 h. The major metabolite of triflusal presents different pharmacokinetic properties by showing a Cmax and tmax of 92.7 mcg/ml and 4.96 h, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The reported volume of distribution for triflusal is of 34L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Triflusal binds almost completely to plasma proteins reaching a 99% of the administered dose. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): In the liver, triflusal undergoes deacetylation, forming its main metabolite 2-OH-4-trifluoromethyl benzoic acid (HTB). This major metabolite seems to have marked antiplatelet properties in vitro. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The elimination pathway of triflusal is primarily renal. Urine analysis has shown the presence of unchanged triflusal, HTB and the glycine conjugate of HTB. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In the healthy human, the half-life is 0.5 +/- 0.1h, while that of HTB is 34.3 +/- 5.3h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance is 0.8 +/- 0.2L/h and 0.18 +/1 0.04L/h for triflusal and HTB, respectively. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is the possibility of producing major systemic hemorrhages.[L1168] •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Triflusal is a medication related to acetylsalicylic acid with antithrombotic effects used in the treatment of thromboembolic diseases.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Triflusal interact? Information: •Drug A: Abciximab •Drug B: Triflusal •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Triflusal. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Triflusal is indicated as prophylaxis of thromboembolic disorders. It has been registered in Spain and in other countries of Europe, South America and South Korea for the prevention of Stroke and myocardial infarction. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Triflusal is an antithrombotic anticoagulant. It irreversibly inhibits the production of thromboxane-B2 in platelets by acetylating cycloxygenase-1. Triflusal affects many other targets such as NF kappa B, which is a gene expression regulatory factor for cycloxygenase-a and cytokines. Numerous studies comparing the efficacy and safety profile (i.e. systemic hemorrhage) between triflusal and acetylsalsylic acid has shown either no significant difference or a better effacy and safety profile for triflusal. Triflusal has been shown to protect cerebral tissue due to its inhibition of lipid peroxidation resulting from anoxia-reoxygenation. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Triflusal is chemically related to acetylsalicylic acid (ASA) and irreversibly inhibits cycloxygenase-1 (COX-1) in platelets. Acetylation of the active group of COX-1 prevents the formation of thromboxane-B2 in platelets. However, it is unique because it spares the arachidonic acid metabolic pathway in endothelial cells. In addition, it favors the production of nitric oxide, a vasodilator. •Absorption (Drug A): No absorption available •Absorption (Drug B): Absorbed in the small intestine with a bioavailability range from 83% to 100%. There is no significant difference between the absorption of the oral solution and capsule formulation. Triflusal displays a Cmax of 11.6 mcg/ml and a tmax of 0.88 h. The major metabolite of triflusal presents different pharmacokinetic properties by showing a Cmax and tmax of 92.7 mcg/ml and 4.96 h, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The reported volume of distribution for triflusal is of 34L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Triflusal binds almost completely to plasma proteins reaching a 99% of the administered dose. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): In the liver, triflusal undergoes deacetylation, forming its main metabolite 2-OH-4-trifluoromethyl benzoic acid (HTB). This major metabolite seems to have marked antiplatelet properties in vitro. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The elimination pathway of triflusal is primarily renal. Urine analysis has shown the presence of unchanged triflusal, HTB and the glycine conjugate of HTB. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In the healthy human, the half-life is 0.5 +/- 0.1h, while that of HTB is 34.3 +/- 5.3h. •Clearance (Drug A): No clearance available •Clearance (Drug B): Renal clearance is 0.8 +/- 0.2L/h and 0.18 +/1 0.04L/h for triflusal and HTB, respectively. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is the possibility of producing major systemic hemorrhages.[L1168] •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Triflusal is a medication related to acetylsalicylic acid with antithrombotic effects used in the treatment of thromboembolic diseases. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Trolamine salicylate interact?

•Drug A: Abciximab •Drug B: Trolamine salicylate •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Trolamine salicylate is combined with Abciximab. •Extended Description: .Concurrent use of salicylates and anticoagulants may lead to increased anticoagulant activity and therefore an increased risk of bleeding, due to additive anticoagulant effects. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for the temporary relief of aches, and pains of muscles and joints associated with backache, lumbago, strains, bruises, sprains and arthritic or rheumatic pain, pain of tendons and ligaments. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trolamine salicylate is a salicylate that inhibits cyclo-oxygenase (COX) enzymes responsible for generating pro-inflammatory factors such as to induce pain and inflammation. It is thought to mediate its analgesic effect through inhibition of COX-2 enzyme, which is an induced enzyme responsible for inflammatory responses and pain in muscle and joint disorders. By inhibiting fatty acid COX enzyme, trolamine salicylate inhibits the production of prostaglandins and thromboxanes in inflammatory cells involved in generating pain and inflammation. It thereby works to temporarily reduce mild to moderate pain. In subjects with muscle soreness from exercise, administration of topical trolamine salicylate was associated with reduced duration and severity of muscule soreness compared to placebo. In subjects with osteoarthritis in hands, trolamine salicylate cream was shown to be effective in achieving temporary relief of minor pain and stiffness. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Inflammation and tissue damage in different conditions including arthritis, bursitis, joint disorder, bruises, and strains or sprains of muscle origin, induce mild to moderate pain and are associated with increase prostaglandin synthesis. This is thought to be a result of COX-2 enzyme induction. COX-2 is induced in inflammatory cells in case of cell injury, infection or activation from inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. Upon activation, COX-2 produces prostanoid mediators of inflammation such as prostaglandins and thromboxanes. Trolamine salicylate mediates its analgesic effect by inhibiting the production of inflammatory mediators that sensitize nociceptive nerve endings and generate pain. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following topical administration of 10% trolamine salicylate in healthy volunteers, salicylic acid could not be detected in serum indicating low systemic absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Topical administration of 1 gram of 10% trolamine salicylate in abdominal rat skin resulted in an approximate extravascular volume of distribution (V/F) of 24.0 mL. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following topical administration of 10% trolamine salicylate in healthy volunteers, urinary recovery of total salicylate during the first 24 hours was 6.9 mg (p < 0.05), which is 1.4% of total dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): It is hazardous in case of ingestion. The carcinogenicity, mutagenicity and effects on reproductive fertility of trolamine salicylate have not been reported. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Asper-flex, Aspercreme, Mobisyl, Myoflex, Sportscreme •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trolamine salicylate is a medication used to relieve minor aches and pains of the muscles and joints.

.Concurrent use of salicylates and anticoagulants may lead to increased anticoagulant activity and therefore an increased risk of bleeding, due to additive anticoagulant effects. The severity of the interaction is moderate.

Question: Does Abciximab and Trolamine salicylate interact? Information: •Drug A: Abciximab •Drug B: Trolamine salicylate •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Trolamine salicylate is combined with Abciximab. •Extended Description: .Concurrent use of salicylates and anticoagulants may lead to increased anticoagulant activity and therefore an increased risk of bleeding, due to additive anticoagulant effects. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for the temporary relief of aches, and pains of muscles and joints associated with backache, lumbago, strains, bruises, sprains and arthritic or rheumatic pain, pain of tendons and ligaments. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Trolamine salicylate is a salicylate that inhibits cyclo-oxygenase (COX) enzymes responsible for generating pro-inflammatory factors such as to induce pain and inflammation. It is thought to mediate its analgesic effect through inhibition of COX-2 enzyme, which is an induced enzyme responsible for inflammatory responses and pain in muscle and joint disorders. By inhibiting fatty acid COX enzyme, trolamine salicylate inhibits the production of prostaglandins and thromboxanes in inflammatory cells involved in generating pain and inflammation. It thereby works to temporarily reduce mild to moderate pain. In subjects with muscle soreness from exercise, administration of topical trolamine salicylate was associated with reduced duration and severity of muscule soreness compared to placebo. In subjects with osteoarthritis in hands, trolamine salicylate cream was shown to be effective in achieving temporary relief of minor pain and stiffness. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Inflammation and tissue damage in different conditions including arthritis, bursitis, joint disorder, bruises, and strains or sprains of muscle origin, induce mild to moderate pain and are associated with increase prostaglandin synthesis. This is thought to be a result of COX-2 enzyme induction. COX-2 is induced in inflammatory cells in case of cell injury, infection or activation from inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. Upon activation, COX-2 produces prostanoid mediators of inflammation such as prostaglandins and thromboxanes. Trolamine salicylate mediates its analgesic effect by inhibiting the production of inflammatory mediators that sensitize nociceptive nerve endings and generate pain. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following topical administration of 10% trolamine salicylate in healthy volunteers, salicylic acid could not be detected in serum indicating low systemic absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Topical administration of 1 gram of 10% trolamine salicylate in abdominal rat skin resulted in an approximate extravascular volume of distribution (V/F) of 24.0 mL. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following topical administration of 10% trolamine salicylate in healthy volunteers, urinary recovery of total salicylate during the first 24 hours was 6.9 mg (p < 0.05), which is 1.4% of total dose. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): No half-life available •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): It is hazardous in case of ingestion. The carcinogenicity, mutagenicity and effects on reproductive fertility of trolamine salicylate have not been reported. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Asper-flex, Aspercreme, Mobisyl, Myoflex, Sportscreme •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Trolamine salicylate is a medication used to relieve minor aches and pains of the muscles and joints. Output: .Concurrent use of salicylates and anticoagulants may lead to increased anticoagulant activity and therefore an increased risk of bleeding, due to additive anticoagulant effects. The severity of the interaction is moderate.

Does Abciximab and Turoctocog alfa pegol interact?

•Drug A: Abciximab •Drug B: Turoctocog alfa pegol •Severity: MAJOR •Description: The therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Turoctocog alfa pegol is indicated for use in adults and children with hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes. It is not indicated for the treatment of von Willebrand disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Based on results obtained from the Pathfinder clinical studies, turoctocog alfa pegol (N8-GP) was shown to provide effective routine prophylaxis in people with severe haemophilia A through a fixed dosing regimen of one injection every 4 days in adults and adolescents, or every 3-4 days (twice-weekly) in children. Furthermore, N8-GP provided effective prophylaxis and maintained a low median annualized bleeding rate (ABR) of 1.18 when administered at doses of 50 IU/kg every 4 days in adults and adolescents. Additionally, N8-GP was also found to be efficacious in the treatment and control of bleeding episodes and the perioperative management of bleeding. Across the clinical trials and age groups, N8-GP was shown to be well tolerated and no safety concerns were identified. The overall safety profile of N8-GP is similar to what has been reported for other long-action FVIII products. Moreover, in general, no FVIII inhibitor antibodies have been detected, and no thromboembolic events have occurred with the use of N8-GP. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The principal characteristic that defines hemophilia A is the limited presence or complete deficiency of human clotting factor VIII in the body. Subsequently, because factor VIII is a critical component that is essential for the extrinsic tissue factor pathway of the blood coagulation cascade process to proceed, individuals with hemophilia A ultimately experience increased bleeding - in comparison to individuals without a factor VIII deficiency - after injury or any kind of medical procedure. Such increased bleeding can be heavy and/or fatal and may occur due to minimal injury or even when there is no injury whatsoever - in which case the bleeding is spontaneous. Furthermore, excessive bleeds that bleed into muscles, organs, and joints are also associated with dangerous complications and regular pain. The turoctocog alfa pegol (N8-GP) drug is consequently recombinant factor VIII (rFVIII) in which specific site-directed glycoPEGylation has been performed in an effort to increase the half-life of the rFVIII moiety without altering its hemostatic activity. In particular, the general rFVIII component of N8-GP is turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-domain. This glycoprotein has the same structure as human clotting factor VIII when activated, and also possesses post-translational modifications that are similar to those of the plasma-derived molecule. In blood, factor VIII predominantly circulates in a stable non-covalent complex with von Willebrand factor (vWF). Concurrently, the tyrosine sulfation site present at the Tyr1680 (native full length) position, which is important for binding to vWF, has been found to be fully sulfated in the turoctocog alfa molecule. Subsequently, when infused into a hemophilia patient, this rFVIII binds to endogenous vWF in the patient’s circulation. The resultant factor VIII/vWF complex consists of two molecules (factor VIII and vWF) with different physiological functions. Factor VIII is activated by thrombin (factor IIa). Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Turoctocog alfa pegol consequently functions predominantly as factor VIII replacement therapy for patients with factor VIII deficient hemophilia A. Finally, the particular N8-GP molecule has a 40-kDa polyethylene glycol (PEG) attached to a specific O -glycan in the truncated B-domain of the general turoctocog alfa rFVIII structure. Upon activation by thrombin, this B-domain possessing the pegylation is cleaved away, leaving active rFVIIIa - which as discussed above, is highly similar to and elicits the same blood clotting activities as native factor VIII. Subsequently, the PEG group of N8-GP ultimately serves to extend the half-life of the overall drug molecule in the body. As an inert chemical, the PEG group prolongs N8-GP's half-life by acting like an obstructive 'cloud' around the rFVIII molecule to which it is attached. Since the PEG group is generally too large to be cleared by the kidneys and does not bind particularly well with the clearance receptors that typically eliminate endogenous factor VIII, N8-GP demonstrates a longer half-life than the general turoctocog alfa rFVIII structure. •Absorption (Drug A): No absorption available •Absorption (Drug B): Studies have determined that the pharmacokinetics of turoctocog alfa pegol (N8-GP) are dose linear. In particular, the area under the plasma activity curve from administration to infinity was a mean 14.74 +/- 5.35 (U h mL^-1), 38.85 +/- 11.41 (U h mL^-1), and 46.76 +/- 20.56 (U h mL^-1) at dosages of 25 U/kg, 50 U/kg, and 75 U/kg, respectively. Moreover, the C(30 min) factor VIII plasma activity 30 minutes after administration for the same three dosage categories was documented as being 0.65 +/- 0.12 U/mL, 1.24 +/- 0.28 U/mL, and 1.93 +/- 0.58 U/mL, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean volume of distribution recorded for turoctocog alfa pegol (N8-GP) is 45.27 +/- 17.78 mL/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the protein binding of turoctocog alfa pegol (N8-GP) is not readily available or accessible. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Once activated by thrombin (clotting factor IIa), factor VIII dissociates from the stable non-covalent complex with von Willebrand Factor (vWF) that it generally circulates about in the blood with. Separated from the protection of its complexation with vWF, it is believed that factor VIII undergoes proteolysis into its component amino acids by phospholipid binding proteases like protein C and activated factor Xa before being cleared from the bloodstream. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Studies regarding the elimination and clearance of factor VIII propose that the clotting factor likely experiences clearance by way of tissue mechanisms such as receptor-mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion. In particular, it is believed that receptor-mediated clearance of free factor VIII molecules is associated with structures like low-density lipoprotein (LDL) receptor-related protein (LRP1), LDL-receptors (LDLRs), heparan-sulfate proteoglycans (HSPG), megalin receptors, asialoglycoprotein receptors (ASGPRs), and various as of yet unidentified carbohydrate receptors. Some of these receptors may operate in association with each other, some may be able to internalize factor VIII by themselves, and some may be expressed on hepatocytes while still others may be expressed on macrophages. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean plasma half-life recorded for turoctocog alfa pegol (N8-GP) is 19.04 +/- 5.53 hours. Regardless, N8-GP is ultimately considered an extended half-life factor VIII molecule which offers a 1.6 fold half-life extension in adults and adolescents and a 1.9 fold half-life extension in children when compared the half-life of standard factor VIII medications. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance recorded for turoctocog alfa pegol (N8-GP) is 1.79 +/- 0/92 (mL^-1 h^-1 kg^-1). •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): At the moment, due to third-party IP agreements, Novo Nordisk will not be able to launch the retail ESPEROCT® (turoctocog alfa pegol) product before 2020 in the USA. Subsequently, despite a relative lack of toxicity data - from clinical studies, post-marketing surveillance, or otherwise - general experience with the medication has suggested that it is well tolerated across all age groups and indications, and no safety concerns were identified after more than 5 years of clinical exposure. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): No summary available

Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Question: Does Abciximab and Turoctocog alfa pegol interact? Information: •Drug A: Abciximab •Drug B: Turoctocog alfa pegol •Severity: MAJOR •Description: The therapeutic efficacy of Turoctocog alfa pegol can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Turoctocog alfa pegol is indicated for use in adults and children with hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes. It is not indicated for the treatment of von Willebrand disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Based on results obtained from the Pathfinder clinical studies, turoctocog alfa pegol (N8-GP) was shown to provide effective routine prophylaxis in people with severe haemophilia A through a fixed dosing regimen of one injection every 4 days in adults and adolescents, or every 3-4 days (twice-weekly) in children. Furthermore, N8-GP provided effective prophylaxis and maintained a low median annualized bleeding rate (ABR) of 1.18 when administered at doses of 50 IU/kg every 4 days in adults and adolescents. Additionally, N8-GP was also found to be efficacious in the treatment and control of bleeding episodes and the perioperative management of bleeding. Across the clinical trials and age groups, N8-GP was shown to be well tolerated and no safety concerns were identified. The overall safety profile of N8-GP is similar to what has been reported for other long-action FVIII products. Moreover, in general, no FVIII inhibitor antibodies have been detected, and no thromboembolic events have occurred with the use of N8-GP. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The principal characteristic that defines hemophilia A is the limited presence or complete deficiency of human clotting factor VIII in the body. Subsequently, because factor VIII is a critical component that is essential for the extrinsic tissue factor pathway of the blood coagulation cascade process to proceed, individuals with hemophilia A ultimately experience increased bleeding - in comparison to individuals without a factor VIII deficiency - after injury or any kind of medical procedure. Such increased bleeding can be heavy and/or fatal and may occur due to minimal injury or even when there is no injury whatsoever - in which case the bleeding is spontaneous. Furthermore, excessive bleeds that bleed into muscles, organs, and joints are also associated with dangerous complications and regular pain. The turoctocog alfa pegol (N8-GP) drug is consequently recombinant factor VIII (rFVIII) in which specific site-directed glycoPEGylation has been performed in an effort to increase the half-life of the rFVIII moiety without altering its hemostatic activity. In particular, the general rFVIII component of N8-GP is turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-domain. This glycoprotein has the same structure as human clotting factor VIII when activated, and also possesses post-translational modifications that are similar to those of the plasma-derived molecule. In blood, factor VIII predominantly circulates in a stable non-covalent complex with von Willebrand factor (vWF). Concurrently, the tyrosine sulfation site present at the Tyr1680 (native full length) position, which is important for binding to vWF, has been found to be fully sulfated in the turoctocog alfa molecule. Subsequently, when infused into a hemophilia patient, this rFVIII binds to endogenous vWF in the patient’s circulation. The resultant factor VIII/vWF complex consists of two molecules (factor VIII and vWF) with different physiological functions. Factor VIII is activated by thrombin (factor IIa). Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Turoctocog alfa pegol consequently functions predominantly as factor VIII replacement therapy for patients with factor VIII deficient hemophilia A. Finally, the particular N8-GP molecule has a 40-kDa polyethylene glycol (PEG) attached to a specific O -glycan in the truncated B-domain of the general turoctocog alfa rFVIII structure. Upon activation by thrombin, this B-domain possessing the pegylation is cleaved away, leaving active rFVIIIa - which as discussed above, is highly similar to and elicits the same blood clotting activities as native factor VIII. Subsequently, the PEG group of N8-GP ultimately serves to extend the half-life of the overall drug molecule in the body. As an inert chemical, the PEG group prolongs N8-GP's half-life by acting like an obstructive 'cloud' around the rFVIII molecule to which it is attached. Since the PEG group is generally too large to be cleared by the kidneys and does not bind particularly well with the clearance receptors that typically eliminate endogenous factor VIII, N8-GP demonstrates a longer half-life than the general turoctocog alfa rFVIII structure. •Absorption (Drug A): No absorption available •Absorption (Drug B): Studies have determined that the pharmacokinetics of turoctocog alfa pegol (N8-GP) are dose linear. In particular, the area under the plasma activity curve from administration to infinity was a mean 14.74 +/- 5.35 (U h mL^-1), 38.85 +/- 11.41 (U h mL^-1), and 46.76 +/- 20.56 (U h mL^-1) at dosages of 25 U/kg, 50 U/kg, and 75 U/kg, respectively. Moreover, the C(30 min) factor VIII plasma activity 30 minutes after administration for the same three dosage categories was documented as being 0.65 +/- 0.12 U/mL, 1.24 +/- 0.28 U/mL, and 1.93 +/- 0.58 U/mL, respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The mean volume of distribution recorded for turoctocog alfa pegol (N8-GP) is 45.27 +/- 17.78 mL/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the protein binding of turoctocog alfa pegol (N8-GP) is not readily available or accessible. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Once activated by thrombin (clotting factor IIa), factor VIII dissociates from the stable non-covalent complex with von Willebrand Factor (vWF) that it generally circulates about in the blood with. Separated from the protection of its complexation with vWF, it is believed that factor VIII undergoes proteolysis into its component amino acids by phospholipid binding proteases like protein C and activated factor Xa before being cleared from the bloodstream. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Studies regarding the elimination and clearance of factor VIII propose that the clotting factor likely experiences clearance by way of tissue mechanisms such as receptor-mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion. In particular, it is believed that receptor-mediated clearance of free factor VIII molecules is associated with structures like low-density lipoprotein (LDL) receptor-related protein (LRP1), LDL-receptors (LDLRs), heparan-sulfate proteoglycans (HSPG), megalin receptors, asialoglycoprotein receptors (ASGPRs), and various as of yet unidentified carbohydrate receptors. Some of these receptors may operate in association with each other, some may be able to internalize factor VIII by themselves, and some may be expressed on hepatocytes while still others may be expressed on macrophages. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The mean plasma half-life recorded for turoctocog alfa pegol (N8-GP) is 19.04 +/- 5.53 hours. Regardless, N8-GP is ultimately considered an extended half-life factor VIII molecule which offers a 1.6 fold half-life extension in adults and adolescents and a 1.9 fold half-life extension in children when compared the half-life of standard factor VIII medications. •Clearance (Drug A): No clearance available •Clearance (Drug B): The mean clearance recorded for turoctocog alfa pegol (N8-GP) is 1.79 +/- 0/92 (mL^-1 h^-1 kg^-1). •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): At the moment, due to third-party IP agreements, Novo Nordisk will not be able to launch the retail ESPEROCT® (turoctocog alfa pegol) product before 2020 in the USA. Subsequently, despite a relative lack of toxicity data - from clinical studies, post-marketing surveillance, or otherwise - general experience with the medication has suggested that it is well tolerated across all age groups and indications, and no safety concerns were identified after more than 5 years of clinical exposure. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): No summary available Output: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Does Abciximab and Turoctocog alfa interact?

•Drug A: Abciximab •Drug B: Turoctocog alfa •Severity: MAJOR •Description: The therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Turoctocog alfa is indicated for the treatment and prophylaxis of bleedings in patients presenting hemophilia A. The treatment with turoctocog alfa is related with its use to control bleeding episodes or as a perioperative management. Hemophilia A is a hereditary hemorrhagic disorder generated by the congenital deficit of the coagulation factor VIII. This disease is manifested as excessive spontaneous or trauma-driven bleeding. The coagulation factor VIII is a robust initiator of thrombin which is later required for the generation of fibrin to form a platelet plug and its gene is expressed in the X chromosome. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): After turoctocog alfa administration, it has been reported a significant improvement in hemostasis. This effect was observed by the amelioration on whole blood clotting time. In clinical trials, there were no reports of development of factor VIII inhibitors and even 90% of the ocurred bleeds were resolved with 1 or 2 infusions of turoctocog alfa. There are no reports of treatment failure. In vitro studies confirmed the ability of turoctocog alfa to improve clot formation and clot stability. All these studies prove that turoctocog alfa is fully functional and its activity is similar to the one showed by other recombinant factor VIII products. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The B domain is known to perform the function of restrict the expression of the endogenous coagulation factor VIII but it has no direct relationship to the function of this factor. In normal conditions during hemostasis, the coagulation factor VIII will be activated by specific thrombin cleavages producing A1, A2 and A3-C1-C2 fragments of activated factor VIII (Factor VIIIa) which will form a complex with the factor IXa and activate the factor X leading to a stable haemostatic plug. Turoctocog contains all function-related domains with a considerably easier intact expression of the protein in mammalian cells by truncating the B domain. This recombinant structure allows it to replace the missing factor VIII and restore hemostasis. •Absorption (Drug A): No absorption available •Absorption (Drug B): In pre-clinical studies, the absorption half-life was reported wot be 5.4 hours. The absorption profile varies depending on the age of the patient where the AUC is 9.92, 11.09 and 15.26 IU hour/ml for the age range of 0-6 years, 6-12 years and over 12 years old respectively. The Cmax according to the different age groups is 1, 1.07 and 1.226 IU/ml for the age range of 0-6 years, 6-12 years and over 12 years old respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In pre-clinical studies, turoctocog distribution was studied based on a two model compartment and it resulted in 59 ml/kg in the central compartment and 13 ml/kg in the peripheral compartment. It also presented an inter-compartmental flow of 0.66 ml/hour kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Because turoctocog alfa is a recombinant protein, there has been not enough studies of protein binding. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Turoctocog alfa is expected to be cleaved by proteolysis into small individual aminoacids that constitute them after receptor mediated cell endocytosis. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): After intravenous administration of turoctocog alfa, the time for complete elimination of the blood plasma is of 50-55 hours. Due to the fact that this drug is a 166 kDa, it is thought that it will be eliminated by tissue mechanisms such as receptor mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In pre-clinical studies, turoctocog half-life was reported to be 16 hours. In knockout mice there are reports of half-life of 7-8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In pre-clinical studies, turoctocog clearance was reported to be 6.5 ml/hour kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): In preclinical safety studies, there was a change in reported systolic pressure after 2-weeks of multiple dosing. Thrombus formation, cardiovascular, neurological or respiratory effects are not expected to be a safety concern. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Novoeight, Zonovate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Turoctocog alfa is an antihemorrhagic agent used for the treatment and prophylaxis of bleeding in patients of all ages with haemophilia A (congenital factor VIII deficiency).

Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Question: Does Abciximab and Turoctocog alfa interact? Information: •Drug A: Abciximab •Drug B: Turoctocog alfa •Severity: MAJOR •Description: The therapeutic efficacy of Turoctocog alfa can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Turoctocog alfa is indicated for the treatment and prophylaxis of bleedings in patients presenting hemophilia A. The treatment with turoctocog alfa is related with its use to control bleeding episodes or as a perioperative management. Hemophilia A is a hereditary hemorrhagic disorder generated by the congenital deficit of the coagulation factor VIII. This disease is manifested as excessive spontaneous or trauma-driven bleeding. The coagulation factor VIII is a robust initiator of thrombin which is later required for the generation of fibrin to form a platelet plug and its gene is expressed in the X chromosome. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): After turoctocog alfa administration, it has been reported a significant improvement in hemostasis. This effect was observed by the amelioration on whole blood clotting time. In clinical trials, there were no reports of development of factor VIII inhibitors and even 90% of the ocurred bleeds were resolved with 1 or 2 infusions of turoctocog alfa. There are no reports of treatment failure. In vitro studies confirmed the ability of turoctocog alfa to improve clot formation and clot stability. All these studies prove that turoctocog alfa is fully functional and its activity is similar to the one showed by other recombinant factor VIII products. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The B domain is known to perform the function of restrict the expression of the endogenous coagulation factor VIII but it has no direct relationship to the function of this factor. In normal conditions during hemostasis, the coagulation factor VIII will be activated by specific thrombin cleavages producing A1, A2 and A3-C1-C2 fragments of activated factor VIII (Factor VIIIa) which will form a complex with the factor IXa and activate the factor X leading to a stable haemostatic plug. Turoctocog contains all function-related domains with a considerably easier intact expression of the protein in mammalian cells by truncating the B domain. This recombinant structure allows it to replace the missing factor VIII and restore hemostasis. •Absorption (Drug A): No absorption available •Absorption (Drug B): In pre-clinical studies, the absorption half-life was reported wot be 5.4 hours. The absorption profile varies depending on the age of the patient where the AUC is 9.92, 11.09 and 15.26 IU hour/ml for the age range of 0-6 years, 6-12 years and over 12 years old respectively. The Cmax according to the different age groups is 1, 1.07 and 1.226 IU/ml for the age range of 0-6 years, 6-12 years and over 12 years old respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): In pre-clinical studies, turoctocog distribution was studied based on a two model compartment and it resulted in 59 ml/kg in the central compartment and 13 ml/kg in the peripheral compartment. It also presented an inter-compartmental flow of 0.66 ml/hour kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Because turoctocog alfa is a recombinant protein, there has been not enough studies of protein binding. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Turoctocog alfa is expected to be cleaved by proteolysis into small individual aminoacids that constitute them after receptor mediated cell endocytosis. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): After intravenous administration of turoctocog alfa, the time for complete elimination of the blood plasma is of 50-55 hours. Due to the fact that this drug is a 166 kDa, it is thought that it will be eliminated by tissue mechanisms such as receptor mediated endocytosis followed by catabolism rather than hepatic metabolism and renal excretion. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In pre-clinical studies, turoctocog half-life was reported to be 16 hours. In knockout mice there are reports of half-life of 7-8 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In pre-clinical studies, turoctocog clearance was reported to be 6.5 ml/hour kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): In preclinical safety studies, there was a change in reported systolic pressure after 2-weeks of multiple dosing. Thrombus formation, cardiovascular, neurological or respiratory effects are not expected to be a safety concern. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Novoeight, Zonovate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Turoctocog alfa is an antihemorrhagic agent used for the treatment and prophylaxis of bleeding in patients of all ages with haemophilia A (congenital factor VIII deficiency). Output: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Does Abciximab and Ublituximab interact?

•Drug A: Abciximab •Drug B: Ublituximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Ublituximab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ublituximab is indicated in adult patients for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease by the FDA. It is also indicated by the EMA to treat relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Treatment with ublituximab reduces CD19+ B-cell counts - used as a surrogate marker for CD20+ B-cells due to ublituximab's interference with the CD20 assay - within 24 hours of the initial infusion. The median time for B-cell counts to return to either baseline or the lower limit of normal (LLN) was 70.3 weeks following the final infusion, and within 1.5 years of the final infusion approximately 58% of patients had returned to baseline or LLN. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): B-cell dysregulation underlies the pathogenesis of various cancers and autoimmune conditions such as multiple sclerosis, neuromyelitis optica spectrum disease, and myelin oligodendrocyte glycoprotein IgG-associated disease. CD20 is an antigen expressed on pre-B cells, immature/mature B-cells, memory B-cells, and a subpopulation of CD3-positive T cells. Anti-CD20 antibodies can therefore induce B-cell depletion through direct cell death, induction of complement pathways, and Fc-gamma receptor (FcγR)-mediated phagocytosis (antibody-dependent cellular cytotoxicity, ADCC). Although several anti-CD20 antibodies have been developed, therapy has been hampered by low CD20 expression by malignant cells in diseases such as B-cell chronic lymphocytic leukemia and suboptimal antibody-dependent cytotoxicity. Ublituximab binds to an epitope on CD20 distinct from that bound by other approved antibodies such as rituximab, ofatumumab, obinutuzumab, and ocrelizumab, with a similar binding constant to rituximab. Uniquely, ublituximab is produced in the rat YB2/0 cell line such that it has a low fucose content (24% compared to 93% for rituximab ), improving its interaction with FcγR, especially FcγRIIIA (CD16) expressed by natural killer cells and macrophages. This difference grants ublituximab enhanced ADCC, including for low CD20-expressing malignant cells. The precise mechanism of action of ublituximab in the treatment of multiple sclerosis is unclear, but is presumed to involve CD20 binding and subsequent cell lysis as described above. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following the administration of the approved recommended dosage of ublituximab, the geometric mean steady-state AUC was 3000 mcg/mL per day and the mean C max was 139 mcg/mL. In patients with relapsing multiple sclerosis, ublituximab exposure increases proportionally over a dose range of 150mg to 600mg. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimated central volume of distribution of ublituximab-xiiy was 3.18 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic proteins, the metabolism of ublituximab likely occurs via degradation to smaller peptides and amino acids by non-specific proteolytic enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The estimated mean terminal half-life of ublituximab-xiiy was 22 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Briumvi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ublituximab is a low-fucose CD20-targeted monoclonal antibody used in the treatment of relapsing forms of multiple sclerosis.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Ublituximab interact? Information: •Drug A: Abciximab •Drug B: Ublituximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Ublituximab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ublituximab is indicated in adult patients for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease by the FDA. It is also indicated by the EMA to treat relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Treatment with ublituximab reduces CD19+ B-cell counts - used as a surrogate marker for CD20+ B-cells due to ublituximab's interference with the CD20 assay - within 24 hours of the initial infusion. The median time for B-cell counts to return to either baseline or the lower limit of normal (LLN) was 70.3 weeks following the final infusion, and within 1.5 years of the final infusion approximately 58% of patients had returned to baseline or LLN. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): B-cell dysregulation underlies the pathogenesis of various cancers and autoimmune conditions such as multiple sclerosis, neuromyelitis optica spectrum disease, and myelin oligodendrocyte glycoprotein IgG-associated disease. CD20 is an antigen expressed on pre-B cells, immature/mature B-cells, memory B-cells, and a subpopulation of CD3-positive T cells. Anti-CD20 antibodies can therefore induce B-cell depletion through direct cell death, induction of complement pathways, and Fc-gamma receptor (FcγR)-mediated phagocytosis (antibody-dependent cellular cytotoxicity, ADCC). Although several anti-CD20 antibodies have been developed, therapy has been hampered by low CD20 expression by malignant cells in diseases such as B-cell chronic lymphocytic leukemia and suboptimal antibody-dependent cytotoxicity. Ublituximab binds to an epitope on CD20 distinct from that bound by other approved antibodies such as rituximab, ofatumumab, obinutuzumab, and ocrelizumab, with a similar binding constant to rituximab. Uniquely, ublituximab is produced in the rat YB2/0 cell line such that it has a low fucose content (24% compared to 93% for rituximab ), improving its interaction with FcγR, especially FcγRIIIA (CD16) expressed by natural killer cells and macrophages. This difference grants ublituximab enhanced ADCC, including for low CD20-expressing malignant cells. The precise mechanism of action of ublituximab in the treatment of multiple sclerosis is unclear, but is presumed to involve CD20 binding and subsequent cell lysis as described above. •Absorption (Drug A): No absorption available •Absorption (Drug B): Following the administration of the approved recommended dosage of ublituximab, the geometric mean steady-state AUC was 3000 mcg/mL per day and the mean C max was 139 mcg/mL. In patients with relapsing multiple sclerosis, ublituximab exposure increases proportionally over a dose range of 150mg to 600mg. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The estimated central volume of distribution of ublituximab-xiiy was 3.18 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): As with other therapeutic proteins, the metabolism of ublituximab likely occurs via degradation to smaller peptides and amino acids by non-specific proteolytic enzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The estimated mean terminal half-life of ublituximab-xiiy was 22 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Briumvi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ublituximab is a low-fucose CD20-targeted monoclonal antibody used in the treatment of relapsing forms of multiple sclerosis. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Ulipristal interact?

•Drug A: Abciximab •Drug B: Ulipristal •Severity: MODERATE •Description: The therapeutic efficacy of Abciximab can be decreased when used in combination with Ulipristal. •Extended Description: Systemic hormonal contraceptives, such as the subject drug, are known to increase the risk of venous thromboembolism (VTE).4,1,3 While specific data regarding the concomitant use of hormonal contraceptives and anticoagulants is sparse, it follows that the procoagulant effects of hormonal contraceptives may oppose the therapeutic effects of anticoagulants, lowering their efficacy and increasing the risk of clotting. The estrogen component of combined hormonal contraceptives appears to the be the primary culprit in their induction of hypercoagulability - its effects appear to be driven by alterations to procoagulant proteins (i.e. clotting factors) and an induced resistance to activated protein C (APC), an endogenous anticoagulant. While it was previously thought that first-pass metabolism of oral contraceptives through the liver was responsible for their prothrombotic effect, more recent studies have suggested that alternative routes of administration (i.e. routes that bypass first-pass metabolism) do not improve the risk of clotting, and this is reflected in the FDA labeling for these non-oral contraceptive options. Progestin-only contraceptives do not appear to carry the same risk of thrombotic events as do estrogen-containing contraceptives. This interaction is likely to be more significant in patients with other risk factors for hormonal contraceptive-induced thrombotic events, such as smoking, age >35, obesity, and hypertension. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): As the product Ella (available in Canada and the US), ulipristal is indicated for use as emergency contraception after unprotected intercourse or possible contraceptive failure when administered within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure. As the product Fibristal (available in Canada), ulipristal is indicated for treatment of the signs and symptoms of uterine fibroids in adult women. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ulipristal is a selective, reversible progestin receptor modulator and its tissue targets include the uterus, cervix, ovaries, and hypothalamus. Ulipristal may act as an agonist or antagonist in the presence or absence of progesterone based on the tissue target. If given mid-follicular phase, development of the follicle growth is delayed and estradiol concentrations decrease. If given at the time when luteinizing hormone peaks, follicular rapture is delayed by several days. If given early-luteal phase, a decrease in endometrial thickness can be observed. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The exact mechanism of action of ulipristal has been heavily debated. On one hand, the majority of official prescribing information labels, monographs, and prior research studies for ulipristal indicated as an emergency contraceptive suggest that its primary mechanism of action revolves around inhibiting or delaying ovulation by suppressing surges in LH that result in the postponement of follicular rupture. Conversely, some of the latest investigations pertaining to ulipristal's mechanism of action as an emergency contraceptive propose that it principally elicits its action by preventing embryo implantation, as opposed to preventing ovulation. Although previous investigations have shown that ulipristal essentially has the ability to prevent ovulation equivalent to placebo (ie. null effect or ability) when administered during LH peaks one to two days before ovulation, the agent still demonstrates a stable and consistently high contraceptive effect of approximately >=80% when used at this time. Subsequently, current studies attempt to investigate how ulipristal could elicit emergency contraception via ovulation prevention under circumstances where ovulation had already clearly been observed. Endometrial biopsy samples studied from such circumstances in such investigations subsequently show that the administered ulipristal causes endometrial tissue to become inhospitable and unsuitable for embryo implantation where a variety of genes characteristic of receptive, pro-gestational endometrium are downregulated. Nevertheless, most if not all proposed mechanisms commonly agree that ulipristal ultimately demonstrates its pharmacological effects by binding to human progesterone receptors and prevents natural, endogenous progesterone from occupying such receptors. Regardless, however, considering current and on-going research into ulipristal's ability to prevent embryo implantation, the notion that the medication can elicit post-fertilization effects potentially raises alerts and/or ethical debates over the use of ulipristal owing to potential abortifacient activity, which is considered to be on par or equipotent to that of mifepristone. Attention should be drawn to the fact that some prescribing information, however, such as the US FDA label for ulipristal indicated for emergency contraception, has included new supplementary commentary since 2018 that directly warns about ulipristal not being indicated for termination of existing pregnancies and suggesting that ulipristal use may confer alterations to the endometrium that may affect implantation and contribute to efficacy. In the treatment of fibroids, ulipristal has been shown to exert direct actions on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tmax, healthy subjects, single oral dose = 60-90 minutes; Cmax, healthy subjects, single oral dose = 176 ± 89 ng/mL; AUC(0-∞), healthy subjects, single oral dose = 556 ± 260 ng·h/mL; •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >94% bound to plasma proteins such as albumin, alpha1-acid glycoprotein, lipoproteins (VLDL, LDL, and HDL- due to its lipophillic nature) •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Ulipristal is metabolized by CYP3A4 and to a lesser extent by CYP1A2 into mono-demethylated (active) and di-methylated (inactive) metabolites. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Mean elimination half-life, single oral dose, healthy subject = 32.4 ± 6.3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean oral clearance, single oral dose, healthy subject (CL/F) = 76.8 ± 64.0L/h •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Ella, Ellaone, Esmya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ulipristal is a selective progesterone receptor modulator used for emergency contraception after unprotected intercourse or in a situation where a planned method of contraception has failed.

Systemic hormonal contraceptives, such as the subject drug, are known to increase the risk of venous thromboembolism (VTE).4,1,3 While specific data regarding the concomitant use of hormonal contraceptives and anticoagulants is sparse, it follows that the procoagulant effects of hormonal contraceptives may oppose the therapeutic effects of anticoagulants, lowering their efficacy and increasing the risk of clotting. The estrogen component of combined hormonal contraceptives appears to the be the primary culprit in their induction of hypercoagulability - its effects appear to be driven by alterations to procoagulant proteins (i.e. clotting factors) and an induced resistance to activated protein C (APC), an endogenous anticoagulant. While it was previously thought that first-pass metabolism of oral contraceptives through the liver was responsible for their prothrombotic effect, more recent studies have suggested that alternative routes of administration (i.e. routes that bypass first-pass metabolism) do not improve the risk of clotting, and this is reflected in the FDA labeling for these non-oral contraceptive options. Progestin-only contraceptives do not appear to carry the same risk of thrombotic events as do estrogen-containing contraceptives. This interaction is likely to be more significant in patients with other risk factors for hormonal contraceptive-induced thrombotic events, such as smoking, age >35, obesity, and hypertension. The severity of the interaction is moderate.

Question: Does Abciximab and Ulipristal interact? Information: •Drug A: Abciximab •Drug B: Ulipristal •Severity: MODERATE •Description: The therapeutic efficacy of Abciximab can be decreased when used in combination with Ulipristal. •Extended Description: Systemic hormonal contraceptives, such as the subject drug, are known to increase the risk of venous thromboembolism (VTE).4,1,3 While specific data regarding the concomitant use of hormonal contraceptives and anticoagulants is sparse, it follows that the procoagulant effects of hormonal contraceptives may oppose the therapeutic effects of anticoagulants, lowering their efficacy and increasing the risk of clotting. The estrogen component of combined hormonal contraceptives appears to the be the primary culprit in their induction of hypercoagulability - its effects appear to be driven by alterations to procoagulant proteins (i.e. clotting factors) and an induced resistance to activated protein C (APC), an endogenous anticoagulant. While it was previously thought that first-pass metabolism of oral contraceptives through the liver was responsible for their prothrombotic effect, more recent studies have suggested that alternative routes of administration (i.e. routes that bypass first-pass metabolism) do not improve the risk of clotting, and this is reflected in the FDA labeling for these non-oral contraceptive options. Progestin-only contraceptives do not appear to carry the same risk of thrombotic events as do estrogen-containing contraceptives. This interaction is likely to be more significant in patients with other risk factors for hormonal contraceptive-induced thrombotic events, such as smoking, age >35, obesity, and hypertension. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): As the product Ella (available in Canada and the US), ulipristal is indicated for use as emergency contraception after unprotected intercourse or possible contraceptive failure when administered within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure. As the product Fibristal (available in Canada), ulipristal is indicated for treatment of the signs and symptoms of uterine fibroids in adult women. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ulipristal is a selective, reversible progestin receptor modulator and its tissue targets include the uterus, cervix, ovaries, and hypothalamus. Ulipristal may act as an agonist or antagonist in the presence or absence of progesterone based on the tissue target. If given mid-follicular phase, development of the follicle growth is delayed and estradiol concentrations decrease. If given at the time when luteinizing hormone peaks, follicular rapture is delayed by several days. If given early-luteal phase, a decrease in endometrial thickness can be observed. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The exact mechanism of action of ulipristal has been heavily debated. On one hand, the majority of official prescribing information labels, monographs, and prior research studies for ulipristal indicated as an emergency contraceptive suggest that its primary mechanism of action revolves around inhibiting or delaying ovulation by suppressing surges in LH that result in the postponement of follicular rupture. Conversely, some of the latest investigations pertaining to ulipristal's mechanism of action as an emergency contraceptive propose that it principally elicits its action by preventing embryo implantation, as opposed to preventing ovulation. Although previous investigations have shown that ulipristal essentially has the ability to prevent ovulation equivalent to placebo (ie. null effect or ability) when administered during LH peaks one to two days before ovulation, the agent still demonstrates a stable and consistently high contraceptive effect of approximately >=80% when used at this time. Subsequently, current studies attempt to investigate how ulipristal could elicit emergency contraception via ovulation prevention under circumstances where ovulation had already clearly been observed. Endometrial biopsy samples studied from such circumstances in such investigations subsequently show that the administered ulipristal causes endometrial tissue to become inhospitable and unsuitable for embryo implantation where a variety of genes characteristic of receptive, pro-gestational endometrium are downregulated. Nevertheless, most if not all proposed mechanisms commonly agree that ulipristal ultimately demonstrates its pharmacological effects by binding to human progesterone receptors and prevents natural, endogenous progesterone from occupying such receptors. Regardless, however, considering current and on-going research into ulipristal's ability to prevent embryo implantation, the notion that the medication can elicit post-fertilization effects potentially raises alerts and/or ethical debates over the use of ulipristal owing to potential abortifacient activity, which is considered to be on par or equipotent to that of mifepristone. Attention should be drawn to the fact that some prescribing information, however, such as the US FDA label for ulipristal indicated for emergency contraception, has included new supplementary commentary since 2018 that directly warns about ulipristal not being indicated for termination of existing pregnancies and suggesting that ulipristal use may confer alterations to the endometrium that may affect implantation and contribute to efficacy. In the treatment of fibroids, ulipristal has been shown to exert direct actions on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Tmax, healthy subjects, single oral dose = 60-90 minutes; Cmax, healthy subjects, single oral dose = 176 ± 89 ng/mL; AUC(0-∞), healthy subjects, single oral dose = 556 ± 260 ng·h/mL; •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >94% bound to plasma proteins such as albumin, alpha1-acid glycoprotein, lipoproteins (VLDL, LDL, and HDL- due to its lipophillic nature) •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Ulipristal is metabolized by CYP3A4 and to a lesser extent by CYP1A2 into mono-demethylated (active) and di-methylated (inactive) metabolites. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Mean elimination half-life, single oral dose, healthy subject = 32.4 ± 6.3 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean oral clearance, single oral dose, healthy subject (CL/F) = 76.8 ± 64.0L/h •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Ella, Ellaone, Esmya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ulipristal is a selective progesterone receptor modulator used for emergency contraception after unprotected intercourse or in a situation where a planned method of contraception has failed. Output: Systemic hormonal contraceptives, such as the subject drug, are known to increase the risk of venous thromboembolism (VTE).4,1,3 While specific data regarding the concomitant use of hormonal contraceptives and anticoagulants is sparse, it follows that the procoagulant effects of hormonal contraceptives may oppose the therapeutic effects of anticoagulants, lowering their efficacy and increasing the risk of clotting. The estrogen component of combined hormonal contraceptives appears to the be the primary culprit in their induction of hypercoagulability - its effects appear to be driven by alterations to procoagulant proteins (i.e. clotting factors) and an induced resistance to activated protein C (APC), an endogenous anticoagulant. While it was previously thought that first-pass metabolism of oral contraceptives through the liver was responsible for their prothrombotic effect, more recent studies have suggested that alternative routes of administration (i.e. routes that bypass first-pass metabolism) do not improve the risk of clotting, and this is reflected in the FDA labeling for these non-oral contraceptive options. Progestin-only contraceptives do not appear to carry the same risk of thrombotic events as do estrogen-containing contraceptives. This interaction is likely to be more significant in patients with other risk factors for hormonal contraceptive-induced thrombotic events, such as smoking, age >35, obesity, and hypertension. The severity of the interaction is moderate.

Does Abciximab and Urokinase interact?

•Drug A: Abciximab •Drug B: Urokinase •Severity: MAJOR •Description: Urokinase may increase the anticoagulant activities of Abciximab. •Extended Description: Urokinase is a thrombolytic enzyme with a potential risk to cause serious bleeding events. Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy. Concurrent administration of urokinase with other anticoagulants may further increase the risk of serious bleeding due to a synergistic anticoagulant effect. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In Canada, urokinase is indicated for lysis of acute massive pulmonary emboli, acute thrombi obstructing coronary arteries, occlusive thromboemboli in peripheral arteries and grafts, and restoration of patency to intravenous catheters. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Urokinase is a serine protease that activates plasminogen to an active fibrinolytic protease. The duration of action is short due to the short half life. Patients should be counselled regarding the risk of bleeding, anaphylaxis, infusion reactions, and cholesterol embolization.[L12138 •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Urokinase is a serine protease. It cleaves plasminogen to form the active fibrinolytic protease, plasmin. •Absorption (Drug A): No absorption available •Absorption (Drug B): Urokinase is delivered intravenously, so the bioavailability is high. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of urokinase is 11.5L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the protein binding of urokinase in plasma is not readily available. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Because urokinase is a protein, it is expected to be metabolized by proteases to smaller proteins and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Urokinase is eliminated in the bile and urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Urokinase has a half life of 12.6±6.2 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Data regarding the clearance of urokinase is not readily available. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Patients experiencing an overdose may present with bleeding. Treat patients with symptomatic and supportive measures which may include application of local pressure, administration of whole blood or plasma, and administration of aminocaproic acid. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Kinlytic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Urokinase is a low molecular weight form of human urokinase used to treat pulmonary embolism and myocardial infarction as well as to clear IV lines.

Urokinase is a thrombolytic enzyme with a potential risk to cause serious bleeding events. Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy. Concurrent administration of urokinase with other anticoagulants may further increase the risk of serious bleeding due to a synergistic anticoagulant effect. The severity of the interaction is major.

Question: Does Abciximab and Urokinase interact? Information: •Drug A: Abciximab •Drug B: Urokinase •Severity: MAJOR •Description: Urokinase may increase the anticoagulant activities of Abciximab. •Extended Description: Urokinase is a thrombolytic enzyme with a potential risk to cause serious bleeding events. Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy. Concurrent administration of urokinase with other anticoagulants may further increase the risk of serious bleeding due to a synergistic anticoagulant effect. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): In Canada, urokinase is indicated for lysis of acute massive pulmonary emboli, acute thrombi obstructing coronary arteries, occlusive thromboemboli in peripheral arteries and grafts, and restoration of patency to intravenous catheters. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Urokinase is a serine protease that activates plasminogen to an active fibrinolytic protease. The duration of action is short due to the short half life. Patients should be counselled regarding the risk of bleeding, anaphylaxis, infusion reactions, and cholesterol embolization.[L12138 •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Urokinase is a serine protease. It cleaves plasminogen to form the active fibrinolytic protease, plasmin. •Absorption (Drug A): No absorption available •Absorption (Drug B): Urokinase is delivered intravenously, so the bioavailability is high. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of urokinase is 11.5L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the protein binding of urokinase in plasma is not readily available. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Because urokinase is a protein, it is expected to be metabolized by proteases to smaller proteins and amino acids. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Urokinase is eliminated in the bile and urine. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Urokinase has a half life of 12.6±6.2 minutes. •Clearance (Drug A): No clearance available •Clearance (Drug B): Data regarding the clearance of urokinase is not readily available. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Patients experiencing an overdose may present with bleeding. Treat patients with symptomatic and supportive measures which may include application of local pressure, administration of whole blood or plasma, and administration of aminocaproic acid. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Kinlytic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Urokinase is a low molecular weight form of human urokinase used to treat pulmonary embolism and myocardial infarction as well as to clear IV lines. Output: Urokinase is a thrombolytic enzyme with a potential risk to cause serious bleeding events. Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy. Concurrent administration of urokinase with other anticoagulants may further increase the risk of serious bleeding due to a synergistic anticoagulant effect. The severity of the interaction is major.

Does Abciximab and Ursodeoxycholic acid interact?

•Drug A: Abciximab •Drug B: Ursodeoxycholic acid •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Ursodeoxycholic acid. •Extended Description: Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ursodeoxycholic acid is indicated for the treatment of patients with primary biliary cholangitis. It is used for the short-term treatment of radiolucent, noncalcified gallbladder stones in patients selected for elective cholecystectomy. It is also used to prevent gallstone formation in obese patients experiencing rapid weight loss. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ursodeoxycholic acid (UDCA) is a secondary bile acid with cytoprotectant, immunomodulating, and choleretic effects. It reduces the cholesterol fraction of biliary lipids. UDCA inhibits the absorption of cholesterol in the intestine and the secretion of cholesterol into bile, decreasing biliary cholesterol saturation. UDCA increases bile acid flow and promotes the secretion of bile acids. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Endogenous hydrophobic bile acids such as deoxycholic acid and chenodeoxycholic acid can exert hepatotoxic effects. Ursodeoxycholic acid is a hydrophilic bile acid that mediates its biological effects via several mechanisms. Ursodeoxycholic acid (UDCA) protects hepatocytes and cholangiocytes from bile acid-induced damage, such as reactive oxygen species (ROS)-induced inflammation and mitochondrial dysfunction. UDCA was shown to reserve hepatocyte cell structures and stimulate anti-apoptotic pathways. It was also shown to prevent the production of ROS by Kupffer cells and resident macrophages in the liver, thus attenuating oxidative stress in the liver. UDCA can also change the hydrophobicity index of the bile acid pool: following oral administration, UDCA forms a major fraction of the human bile acid pool and competitively displaces the hydrophobic or more toxic bile acids. It increases the absorption of hydrophilic bile acids. There are several proposed mechanisms of choleretic actions of UDCA: UDCA increases intracellular calcium levels, stimulating transport proteins and vesicular exocytosis in cholestatic hepatocytes. UDCA may also upregulate the expression of membrane transport proteins like the chloride-bicarbonate anion exchanger (AE2), which is involved in biliary secretion and is often observed to be defective in primary biliary cholangitis. In rats, UDCA reduced hepatic expression of major histocompatibility complex (MHC) class I antigens, suggesting immunomodulating effects. UDCA acts as a partial agonist at the bile acid receptor, also known as the farnesoid X receptor (FXR), and has negligible effects on cholesterol and lipid synthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Normally, endogenous ursodeoxycholic acid constitutes a minor fraction (about 5%) of the total human bile acid pool. Following oral administration, the majority of ursodiol is absorbed by passive diffusion, and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. During chronic administration of ursodiol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of ursodeoxycholic acid (UDCA) has not been determined; however, it is expected to be small since UDCA is mostly distributed in the bile in the gallbladder and small intestines. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Unconjugated ursodeoxycholic acid is at least 70% bound to plasma proteins in health individuals. There is no information regarding the protein binding of conjugated ursodeoxycholic acid. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Upon administration, ursodeoxycholic acid (UDCA) enters the portal vein and into the liver, where it undergoes conjugation with glycine or taurine. UDCA is also decreased into bile. Glycine or taurine conjugates are absorbed in the small intestine via passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free UDCA that can be reabsorbed and re-conjugated in the liver. Nonabsorbed UDCA passes into the colon, where it undergoes 7-dehydroxylation by intestinal bacteria to lithocholic acid. Some UDCA is epimerized to chenodeoxycholic acid via a 7-oxo intermediate. Chenodeoxycholic acid also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Ursodeoxycholic acid is excreted primarily in the feces. Renal elimination is a minor elimination pathway. With treatment, urinary excretion increases but remains less than 1% except in severe cholestatic liver disease. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The estimated half-life ranges from 3.5 to 5.8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD 50 in rats is >4600-5000 mg/kg. It is over 7500 mg/kg for mice. Ursodeoxycholic acid (UDCA) is associated with rare hepatotoxicities, such as jaundice, worsening pre-existing liver diseases, and hepatitis. There have been no reports of accidental or intentional overdosage with UDCA. A single oral dose of UDCA at 1.5 g/kg was lethal in hamsters. Single oral doses of UDCA at 10 g/kg in mice and dogs and 5 g/kg in rats were not lethal. Symptoms of acute toxicity were salivation and vomiting in dogs, while ataxia, dyspnea, ptosis, agonal convulsions and coma were observed in hamsters. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Reltone, Urso, Urso Forte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide ursodesoxycholique Acido ursodeossicolico Acido ursodeoxicolico Acidum ursodeoxycholicum UDCA Ursodeoxycholate Ursodeoxycholic acid Ursodiol •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ursodeoxycholic acid is a bile acid used for the treatment of primary biliary cirrhosis (PBC).

Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. The severity of the interaction is moderate.

Question: Does Abciximab and Ursodeoxycholic acid interact? Information: •Drug A: Abciximab •Drug B: Ursodeoxycholic acid •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Ursodeoxycholic acid. •Extended Description: Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ursodeoxycholic acid is indicated for the treatment of patients with primary biliary cholangitis. It is used for the short-term treatment of radiolucent, noncalcified gallbladder stones in patients selected for elective cholecystectomy. It is also used to prevent gallstone formation in obese patients experiencing rapid weight loss. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ursodeoxycholic acid (UDCA) is a secondary bile acid with cytoprotectant, immunomodulating, and choleretic effects. It reduces the cholesterol fraction of biliary lipids. UDCA inhibits the absorption of cholesterol in the intestine and the secretion of cholesterol into bile, decreasing biliary cholesterol saturation. UDCA increases bile acid flow and promotes the secretion of bile acids. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Endogenous hydrophobic bile acids such as deoxycholic acid and chenodeoxycholic acid can exert hepatotoxic effects. Ursodeoxycholic acid is a hydrophilic bile acid that mediates its biological effects via several mechanisms. Ursodeoxycholic acid (UDCA) protects hepatocytes and cholangiocytes from bile acid-induced damage, such as reactive oxygen species (ROS)-induced inflammation and mitochondrial dysfunction. UDCA was shown to reserve hepatocyte cell structures and stimulate anti-apoptotic pathways. It was also shown to prevent the production of ROS by Kupffer cells and resident macrophages in the liver, thus attenuating oxidative stress in the liver. UDCA can also change the hydrophobicity index of the bile acid pool: following oral administration, UDCA forms a major fraction of the human bile acid pool and competitively displaces the hydrophobic or more toxic bile acids. It increases the absorption of hydrophilic bile acids. There are several proposed mechanisms of choleretic actions of UDCA: UDCA increases intracellular calcium levels, stimulating transport proteins and vesicular exocytosis in cholestatic hepatocytes. UDCA may also upregulate the expression of membrane transport proteins like the chloride-bicarbonate anion exchanger (AE2), which is involved in biliary secretion and is often observed to be defective in primary biliary cholangitis. In rats, UDCA reduced hepatic expression of major histocompatibility complex (MHC) class I antigens, suggesting immunomodulating effects. UDCA acts as a partial agonist at the bile acid receptor, also known as the farnesoid X receptor (FXR), and has negligible effects on cholesterol and lipid synthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Normally, endogenous ursodeoxycholic acid constitutes a minor fraction (about 5%) of the total human bile acid pool. Following oral administration, the majority of ursodiol is absorbed by passive diffusion, and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. During chronic administration of ursodiol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of ursodeoxycholic acid (UDCA) has not been determined; however, it is expected to be small since UDCA is mostly distributed in the bile in the gallbladder and small intestines. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Unconjugated ursodeoxycholic acid is at least 70% bound to plasma proteins in health individuals. There is no information regarding the protein binding of conjugated ursodeoxycholic acid. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Upon administration, ursodeoxycholic acid (UDCA) enters the portal vein and into the liver, where it undergoes conjugation with glycine or taurine. UDCA is also decreased into bile. Glycine or taurine conjugates are absorbed in the small intestine via passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free UDCA that can be reabsorbed and re-conjugated in the liver. Nonabsorbed UDCA passes into the colon, where it undergoes 7-dehydroxylation by intestinal bacteria to lithocholic acid. Some UDCA is epimerized to chenodeoxycholic acid via a 7-oxo intermediate. Chenodeoxycholic acid also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Ursodeoxycholic acid is excreted primarily in the feces. Renal elimination is a minor elimination pathway. With treatment, urinary excretion increases but remains less than 1% except in severe cholestatic liver disease. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The estimated half-life ranges from 3.5 to 5.8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The oral LD 50 in rats is >4600-5000 mg/kg. It is over 7500 mg/kg for mice. Ursodeoxycholic acid (UDCA) is associated with rare hepatotoxicities, such as jaundice, worsening pre-existing liver diseases, and hepatitis. There have been no reports of accidental or intentional overdosage with UDCA. A single oral dose of UDCA at 1.5 g/kg was lethal in hamsters. Single oral doses of UDCA at 10 g/kg in mice and dogs and 5 g/kg in rats were not lethal. Symptoms of acute toxicity were salivation and vomiting in dogs, while ataxia, dyspnea, ptosis, agonal convulsions and coma were observed in hamsters. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Reltone, Urso, Urso Forte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide ursodesoxycholique Acido ursodeossicolico Acido ursodeoxicolico Acidum ursodeoxycholicum UDCA Ursodeoxycholate Ursodeoxycholic acid Ursodiol •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ursodeoxycholic acid is a bile acid used for the treatment of primary biliary cirrhosis (PBC). Output: Antiplatelet agents may enhance the bleeding risk when administered with cholic acid due to the additive effects of both drugs. The severity of the interaction is moderate.

Does Abciximab and Ustekinumab interact?

•Drug A: Abciximab •Drug B: Ustekinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Ustekinumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in patients 6 years of age and older who are candidates for phototherapy or systemic therapy. In adult patients, it is also indicated for the management of active psoriatic arthritis (PsA) alone or in combination with methotrexate, moderately to severely active Crohn’s disease (CD) and moderately to severely active ulcerative colitis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ustekinumab is a targeted antibody therapy that suppresses immune responses. It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions. It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8. The formation of cytochrome P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation. Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity. While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs, there were no clinically significant effects on human CYP enzyme activities. The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin (IL)-12 and IL-23 are heterodimeric cytokines that evoke immune and inflammatory responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. The role of IL-12 and IL-23 were implicated in a variety of chronic inflammatory conditions, such as psoriasis and inflammatory bowel diseases. They modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets, as CD4+ T cells can differentiate into T-helper (Th) effector lineages based on the environment. Th cells can further activate the downstream pro-inflammatory mediators and transcription factors such as TNFα and IFNγ that drive innate and adaptive immunity. IL-12 and IL-23 share a common p40 subunit, paired with p35 and p19 subunits of IL-12 and IL-23, respectively. The antigen-binding fragment (Fab) of ustekinumab binds the D1 domain of the p40 subunit of IL-12 and IL-23 in a 1:1 ratio. This prevents IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of NK and T cells. Ustekinumab only binds to IL-12 and IL-23 that are unbound to IL-12Rβ1, so it is unlikely to initiate Fc effector functions, such as ADCC or CDC. Inhibition of the IL-12/23 signalling pathway leads to profound suppression of both the Th1 and Th17 cell lineage of cytokines and chemokines and their inflammatory pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): The median Tmax following a single subcutaneous dose administration of 45mg and 90mg in adults with psoriasis was 13.5 days and 7 days, respectively. The median Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45mg and 90mg, respectively. The median AUC was 84.9 μg·day/mL and 226.9 μg·day/mL, respectively. Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn’s disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis. The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis. The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis. The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76 to 161 mL/kg in patients with psoriasis receiving a single subcutaneous dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information on plasma protein binding of ustekinumab. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolic pathway of ustekinumab has not been fully characterized; it is expected to undergo nonspecific protein degradation via catabolic pathways in the same manner as endogenous IgG. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): There is limited information on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Following administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively. The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis. •Clearance (Drug A): No clearance available •Clearance (Drug B): The median apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7 to 5.3 mL/day/kg. In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Signs of dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials. Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Stelara •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ustekinumab is a targeted antibody therapy used to manage inflammatory conditions such as plaque psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Ustekinumab interact? Information: •Drug A: Abciximab •Drug B: Ustekinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Ustekinumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in patients 6 years of age and older who are candidates for phototherapy or systemic therapy. In adult patients, it is also indicated for the management of active psoriatic arthritis (PsA) alone or in combination with methotrexate, moderately to severely active Crohn’s disease (CD) and moderately to severely active ulcerative colitis. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Ustekinumab is a targeted antibody therapy that suppresses immune responses. It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions. It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8. The formation of cytochrome P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation. Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity. While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs, there were no clinically significant effects on human CYP enzyme activities. The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Interleukin (IL)-12 and IL-23 are heterodimeric cytokines that evoke immune and inflammatory responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. The role of IL-12 and IL-23 were implicated in a variety of chronic inflammatory conditions, such as psoriasis and inflammatory bowel diseases. They modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets, as CD4+ T cells can differentiate into T-helper (Th) effector lineages based on the environment. Th cells can further activate the downstream pro-inflammatory mediators and transcription factors such as TNFα and IFNγ that drive innate and adaptive immunity. IL-12 and IL-23 share a common p40 subunit, paired with p35 and p19 subunits of IL-12 and IL-23, respectively. The antigen-binding fragment (Fab) of ustekinumab binds the D1 domain of the p40 subunit of IL-12 and IL-23 in a 1:1 ratio. This prevents IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of NK and T cells. Ustekinumab only binds to IL-12 and IL-23 that are unbound to IL-12Rβ1, so it is unlikely to initiate Fc effector functions, such as ADCC or CDC. Inhibition of the IL-12/23 signalling pathway leads to profound suppression of both the Th1 and Th17 cell lineage of cytokines and chemokines and their inflammatory pathways. •Absorption (Drug A): No absorption available •Absorption (Drug B): The median Tmax following a single subcutaneous dose administration of 45mg and 90mg in adults with psoriasis was 13.5 days and 7 days, respectively. The median Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45mg and 90mg, respectively. The median AUC was 84.9 μg·day/mL and 226.9 μg·day/mL, respectively. Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn’s disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis. The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis. The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis. The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76 to 161 mL/kg in patients with psoriasis receiving a single subcutaneous dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information on plasma protein binding of ustekinumab. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The metabolic pathway of ustekinumab has not been fully characterized; it is expected to undergo nonspecific protein degradation via catabolic pathways in the same manner as endogenous IgG. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): There is limited information on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Following administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively. The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis. •Clearance (Drug A): No clearance available •Clearance (Drug B): The median apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7 to 5.3 mL/day/kg. In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Signs of dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials. Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Stelara •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Ustekinumab is a targeted antibody therapy used to manage inflammatory conditions such as plaque psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Valdecoxib interact?

•Drug A: Abciximab •Drug B: Valdecoxib •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Valdecoxib is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of osteoarthritis and dysmenorrhoea •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Oral bioavailability is 83%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 86 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic (involves CYP3A4 and 2C9) •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 8-11 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): oral cl=6 L/h 6 – 7 L/h [In patients undergoing hemodialysis] 6 – 7 L/h [healthy elderly subjects] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Bextra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Valdecoxib is a COX-2 inhibitor used to treat osteoarthritis and dysmenorrhoea.

Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Valdecoxib interact? Information: •Drug A: Abciximab •Drug B: Valdecoxib •Severity: MODERATE •Description: The risk or severity of bleeding and hemorrhage can be increased when Valdecoxib is combined with Abciximab. •Extended Description: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of osteoarthritis and dysmenorrhoea •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation. •Absorption (Drug A): No absorption available •Absorption (Drug B): Oral bioavailability is 83%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 86 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic (involves CYP3A4 and 2C9) •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 8-11 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): oral cl=6 L/h 6 – 7 L/h [In patients undergoing hemodialysis] 6 – 7 L/h [healthy elderly subjects] •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Bextra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Valdecoxib is a COX-2 inhibitor used to treat osteoarthritis and dysmenorrhoea. Output: Both anticoagulants and non-steroidal anti-inflammatory agents are associated with a risk for bleeding events. Concomitant use of anticoagulants with over-the-counter NSAIDs may significantly increase the risk for gastrointestinal hemorrhage while concomitant use of anticoagulants with acetaminophen may lead to increased risk for general all-site bleeding events. NSAIDs such as ibuprofen are substrates of CYP2C9, which may also interfere with the metabolism of S-warfarin and further increase the risk for warfarin-associated bleeding. The severity of the interaction is moderate.

Does Abciximab and Vedolizumab interact?

•Drug A: Abciximab •Drug B: Vedolizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Vedolizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vedolizumab is indicated for adult patients with moderately to severely active Ulcerative Colitis or Crohn’s disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Non-clinical studies have shown that the pharmacodynamic effects of vedolizumab are reversible upon removal of the antibody: pharmacologic activity of cells inhibited by vedolizumab could be partially restored within 24 hours after removal, with near complete restoration within 4 days. There are no known drug interactions as vedolizumab is a humanized antibody and does not modulate the production of cytokines, which is known to affect drug metabolism. The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is mainly expressed on gut endothelial cells and plays a critical role in homing T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to chronic inflammation, a hallmark of ulcerative colitis and Crohn’s disease. Inhibition of α4β7 integrin by vedolizumab prevents the adhesion of lymphocytes to its natural ligand, thus decreasing the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed. In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn’s disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells. A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to vedolizumab for four or six weeks compared to placebo control as assessed by histopathology. In a study of 14 healthy subjects, vedolizumab did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with MAdCAM-1. Vedolizumab does not bind to or inhibit the function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1). •Absorption (Drug A): No absorption available •Absorption (Drug B): The intended route of administration is intravenous, therefore there is no absorption data and bioavailability is expected to be 100%. Following the administration of 300 mg of vedolizumab as a 30-minute intravenous infusion from week 0 to 2 and 300 mg every eight weeks starting from Week 6, the trough serum concentration of vedolizumab is 26.3 ± 12.9 and 27.4 ± 19.2 mcg/mL for Ulcerative Colitis and Crohn’s Disease patients respectively at week 6. At week 46, the trough serum concentration of vedolizumab is 11.2 ± 7.2 and 13.0 ± 9.1 mcg/mL for Ulcerative Colitis and Crohn’s Disease patients respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Serum apparent volume of distribution at steady-state has been found to be moderately greater than the serum volume (approximately 5L). It is therefore expected to be confined to the systemic circulation, as expected for a high molecular weight protein. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Vedolizumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Renal clearance is negligible as vedolizumab is a high molecular weight protein. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Vedolizumab has a long terminal elimination half-life of 25 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day or 0.180 to 0.266 ml/hr/kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Elevated transaminase levels with or without elevated bilirubin have occurred in patients who have received this drug. Progressive multifocal leukoencephalopathy (PML) has not been reported with the use of this drug, however, it has occurred in patients who have received different integrin receptor antagonists and is therefore considered a risk for this product. The use of vedolizumab may increase the risk of developing infections, and one study found that nasopharyngitis occurs more frequently with vedolizumab than with THE placebo for Crohn’s disease patients. Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified a vedolizumab-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy. No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Vedolizumab administered during pregnancy could affect immune responses in the in-utero-exposed newborn and infant. The clinical significance of low levels of vedolizumab in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Entyvio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vedolizumab is an integrin blocker and anti-inflammatory agent used to manage ulcerative colitis and Crohn's disease in adults.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Abciximab and Vedolizumab interact? Information: •Drug A: Abciximab •Drug B: Vedolizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abciximab is combined with Vedolizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vedolizumab is indicated for adult patients with moderately to severely active Ulcerative Colitis or Crohn’s disease. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Non-clinical studies have shown that the pharmacodynamic effects of vedolizumab are reversible upon removal of the antibody: pharmacologic activity of cells inhibited by vedolizumab could be partially restored within 24 hours after removal, with near complete restoration within 4 days. There are no known drug interactions as vedolizumab is a humanized antibody and does not modulate the production of cytokines, which is known to affect drug metabolism. The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is mainly expressed on gut endothelial cells and plays a critical role in homing T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to chronic inflammation, a hallmark of ulcerative colitis and Crohn’s disease. Inhibition of α4β7 integrin by vedolizumab prevents the adhesion of lymphocytes to its natural ligand, thus decreasing the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed. In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn’s disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells. A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to vedolizumab for four or six weeks compared to placebo control as assessed by histopathology. In a study of 14 healthy subjects, vedolizumab did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with MAdCAM-1. Vedolizumab does not bind to or inhibit the function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1). •Absorption (Drug A): No absorption available •Absorption (Drug B): The intended route of administration is intravenous, therefore there is no absorption data and bioavailability is expected to be 100%. Following the administration of 300 mg of vedolizumab as a 30-minute intravenous infusion from week 0 to 2 and 300 mg every eight weeks starting from Week 6, the trough serum concentration of vedolizumab is 26.3 ± 12.9 and 27.4 ± 19.2 mcg/mL for Ulcerative Colitis and Crohn’s Disease patients respectively at week 6. At week 46, the trough serum concentration of vedolizumab is 11.2 ± 7.2 and 13.0 ± 9.1 mcg/mL for Ulcerative Colitis and Crohn’s Disease patients respectively. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Serum apparent volume of distribution at steady-state has been found to be moderately greater than the serum volume (approximately 5L). It is therefore expected to be confined to the systemic circulation, as expected for a high molecular weight protein. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Vedolizumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Renal clearance is negligible as vedolizumab is a high molecular weight protein. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Vedolizumab has a long terminal elimination half-life of 25 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day or 0.180 to 0.266 ml/hr/kg. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Elevated transaminase levels with or without elevated bilirubin have occurred in patients who have received this drug. Progressive multifocal leukoencephalopathy (PML) has not been reported with the use of this drug, however, it has occurred in patients who have received different integrin receptor antagonists and is therefore considered a risk for this product. The use of vedolizumab may increase the risk of developing infections, and one study found that nasopharyngitis occurs more frequently with vedolizumab than with THE placebo for Crohn’s disease patients. Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified a vedolizumab-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy. No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage. Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Vedolizumab administered during pregnancy could affect immune responses in the in-utero-exposed newborn and infant. The clinical significance of low levels of vedolizumab in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Entyvio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vedolizumab is an integrin blocker and anti-inflammatory agent used to manage ulcerative colitis and Crohn's disease in adults. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Abciximab and Venlafaxine interact?

•Drug A: Abciximab •Drug B: Venlafaxine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Venlafaxine. •Extended Description: Venlafaxine can cause platelet aggregation and prolong blood clot formation time.1 Concomitant use of venlafaxine with an anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Venlafaxine is indicated for the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The exact mechanism of action of venlafaxine in the treatment of various psychiatric conditions has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibits the reuptake of both serotonin and norepinephrine at the presynaptic terminal. This results in increased levels of neurotransmitters available at the synapse that can stimulate postsynaptic receptors. It is suggested that venlafaxine has a 30-fold selectivity for serotonin compared to norepinephrine: venlafaxine initially inhibits serotonin reuptake at low doses, and with higher doses, it inhibits norepinephrine reuptake in addition to serotonin. Venlafaxine and ODV are also weak inhibitors of dopamine reuptake. •Absorption (Drug A): No absorption available •Absorption (Drug B): Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, C max was 150 ng/mL and T max was 5.5 hours. C max and T max of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, C max was 225 ng/mL and T max was two hours. C max and T max of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Venlafaxine and ODV is 27% and 30% bound to plasma proteins, respectively. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral LD 50 was 350 mg/kg in female rats and 700 mg/kg in male rats. There are reports of acute overdosage with venlafaxine either alone or in combination with other drugs including alcohol. Doses up to several-fold higher than the usual therapeutic dose have been ingested in these cases of acute overdosage. Somnolence is the most commonly reported symptom, along with other symptoms such as paresthesia of the extremities, moderate dizziness, altered consciousness, nausea, vomiting, numb hands and feet, hot-cold spells (which occur a few days after the overdose event), hypotension, convulsions, sinus and ventricular tachycardia, rhabdomyolysis, vertigo, liver necrosis, electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), serotonin syndrome, and death. There is no known antidote for venlafaxine overdose. Cases of overdose have been managed with or without symptomatic treatment, hospitalization, and activated charcoal. Retrospective studies suggest that the risk of fatal outcomes from venlafaxine overdosage is higher than that of SSRI antidepressants, but lower than that of tricyclic antidepressants. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Effexor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of major depression, generalized or social anxiety disorder, and panic disorder.

Venlafaxine can cause platelet aggregation and prolong blood clot formation time.1 Concomitant use of venlafaxine with an anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. The severity of the interaction is minor.

Question: Does Abciximab and Venlafaxine interact? Information: •Drug A: Abciximab •Drug B: Venlafaxine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Venlafaxine. •Extended Description: Venlafaxine can cause platelet aggregation and prolong blood clot formation time.1 Concomitant use of venlafaxine with an anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Venlafaxine is indicated for the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The exact mechanism of action of venlafaxine in the treatment of various psychiatric conditions has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibits the reuptake of both serotonin and norepinephrine at the presynaptic terminal. This results in increased levels of neurotransmitters available at the synapse that can stimulate postsynaptic receptors. It is suggested that venlafaxine has a 30-fold selectivity for serotonin compared to norepinephrine: venlafaxine initially inhibits serotonin reuptake at low doses, and with higher doses, it inhibits norepinephrine reuptake in addition to serotonin. Venlafaxine and ODV are also weak inhibitors of dopamine reuptake. •Absorption (Drug A): No absorption available •Absorption (Drug B): Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, C max was 150 ng/mL and T max was 5.5 hours. C max and T max of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, C max was 225 ng/mL and T max was two hours. C max and T max of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV). •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Venlafaxine and ODV is 27% and 30% bound to plasma proteins, respectively. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. •Clearance (Drug A): No clearance available •Clearance (Drug B): Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral LD 50 was 350 mg/kg in female rats and 700 mg/kg in male rats. There are reports of acute overdosage with venlafaxine either alone or in combination with other drugs including alcohol. Doses up to several-fold higher than the usual therapeutic dose have been ingested in these cases of acute overdosage. Somnolence is the most commonly reported symptom, along with other symptoms such as paresthesia of the extremities, moderate dizziness, altered consciousness, nausea, vomiting, numb hands and feet, hot-cold spells (which occur a few days after the overdose event), hypotension, convulsions, sinus and ventricular tachycardia, rhabdomyolysis, vertigo, liver necrosis, electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), serotonin syndrome, and death. There is no known antidote for venlafaxine overdose. Cases of overdose have been managed with or without symptomatic treatment, hospitalization, and activated charcoal. Retrospective studies suggest that the risk of fatal outcomes from venlafaxine overdosage is higher than that of SSRI antidepressants, but lower than that of tricyclic antidepressants. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Effexor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of major depression, generalized or social anxiety disorder, and panic disorder. Output: Venlafaxine can cause platelet aggregation and prolong blood clot formation time.1 Concomitant use of venlafaxine with an anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. The severity of the interaction is minor.

Does Abciximab and Vinblastine interact?

•Drug A: Abciximab •Drug B: Vinblastine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vinblastine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For treatment of breast cancer, testicular cancer, lymphomas, neuroblastoma, Hodgkin's and non-Hodgkin's lymphomas, mycosis fungoides, histiocytosis, and Kaposi's sarcoma. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vinblastine is a vinca alkaloid antineoplastic agent. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units: vindoline and catharanthine. The vinca alkaloids have become clinically useful since the discovery of their antitumour properties in 1959. Initially, extracts of the periwinkle plant ( Catharanthus roseus ) were investigated because of putative hypoglycemic properties, but were noted to cause marrow suppression in rats and antileukemic effects in vitro. Vinblastine has some immunosuppressant effect. The vinca alkaloids are considered to be cell cycle phase-specific. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The antitumor activity of vinblastine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinblastine binds to the microtubular proteins of the mitotic spindle, leading to crystallization of the microtubule and mitotic arrest or cell death. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98-99% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. Metabolism of vinblastine has been shown to be mediated by hepatic cytochrome P450 3A isoenzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The major route of excretion may be through the biliary system. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Triphasic: 35 min, 53 min, and 19 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral, mouse: LD 50 = 423 mg/kg; Oral, rat: LD 50 = 305 mg/kg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vinblastine is a vinca alkaloid used to treat breast cancer, testicular cancer, neuroblastoma, Hodgkin's and non-Hodgkins lymphoma, mycosis fungoides, histiocytosis, and Kaposi's sarcoma.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Vinblastine interact? Information: •Drug A: Abciximab •Drug B: Vinblastine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vinblastine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For treatment of breast cancer, testicular cancer, lymphomas, neuroblastoma, Hodgkin's and non-Hodgkin's lymphomas, mycosis fungoides, histiocytosis, and Kaposi's sarcoma. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vinblastine is a vinca alkaloid antineoplastic agent. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units: vindoline and catharanthine. The vinca alkaloids have become clinically useful since the discovery of their antitumour properties in 1959. Initially, extracts of the periwinkle plant ( Catharanthus roseus ) were investigated because of putative hypoglycemic properties, but were noted to cause marrow suppression in rats and antileukemic effects in vitro. Vinblastine has some immunosuppressant effect. The vinca alkaloids are considered to be cell cycle phase-specific. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The antitumor activity of vinblastine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vinblastine binds to the microtubular proteins of the mitotic spindle, leading to crystallization of the microtubule and mitotic arrest or cell death. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98-99% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. Metabolism of vinblastine has been shown to be mediated by hepatic cytochrome P450 3A isoenzymes. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The major route of excretion may be through the biliary system. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Triphasic: 35 min, 53 min, and 19 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Oral, mouse: LD 50 = 423 mg/kg; Oral, rat: LD 50 = 305 mg/kg. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vinblastine is a vinca alkaloid used to treat breast cancer, testicular cancer, neuroblastoma, Hodgkin's and non-Hodgkins lymphoma, mycosis fungoides, histiocytosis, and Kaposi's sarcoma. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Vindesine interact?

•Drug A: Abciximab •Drug B: Vindesine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vindesine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of acute leukaemia, malignant lymphoma, Hodgkin's disease, acute erythraemia and acute panmyelosis •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vindesine is indicated for the treatment of acute lymphocytic leukemia of childhood that is resistant to vincristine and non-oat cell lung cancer. Vindesine causes the arrest of cells in metaphase mitosis. It is three times more potent than vincristine and nearly 10 times more potent than vinblastine in causing mitotic arrest in in vitro studies at doses designed to arrest from 10 to 15% of the cells in mitosis. Vindesine and vincristine are approximately equipotent at dose levels that arrest 40 to 50% of the cells in mitosis. Unlike vinblastine, vindesine produces very few postmetaphase cells. Vindesine has demonstrated activity in patients who have relapsed while receiving multiple-agent treatment that included vincristine. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vindesine acts by causing the arrest of cells in metaphase mitosis through its inhibition tubulin mitotic funcitoning. The drug is cell-cycle specific for the S phase. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 65-75% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 24 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desacetylvinblastine amide Vindesina Vindesine Vindesinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vindesine is a vinca alkaloid derived from vinblastine used for various types of malignancies, but mainly acute lymphocytic leukemia (ALL).

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Vindesine interact? Information: •Drug A: Abciximab •Drug B: Vindesine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vindesine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of acute leukaemia, malignant lymphoma, Hodgkin's disease, acute erythraemia and acute panmyelosis •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vindesine is indicated for the treatment of acute lymphocytic leukemia of childhood that is resistant to vincristine and non-oat cell lung cancer. Vindesine causes the arrest of cells in metaphase mitosis. It is three times more potent than vincristine and nearly 10 times more potent than vinblastine in causing mitotic arrest in in vitro studies at doses designed to arrest from 10 to 15% of the cells in mitosis. Vindesine and vincristine are approximately equipotent at dose levels that arrest 40 to 50% of the cells in mitosis. Unlike vinblastine, vindesine produces very few postmetaphase cells. Vindesine has demonstrated activity in patients who have relapsed while receiving multiple-agent treatment that included vincristine. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vindesine acts by causing the arrest of cells in metaphase mitosis through its inhibition tubulin mitotic funcitoning. The drug is cell-cycle specific for the S phase. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 65-75% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 24 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desacetylvinblastine amide Vindesina Vindesine Vindesinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vindesine is a vinca alkaloid derived from vinblastine used for various types of malignancies, but mainly acute lymphocytic leukemia (ALL). Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Vinorelbine interact?

•Drug A: Abciximab •Drug B: Vinorelbine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vinorelbine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vinorelbine tartrate is indicated for adults in the treatment of advanced non-small cell lung cancer (NSCLC), as a single therapy or in combination with other chemotherapeutic drugs. Used in relapsed or refractory Hodgkin lymphoma, in combination with other chemotherapy agents. For the treatment of desmoid tumor or aggressive fibromatosis, in combination with methotrexate. For the treatment of recurrent or metastatic squamous cell head and neck cancer. For the treatment of recurrent ovarian cancer. For the treatment of metastatic breast cancer, in patients previously treated with anthracyline and/or taxane therapy. For the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with trastuzumab and everolimus. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vinorelbine is a semi-synthetic vinca-alkaloid with a wide spectrum of anti-tumor activity. The vinca-alkaloids are considered spindle poisons. They work by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system which appears during cell division in proliferating cancer cells. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vinca alkaloids are structurally similar compounds composed of two multi-ringed units, vindoline, and catharanthine. Vinorelbine tartrate is a vinca alkaloid in which the catharanthine component is the target of structural modification,. This structural modification contributes to unique pharmacologic properties.The antitumor activity of vinorelbine tartrate is believed to be owed to the inhibition of mitosis at metaphase via its interaction with tubulin. Vinorelbine is a mitotic spindle poison that interferes with chromosomal segregation during mitosis, also known as cell division. It pauses cells at the G2/M phases, when present at concentrations close to the half maximal inhibitory concentration (IC50). Microtubules, which are derived from polymers of tubulin, are the main target of vinorelbine. The chemical modification used to produce vinorelbine allows for the opening of the eight-member catharanthine ring with the formation of both a covalent and reversible bond with tubulin. The relative contribution of different microtubule-associated proteins in the production of tubulin vary between neural tissue and proliferating cells and this has important functional implications. The ability of vinorelbine to bind specifically to mitotic rather than other microtubules has been shown and may suggest that neurotoxicity is less likely to be a problem than with the molecular mechanism of action. As with other anti-microtubule agents, vinorelbine is known to contribute apoptosis in malignant cells. The exact mechanisms by which this process occurs are complex and many details are yet to be elucidated. The disarray of the microtubule structure has a number of effects, including the induction of tumor suppressor gene p53 and activation/inactivation of a number of protein kinases involved in essential signaling pathways, including p21 WAF1/CIP1 and Ras/Raf, PKC/PKA. These molecular changes lead to phosphorylation and consequently inactivation of the apoptosis inhibitor Bcl2. This, in turn, results in a decrease in the formation of heterodimers between Bcl2 and the pro-apoptotic gene BAX, stimulating the sequence of cell apoptosis. Vinorelbine tartrate also possibly interferes with amino acid, cyclic AMP and glutathione metabolism, calmodulin-dependent Ca++-transport ATPase activity, cellular respiration, and nucleic acid and lipid biosynthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. Vinorelbine is highly bound to platelets and lymphocytes and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution is large, indicating extensive extravascular distribution. The steady-state volume of distribution values range from 25.4 to 40.1 L/kg, according to one study. Widely distributed, with highest amounts found in elimination organs such as liver and kidneys, minimal in heart and brain. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 80-90% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Vinorelbine undergoes substantial hepatic elimination in humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine,. Vinorelbine is metabolized into two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily,. As the liver provides the main route for metabolism of the drug, patients with hepatic impairment may demonstrate increased toxicity with standard dosing, however, there are no available data on this. Likewise, the contribution of cytochrome P450 enzyme action to vinorelbine metabolism has potential implications in patients receiving other drugs metabolized by this route. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60%. After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal phase half-life averaged 27.7 to 43.6 hours; the mean plasma clearances ranged from 0.97 to 1.26 L/hr/kg. •Clearance (Drug A): No clearance available •Clearance (Drug B): The plasma clearance of vinorelbine is high, approaching the same as hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution. In comparison to vinblastine or vincristine. The clearance was found to be in the range of 0.29-1./26 L/ per kg in 4 clinical trials of patients receiving 30 mg/m2 of vinorelbine. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Due to the wide array of adverse effects of this drug, the toxicity of is categorized into organ systems. Hematologic: Granulocytopenia was the primary dose-limiting toxicity with vinorelbine tartrate therapy; it is generally reversible and not cumulative. In one study, granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of NSCLC and 9% of breast cancer patients. Infectious (septic) deaths occurred in about 1% of patients. Grade 3 or 4 anemia occurred in about 1% of lung cancer and approximately 14% of breast cancer patients. Blood transfusions were administered to 18% of patients who received vinorelbine tartrate therapy. The incidence of Grade 3 and 4 thrombocytopenia was found to be less than 1%. Neurologic: Mild to moderate peripheral neuropathy may occur. Symptoms of paresthesia and hypesthesia are reported as the most commonly reported neurologic toxicities of this drug. The loss of deep tendon reflexes (DTR) occurs in less than 5% of patients, according to one study. The development of severe peripheral neuropathy is rare. Dermatologic: Alopecia has been reported in only about 12% of patients and is usually reported as mild. Vinorelbine tartrate is a moderate vesicant, leading to injection site reactions. Symptoms include erythema, pain at the injection site and vein discoloration occurred in about 1/3 of all patients. Chemical phlebitis along the vein, near the site of injection, has been reported. Respiratory: Shortness of breath was reported in 3% of NSCLC and 9% of breast cancer patients, and was severe in 2% of each patient population. Interstitial pulmonary changes have been documented in a few patients. Gastrointestinal: Mild or moderate nausea symptoms occurred in 32% of NSCLC and 47% of breast cancer patients treated with vinorelbine tartrate. Severe nausea was occurred infrequently (1% and 3% in NSCLC and breast cancer patients, respectively). Prophylactic administration of anti-emetics was not routine in patients treated with single-agent vinorelbine tartrate. Constipation occurred in about 28% of NSCLC and 38% of breast cancer patients. The paralytic ileus incidence of less than 2% of patients. Vomiting, diarrhea, anorexia and stomatitis were found to be mild or moderate and occurred in less than 20% of study patients. Hepatic: Transient elevations of liver enzymes were reported without clinical symptoms. Cardiovascular: Chest pain was reported in 5% of NSCLC and 8% of breast cancer patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction; however, these have not been shown definitely attributable to vinorelbine tartrate. Other: Muscle weakness (asthenia) occurred in about 25% of patients with NSCLC and 41% of patients with breast cancer. It was usually mild or moderate but showed a linear increase with cumulative doses. Several other toxicities reported in approximately 5% of patients include jaw pain, myalgia, arthralgia, headache, dysphagia, and skin rash. Hemorrhagic cystitis (bladder inflammation with blood in urine) and the syndrome of inappropriate ADH secretion were both reported in less than 1% of patients. The treatment of these entities are mainly symptomatic. The carcinogenic potential of Vinorelbine has not been adequately studied. Vinorelbine has been demonstrated to affect chromosome number and likely the chromosome structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice were observed). •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vinorelbine is a vinca alkaloid used in the treatment of metastatic non-small cell lung carcinoma (NSLC) and in conjunction with other drugs in locally advanced NSCLC.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Vinorelbine interact? Information: •Drug A: Abciximab •Drug B: Vinorelbine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vinorelbine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vinorelbine tartrate is indicated for adults in the treatment of advanced non-small cell lung cancer (NSCLC), as a single therapy or in combination with other chemotherapeutic drugs. Used in relapsed or refractory Hodgkin lymphoma, in combination with other chemotherapy agents. For the treatment of desmoid tumor or aggressive fibromatosis, in combination with methotrexate. For the treatment of recurrent or metastatic squamous cell head and neck cancer. For the treatment of recurrent ovarian cancer. For the treatment of metastatic breast cancer, in patients previously treated with anthracyline and/or taxane therapy. For the treatment of HER2-positive, trastuzumab-resistant, advanced breast cancer in patients previously treated with a taxane, in combination with trastuzumab and everolimus. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vinorelbine is a semi-synthetic vinca-alkaloid with a wide spectrum of anti-tumor activity. The vinca-alkaloids are considered spindle poisons. They work by interfering with the polymerization of tubulin, a protein responsible for building the microtubule system which appears during cell division in proliferating cancer cells. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vinca alkaloids are structurally similar compounds composed of two multi-ringed units, vindoline, and catharanthine. Vinorelbine tartrate is a vinca alkaloid in which the catharanthine component is the target of structural modification,. This structural modification contributes to unique pharmacologic properties.The antitumor activity of vinorelbine tartrate is believed to be owed to the inhibition of mitosis at metaphase via its interaction with tubulin. Vinorelbine is a mitotic spindle poison that interferes with chromosomal segregation during mitosis, also known as cell division. It pauses cells at the G2/M phases, when present at concentrations close to the half maximal inhibitory concentration (IC50). Microtubules, which are derived from polymers of tubulin, are the main target of vinorelbine. The chemical modification used to produce vinorelbine allows for the opening of the eight-member catharanthine ring with the formation of both a covalent and reversible bond with tubulin. The relative contribution of different microtubule-associated proteins in the production of tubulin vary between neural tissue and proliferating cells and this has important functional implications. The ability of vinorelbine to bind specifically to mitotic rather than other microtubules has been shown and may suggest that neurotoxicity is less likely to be a problem than with the molecular mechanism of action. As with other anti-microtubule agents, vinorelbine is known to contribute apoptosis in malignant cells. The exact mechanisms by which this process occurs are complex and many details are yet to be elucidated. The disarray of the microtubule structure has a number of effects, including the induction of tumor suppressor gene p53 and activation/inactivation of a number of protein kinases involved in essential signaling pathways, including p21 WAF1/CIP1 and Ras/Raf, PKC/PKA. These molecular changes lead to phosphorylation and consequently inactivation of the apoptosis inhibitor Bcl2. This, in turn, results in a decrease in the formation of heterodimers between Bcl2 and the pro-apoptotic gene BAX, stimulating the sequence of cell apoptosis. Vinorelbine tartrate also possibly interferes with amino acid, cyclic AMP and glutathione metabolism, calmodulin-dependent Ca++-transport ATPase activity, cellular respiration, and nucleic acid and lipid biosynthesis. •Absorption (Drug A): No absorption available •Absorption (Drug B): Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. Vinorelbine is highly bound to platelets and lymphocytes and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution is large, indicating extensive extravascular distribution. The steady-state volume of distribution values range from 25.4 to 40.1 L/kg, according to one study. Widely distributed, with highest amounts found in elimination organs such as liver and kidneys, minimal in heart and brain. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 80-90% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Vinorelbine undergoes substantial hepatic elimination in humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine,. Vinorelbine is metabolized into two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide. Therapeutic doses of vinorelbine (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinorelbine is mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily,. As the liver provides the main route for metabolism of the drug, patients with hepatic impairment may demonstrate increased toxicity with standard dosing, however, there are no available data on this. Likewise, the contribution of cytochrome P450 enzyme action to vinorelbine metabolism has potential implications in patients receiving other drugs metabolized by this route. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60%. After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): The terminal phase half-life averaged 27.7 to 43.6 hours; the mean plasma clearances ranged from 0.97 to 1.26 L/hr/kg. •Clearance (Drug A): No clearance available •Clearance (Drug B): The plasma clearance of vinorelbine is high, approaching the same as hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution. In comparison to vinblastine or vincristine. The clearance was found to be in the range of 0.29-1./26 L/ per kg in 4 clinical trials of patients receiving 30 mg/m2 of vinorelbine. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Due to the wide array of adverse effects of this drug, the toxicity of is categorized into organ systems. Hematologic: Granulocytopenia was the primary dose-limiting toxicity with vinorelbine tartrate therapy; it is generally reversible and not cumulative. In one study, granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of NSCLC and 9% of breast cancer patients. Infectious (septic) deaths occurred in about 1% of patients. Grade 3 or 4 anemia occurred in about 1% of lung cancer and approximately 14% of breast cancer patients. Blood transfusions were administered to 18% of patients who received vinorelbine tartrate therapy. The incidence of Grade 3 and 4 thrombocytopenia was found to be less than 1%. Neurologic: Mild to moderate peripheral neuropathy may occur. Symptoms of paresthesia and hypesthesia are reported as the most commonly reported neurologic toxicities of this drug. The loss of deep tendon reflexes (DTR) occurs in less than 5% of patients, according to one study. The development of severe peripheral neuropathy is rare. Dermatologic: Alopecia has been reported in only about 12% of patients and is usually reported as mild. Vinorelbine tartrate is a moderate vesicant, leading to injection site reactions. Symptoms include erythema, pain at the injection site and vein discoloration occurred in about 1/3 of all patients. Chemical phlebitis along the vein, near the site of injection, has been reported. Respiratory: Shortness of breath was reported in 3% of NSCLC and 9% of breast cancer patients, and was severe in 2% of each patient population. Interstitial pulmonary changes have been documented in a few patients. Gastrointestinal: Mild or moderate nausea symptoms occurred in 32% of NSCLC and 47% of breast cancer patients treated with vinorelbine tartrate. Severe nausea was occurred infrequently (1% and 3% in NSCLC and breast cancer patients, respectively). Prophylactic administration of anti-emetics was not routine in patients treated with single-agent vinorelbine tartrate. Constipation occurred in about 28% of NSCLC and 38% of breast cancer patients. The paralytic ileus incidence of less than 2% of patients. Vomiting, diarrhea, anorexia and stomatitis were found to be mild or moderate and occurred in less than 20% of study patients. Hepatic: Transient elevations of liver enzymes were reported without clinical symptoms. Cardiovascular: Chest pain was reported in 5% of NSCLC and 8% of breast cancer patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction; however, these have not been shown definitely attributable to vinorelbine tartrate. Other: Muscle weakness (asthenia) occurred in about 25% of patients with NSCLC and 41% of patients with breast cancer. It was usually mild or moderate but showed a linear increase with cumulative doses. Several other toxicities reported in approximately 5% of patients include jaw pain, myalgia, arthralgia, headache, dysphagia, and skin rash. Hemorrhagic cystitis (bladder inflammation with blood in urine) and the syndrome of inappropriate ADH secretion were both reported in less than 1% of patients. The treatment of these entities are mainly symptomatic. The carcinogenic potential of Vinorelbine has not been adequately studied. Vinorelbine has been demonstrated to affect chromosome number and likely the chromosome structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice were observed). •Brand Names (Drug A): No brand names available •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vinorelbine is a vinca alkaloid used in the treatment of metastatic non-small cell lung carcinoma (NSLC) and in conjunction with other drugs in locally advanced NSCLC. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Vitamin E interact?

•Drug A: Abciximab •Drug B: Vitamin E •Severity: MODERATE •Description: Vitamin E may increase the antiplatelet activities of Abciximab. •Extended Description: Alpha-tocopherol, a form of Vitamin E, inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in platelets, therefore inhibiting the production of platelets. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, which in turn increases the release of prostacyclin from the endothelium. The prostacyclin dilates blood vessels and inhibits platelet aggregation, increasing the risk of bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vitamin E supplementation is indicated for treatment of vitamin E deficiency which can occur in cystic fibrosis, cholestasis and severe liver disease, abetalipoproteinemia or simply poor diet. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vitamin E is a collective term used to describe 8 separate fat soluble antioxidants, most commonly alpha-tocopherol. Vitamin E acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Vitamin E deficiency is seen in persons with abetalipoproteinemia, premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), cystic fibrosis, and cholestasis and severe liver disease. Preliminary research suggests vitamin E may help prevent or delay coronary heart disease and protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of vitamin E have been linked to increased incidence of breast and colon cancer. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action for most of vitamin E's effects are still unknown. Vitamin E is an antioxidant, preventing free radical reactions with cell membranes. Though in some cases vitamin E has been shown to have pro-oxidant activity. One mechanism of vitamin E's antioxidant effect is in the termination of lipid peroxidation. Vitamin E reacts with unstable lipid radicals, producing stable lipids and a relatively stable vitamin E radical. The vitamin E radical is then reduced back to stable vitamin E by reaction with ascorbate or glutathione. •Absorption (Drug A): No absorption available •Absorption (Drug B): 10-33% of deuterium labelled vitamin E is absorbed in the small intestine. Absorption of Vitamin E is dependant upon absorption of the fat in which it is dissolved. For patients with poor fat absorption, a water soluble form of vitamin E may need to be substituted such as tocopheryl polyethylene glycol-1000 succinate. In other studies the oral bioavailability of alpha-tocopherol was 36%, gamma-tocotrienol was 9%. The time to maximum concentration was 9.7 hours for alpha-tocopherol and 2.4 hours for gamma-tocotrienol. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.41L/kg in premature neonates given a 20mg/kg intramuscular injection. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Vitamin E is bound to lipoproteins in blood. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Alpha and gamma tocopherol are undergo beta oxidation and a process mediated by cytochrome P450s such as CYP4F2, CYP3A4, and CYP3A5. These processes convert alpha and gamma tocopherol to alpha-CEHC (2,5,7,8-tetramethyl-2-(2’-carboxyethyl)-6-hydroxychroman) and gamma-CEHC (2,7,8-trimethyl-2-(2’-carboxyethyl)-6-hydroxychroman) respectively, however the full process is not known. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Alpha tocopherol is excreted in urine as well as bile in the feces mainly as a carboxyethyl-hydrochroman (CEHC) metabolite, but it can be excreted in it's natural form. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 44 hours in premature neonates given a 20mg/kg intramuscular injection. 12 minutes in intravenous injection of intestinal lymph. •Clearance (Drug A): No clearance available •Clearance (Drug B): 6.5mL/hr/kg in premature neonates given a 20mg/kg intramuscular injection. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no data available for effects in pregnancy, breast feeding, hepatic impairment, or renal impairment. However, it appears that the process of vitamin E elimination is strict and self regulating enough that vitamin E toxicity is exceedingly rare. Studies showing adverse effects from excess vitamin E generally involve people consuming more than 1000mg/day for weeks to months. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Mvc-fluoride, Vitafol-one •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): alpha-tocopherol •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vitamin E is an antioxidant vitamin used in many skin creams and multivitamin preparations.

Alpha-tocopherol, a form of Vitamin E, inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in platelets, therefore inhibiting the production of platelets. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, which in turn increases the release of prostacyclin from the endothelium. The prostacyclin dilates blood vessels and inhibits platelet aggregation, increasing the risk of bleeding. The severity of the interaction is moderate.

Question: Does Abciximab and Vitamin E interact? Information: •Drug A: Abciximab •Drug B: Vitamin E •Severity: MODERATE •Description: Vitamin E may increase the antiplatelet activities of Abciximab. •Extended Description: Alpha-tocopherol, a form of Vitamin E, inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in platelets, therefore inhibiting the production of platelets. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, which in turn increases the release of prostacyclin from the endothelium. The prostacyclin dilates blood vessels and inhibits platelet aggregation, increasing the risk of bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vitamin E supplementation is indicated for treatment of vitamin E deficiency which can occur in cystic fibrosis, cholestasis and severe liver disease, abetalipoproteinemia or simply poor diet. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vitamin E is a collective term used to describe 8 separate fat soluble antioxidants, most commonly alpha-tocopherol. Vitamin E acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Vitamin E deficiency is seen in persons with abetalipoproteinemia, premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), cystic fibrosis, and cholestasis and severe liver disease. Preliminary research suggests vitamin E may help prevent or delay coronary heart disease and protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of vitamin E have been linked to increased incidence of breast and colon cancer. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): The mechanism of action for most of vitamin E's effects are still unknown. Vitamin E is an antioxidant, preventing free radical reactions with cell membranes. Though in some cases vitamin E has been shown to have pro-oxidant activity. One mechanism of vitamin E's antioxidant effect is in the termination of lipid peroxidation. Vitamin E reacts with unstable lipid radicals, producing stable lipids and a relatively stable vitamin E radical. The vitamin E radical is then reduced back to stable vitamin E by reaction with ascorbate or glutathione. •Absorption (Drug A): No absorption available •Absorption (Drug B): 10-33% of deuterium labelled vitamin E is absorbed in the small intestine. Absorption of Vitamin E is dependant upon absorption of the fat in which it is dissolved. For patients with poor fat absorption, a water soluble form of vitamin E may need to be substituted such as tocopheryl polyethylene glycol-1000 succinate. In other studies the oral bioavailability of alpha-tocopherol was 36%, gamma-tocotrienol was 9%. The time to maximum concentration was 9.7 hours for alpha-tocopherol and 2.4 hours for gamma-tocotrienol. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 0.41L/kg in premature neonates given a 20mg/kg intramuscular injection. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Vitamin E is bound to lipoproteins in blood. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Alpha and gamma tocopherol are undergo beta oxidation and a process mediated by cytochrome P450s such as CYP4F2, CYP3A4, and CYP3A5. These processes convert alpha and gamma tocopherol to alpha-CEHC (2,5,7,8-tetramethyl-2-(2’-carboxyethyl)-6-hydroxychroman) and gamma-CEHC (2,7,8-trimethyl-2-(2’-carboxyethyl)-6-hydroxychroman) respectively, however the full process is not known. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Alpha tocopherol is excreted in urine as well as bile in the feces mainly as a carboxyethyl-hydrochroman (CEHC) metabolite, but it can be excreted in it's natural form. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 44 hours in premature neonates given a 20mg/kg intramuscular injection. 12 minutes in intravenous injection of intestinal lymph. •Clearance (Drug A): No clearance available •Clearance (Drug B): 6.5mL/hr/kg in premature neonates given a 20mg/kg intramuscular injection. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is no data available for effects in pregnancy, breast feeding, hepatic impairment, or renal impairment. However, it appears that the process of vitamin E elimination is strict and self regulating enough that vitamin E toxicity is exceedingly rare. Studies showing adverse effects from excess vitamin E generally involve people consuming more than 1000mg/day for weeks to months. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Mvc-fluoride, Vitafol-one •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): alpha-tocopherol •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vitamin E is an antioxidant vitamin used in many skin creams and multivitamin preparations. Output: Alpha-tocopherol, a form of Vitamin E, inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in platelets, therefore inhibiting the production of platelets. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, which in turn increases the release of prostacyclin from the endothelium. The prostacyclin dilates blood vessels and inhibits platelet aggregation, increasing the risk of bleeding. The severity of the interaction is moderate.

Does Abciximab and Von Willebrand factor human interact?

•Drug A: Abciximab •Drug B: Von Willebrand factor human •Severity: MAJOR •Description: The therapeutic efficacy of Von Willebrand factor human can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): The von Willebrand factor (vWF) is indicated to manage and control bleeding episodes in adults with von Willebrand disease. It is also used for perioperative management of bleeding in these patients. It is also used for routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy. In combination with antihemophilic factor human, vWF is also used to manage and control bleeding associated with von Willebrand disease in children and adults, as well as for perioperative management of bleeding in these patients. This combination product is also used for the management and control of bleeding episodes in adolescents and adults with hemophilia A, as well as for routine prophylaxis to reduce the frequency of bleeding episodes. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): von Willebrand factor (vWF) promotes hemostasis. The binding capacity and affinity of exogenous human vWF to factor VIII in plasma is comparable to that of endogenous vWF, allowing for vWF to reduce factor VIII clearance. In patients with type 3 von Willebrand disease, a single infusion of human vWF led to an increase of factor VIII coagulation activity with peak levels observed approximately 24 hours post-infusion. The efficacy in clinical trials of vWF in surgical procedures is 96.7% regardless of the type of von Willebrand disease.[L1880] •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Clotting factor VIII or coagulation factor VIII is a glycoprotein involved in the intrinsic pathway of the blood coagulation cascade. It normally circulates in human plasma in a stable complex with von Willebrand factor (vWF), which is a multimeric glycoprotein. vWF acts as a carrier and stabilizing protein for coagulation factor VIII, as it is prone to rapid proteolysis and clearance from plasma. vWF consists of disulfide bridge linked dimers of the 225-kDa single-chain molecule, with the large multimer of vWF being the most effective in supporting adhesion between platelet and collagen or platelet receptors. vWF in circulation functions as a molecular carrier for various proteins other than coagulation factor VIII, such as osteoprotegerin and galectins and recruits platelets upon vascular injury to promote platelet adhesion to the damaged vascular sub-endothelial matrix and platelet aggregation. Both coagulation factor VIII and vWF are essential blood clotting factors in normal hemostasis; however, certain blood disorders such as hemophilia A and von Willebrand disease are associated with reduced or deficient levels of functional clotting factors. Reduced levels of vWF in plasma lead to decreased levels and activity of factor VIII, and abnormal platelet function, thereby resulting in excessive bleeding. Exogenous sources of human vWD aim to restore the levels of vWF in circulation to control and prevent bleeding episodes in patients with the reduced capability of blood clotting. Exogenous vWF treatment is also available as a combination product also containing exogenous coagulation factor VIII to replenish the levels of both clotting factors. •Absorption (Drug A): No absorption available •Absorption (Drug B): In patients with Type 3 von Willebrand disease who were previously treated on-demand with any vWF product prior to study entry, the mean (SD) C max of recombinant vWF at steady state was 86.4 (34.2) IU/dL. In patients who were previously treated prophylactically with a plasma-derived vWF product, the mean (SD) C max was 90.6 (33.7) IU/dL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of the human concentrate vWF is 69.7 mL/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The vWF normally forms a complex with coagulation factor VIII in circulation. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): ADAMTS13, or von Willebrand factor-cleaving protease, is a disintegrin and metalloprotease that normally cleaves vWF. Proteolysis of vWF occurs primarily in the cleavage site at domain A2, which is a target domain for ADAMTS13. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As with endogenous vWF, exogenous sources of vWF are also expected to undergo elimination by the liver and spleen, which take up vWF as part of an active regulatory mechanism. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In patients with Type 3 von Willebrand disease who were previously treated on-demand with any vWF product prior to study entry, the mean (SD) half-life of recombinant vWF at steady state was 16.5 (4.13) hours. In patients who were previously treated prophylactically with a plasma-derived vWF product, the mean (SD) half-life was 14.1 (6.13) hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with Type 3 von Willebrand disease who were previously treated on-demand with any vWF product prior to study entry, the mean (SD) clearance of recombinant vWF at steady state was 0.04 (0.012) (dL/kg)/h. In patients who were previously treated prophylactically with a plasma-derived vWF product, the mean (SD) clearance was 0.04 (0.014) (dL/kg)/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is limited information regarding the LD 50 and overdose of vWF. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Vonvendi, Wilate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Von Willebrand factor human is a blood clotting factor used to manage bleeding episodes in von Willebrand disease and hemophilia A.

Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Question: Does Abciximab and Von Willebrand factor human interact? Information: •Drug A: Abciximab •Drug B: Von Willebrand factor human •Severity: MAJOR •Description: The therapeutic efficacy of Von Willebrand factor human can be decreased when used in combination with Abciximab. •Extended Description: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): The von Willebrand factor (vWF) is indicated to manage and control bleeding episodes in adults with von Willebrand disease. It is also used for perioperative management of bleeding in these patients. It is also used for routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy. In combination with antihemophilic factor human, vWF is also used to manage and control bleeding associated with von Willebrand disease in children and adults, as well as for perioperative management of bleeding in these patients. This combination product is also used for the management and control of bleeding episodes in adolescents and adults with hemophilia A, as well as for routine prophylaxis to reduce the frequency of bleeding episodes. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): von Willebrand factor (vWF) promotes hemostasis. The binding capacity and affinity of exogenous human vWF to factor VIII in plasma is comparable to that of endogenous vWF, allowing for vWF to reduce factor VIII clearance. In patients with type 3 von Willebrand disease, a single infusion of human vWF led to an increase of factor VIII coagulation activity with peak levels observed approximately 24 hours post-infusion. The efficacy in clinical trials of vWF in surgical procedures is 96.7% regardless of the type of von Willebrand disease.[L1880] •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Clotting factor VIII or coagulation factor VIII is a glycoprotein involved in the intrinsic pathway of the blood coagulation cascade. It normally circulates in human plasma in a stable complex with von Willebrand factor (vWF), which is a multimeric glycoprotein. vWF acts as a carrier and stabilizing protein for coagulation factor VIII, as it is prone to rapid proteolysis and clearance from plasma. vWF consists of disulfide bridge linked dimers of the 225-kDa single-chain molecule, with the large multimer of vWF being the most effective in supporting adhesion between platelet and collagen or platelet receptors. vWF in circulation functions as a molecular carrier for various proteins other than coagulation factor VIII, such as osteoprotegerin and galectins and recruits platelets upon vascular injury to promote platelet adhesion to the damaged vascular sub-endothelial matrix and platelet aggregation. Both coagulation factor VIII and vWF are essential blood clotting factors in normal hemostasis; however, certain blood disorders such as hemophilia A and von Willebrand disease are associated with reduced or deficient levels of functional clotting factors. Reduced levels of vWF in plasma lead to decreased levels and activity of factor VIII, and abnormal platelet function, thereby resulting in excessive bleeding. Exogenous sources of human vWD aim to restore the levels of vWF in circulation to control and prevent bleeding episodes in patients with the reduced capability of blood clotting. Exogenous vWF treatment is also available as a combination product also containing exogenous coagulation factor VIII to replenish the levels of both clotting factors. •Absorption (Drug A): No absorption available •Absorption (Drug B): In patients with Type 3 von Willebrand disease who were previously treated on-demand with any vWF product prior to study entry, the mean (SD) C max of recombinant vWF at steady state was 86.4 (34.2) IU/dL. In patients who were previously treated prophylactically with a plasma-derived vWF product, the mean (SD) C max was 90.6 (33.7) IU/dL. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The volume of distribution of the human concentrate vWF is 69.7 mL/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The vWF normally forms a complex with coagulation factor VIII in circulation. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): ADAMTS13, or von Willebrand factor-cleaving protease, is a disintegrin and metalloprotease that normally cleaves vWF. Proteolysis of vWF occurs primarily in the cleavage site at domain A2, which is a target domain for ADAMTS13. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As with endogenous vWF, exogenous sources of vWF are also expected to undergo elimination by the liver and spleen, which take up vWF as part of an active regulatory mechanism. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): In patients with Type 3 von Willebrand disease who were previously treated on-demand with any vWF product prior to study entry, the mean (SD) half-life of recombinant vWF at steady state was 16.5 (4.13) hours. In patients who were previously treated prophylactically with a plasma-derived vWF product, the mean (SD) half-life was 14.1 (6.13) hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): In patients with Type 3 von Willebrand disease who were previously treated on-demand with any vWF product prior to study entry, the mean (SD) clearance of recombinant vWF at steady state was 0.04 (0.012) (dL/kg)/h. In patients who were previously treated prophylactically with a plasma-derived vWF product, the mean (SD) clearance was 0.04 (0.014) (dL/kg)/h. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is limited information regarding the LD 50 and overdose of vWF. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Vonvendi, Wilate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Von Willebrand factor human is a blood clotting factor used to manage bleeding episodes in von Willebrand disease and hemophilia A. Output: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. The severity of the interaction is major.

Does Abciximab and Vorapaxar interact?

•Drug A: Abciximab •Drug B: Vorapaxar •Severity: MAJOR •Description: The risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Abciximab. •Extended Description: Vorapaxar is an anti-platelet agent with an increased risk for bleeding in proportion to the patient’s underlying bleeding risk. Concomitant use of vorapaxar with other medications known to increase the risk of bleeding, such as anticoagulants, may lead to increased risk for non-fatal and fatal bleeding events including intracranial hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vorapaxar is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). It is usually co-administered with acetylsalicylic acid (ASA) and/or clopidogrel, and should therefore be administered as an addition to these medications as it has not been studied alone. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vorapaxar inhibits platelet aggregation through the reversible antagonism of protease-activated receptor 1 (PAR-1), also known as thrombin receptor. PARs are a family of G-protein coupled receptors highly expressed on platelets and activated by serine protease activity of thrombin to mediate thrombotic response. By blocking PAR-1 activating, vorapaxar inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen or a thromboxane mimetic. •Absorption (Drug A): No absorption available •Absorption (Drug B): After oral administration, vorapaxar is rapidly absorbed and peak concentrations occur at a median tmax of 1 hour under faster conditions. Vorapaxar may be taken with or without food as ingestion with a high-fat meal did not result in meaningful changes in AUC. The mean absolute bioavailability is 100%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 424 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Vorapaxar is extensively bound (>99%) to human plasma proteins, such as human serum albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Vorapaxar is metabolized to its major circulating metabolite, M20, and its predominant metabolite excreted into feces, M19, by CYP3A4 and CYP 2J2. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Vorapaxar is primarily eliminated as its metabolite M19 through the feces (91.5%), and partially eliminated in the urine (8.5%). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Vorapaxar has an effective half life of 3-4 days and an apparent terminal half life of 8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is an increased risk of bleeding and intracranial hemorrhage (ICH), which is why the use of vorapaxar is contraindicated in patients with a history of stroke, trans-ischemic attack (TIA), ICH, or active pathological bleeding such as peptic ulcer. Animal studies have suggested that there is a low probability of embryo/fetal toxicities, however there are no adequate and well-controlled studies describing use in pregnant women. Vorapaxar should also be avoided during breastfeeding as it is unknown whether vorapaxar or its metabolites are excreted in human milk, however it has been shown to be actively secreted in the milk of rats. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zontivity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vorapaxar •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vorapaxar is a platelet aggregation inhibitor used to reduce thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD).

Vorapaxar is an anti-platelet agent with an increased risk for bleeding in proportion to the patient’s underlying bleeding risk. Concomitant use of vorapaxar with other medications known to increase the risk of bleeding, such as anticoagulants, may lead to increased risk for non-fatal and fatal bleeding events including intracranial hemorrhage. The severity of the interaction is major.

Question: Does Abciximab and Vorapaxar interact? Information: •Drug A: Abciximab •Drug B: Vorapaxar •Severity: MAJOR •Description: The risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Abciximab. •Extended Description: Vorapaxar is an anti-platelet agent with an increased risk for bleeding in proportion to the patient’s underlying bleeding risk. Concomitant use of vorapaxar with other medications known to increase the risk of bleeding, such as anticoagulants, may lead to increased risk for non-fatal and fatal bleeding events including intracranial hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vorapaxar is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). It is usually co-administered with acetylsalicylic acid (ASA) and/or clopidogrel, and should therefore be administered as an addition to these medications as it has not been studied alone. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vorapaxar inhibits platelet aggregation through the reversible antagonism of protease-activated receptor 1 (PAR-1), also known as thrombin receptor. PARs are a family of G-protein coupled receptors highly expressed on platelets and activated by serine protease activity of thrombin to mediate thrombotic response. By blocking PAR-1 activating, vorapaxar inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen or a thromboxane mimetic. •Absorption (Drug A): No absorption available •Absorption (Drug B): After oral administration, vorapaxar is rapidly absorbed and peak concentrations occur at a median tmax of 1 hour under faster conditions. Vorapaxar may be taken with or without food as ingestion with a high-fat meal did not result in meaningful changes in AUC. The mean absolute bioavailability is 100%. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): 424 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Vorapaxar is extensively bound (>99%) to human plasma proteins, such as human serum albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Vorapaxar is metabolized to its major circulating metabolite, M20, and its predominant metabolite excreted into feces, M19, by CYP3A4 and CYP 2J2. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Vorapaxar is primarily eliminated as its metabolite M19 through the feces (91.5%), and partially eliminated in the urine (8.5%). •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Vorapaxar has an effective half life of 3-4 days and an apparent terminal half life of 8 days. •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): There is an increased risk of bleeding and intracranial hemorrhage (ICH), which is why the use of vorapaxar is contraindicated in patients with a history of stroke, trans-ischemic attack (TIA), ICH, or active pathological bleeding such as peptic ulcer. Animal studies have suggested that there is a low probability of embryo/fetal toxicities, however there are no adequate and well-controlled studies describing use in pregnant women. Vorapaxar should also be avoided during breastfeeding as it is unknown whether vorapaxar or its metabolites are excreted in human milk, however it has been shown to be actively secreted in the milk of rats. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zontivity •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vorapaxar •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vorapaxar is a platelet aggregation inhibitor used to reduce thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). Output: Vorapaxar is an anti-platelet agent with an increased risk for bleeding in proportion to the patient’s underlying bleeding risk. Concomitant use of vorapaxar with other medications known to increase the risk of bleeding, such as anticoagulants, may lead to increased risk for non-fatal and fatal bleeding events including intracranial hemorrhage. The severity of the interaction is major.

Does Abciximab and Vorinostat interact?

•Drug A: Abciximab •Drug B: Vorinostat •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vorinostat. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC 50 < 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 71% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zolinza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Octanedioic acid hydroxyamide phenylamide SAHA Suberanilohydroxamic acid Suberoylanilide hydroxamic acid Vorinostat Vorinostatum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vorinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T- cell lymphoma (CTCL) following prior systemic therapies.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Vorinostat interact? Information: •Drug A: Abciximab •Drug B: Vorinostat •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Vorinostat. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC 50 < 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized. •Absorption (Drug A): No absorption available •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 71% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): 2 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Zolinza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Octanedioic acid hydroxyamide phenylamide SAHA Suberanilohydroxamic acid Suberoylanilide hydroxamic acid Vorinostat Vorinostatum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vorinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T- cell lymphoma (CTCL) following prior systemic therapies. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Abciximab and Vortioxetine interact?

•Drug A: Abciximab •Drug B: Vortioxetine •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Vortioxetine is combined with Abciximab. •Extended Description: Prescribing information for vortioxetine states that its concomitant use with other drugs capable of interfering with hemostasis may lead to an increased risk of hemorrhage. Platelet aggregation - and consequently hemostasis - is mediated in part by serotonin, and for this reason the inhibition of serotonin transporters by drugs like vortioxetine may also interfere with hemostasis. The co-administration of additional agents that may cause the same or similar effects (e.g. antiplatelet agents) may therefore result in additive antiplatelet activity and an increased risk of bleeding episodes. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vortioxetine is indicated for the treatment of major depressive disorder (MDD). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin by inhibition of the serotonin transporter (IC50=5.4 nM). Specifically, vortioxetine binds to 5­HT3 (Ki=3.7 nM), 5­HT1A (Ki=15 nM), 5­HT7 (Ki=19 nM), 5­HT1D (Ki=54 nM), and 5­HT1B (Ki=33 nM), receptors and is a 5­HT3, 5­HT1D, and 5­HT7 receptor antagonist, 5­HT1B receptor partial agonist, and 5­HT1A receptor agonist. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vortioxetine is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonin transporter, while also acting as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. •Absorption (Drug A): No absorption available •Absorption (Drug B): The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following a single oral dose of [14C]­labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Mean terminal half­life is approximately 66 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The most commonly reported adverse effects during clinical trials were nausea, diarrhea, and dry mouth. The FDA label includes a blackbox warning for the following risks and complications: serotonin syndrome, especially when combined with other serotonergic agents; increased risk of abnormal bleeding, especially when combined with NSAIDs, aspirin, or other drugs that affect coagulation; activation of mania/hypomania; hyponatremia; and suicidal thoughts and behaviour in children, adolescents, and young adults. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Brintellix, Trintellix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vortioxetine is a serotonin modulating antidepressant indicated for the treatment of major depressive disorder (MDD).

Prescribing information for vortioxetine states that its concomitant use with other drugs capable of interfering with hemostasis may lead to an increased risk of hemorrhage. Platelet aggregation - and consequently hemostasis - is mediated in part by serotonin, and for this reason the inhibition of serotonin transporters by drugs like vortioxetine may also interfere with hemostasis. The co-administration of additional agents that may cause the same or similar effects (e.g. antiplatelet agents) may therefore result in additive antiplatelet activity and an increased risk of bleeding episodes. The severity of the interaction is moderate.

Question: Does Abciximab and Vortioxetine interact? Information: •Drug A: Abciximab •Drug B: Vortioxetine •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Vortioxetine is combined with Abciximab. •Extended Description: Prescribing information for vortioxetine states that its concomitant use with other drugs capable of interfering with hemostasis may lead to an increased risk of hemorrhage. Platelet aggregation - and consequently hemostasis - is mediated in part by serotonin, and for this reason the inhibition of serotonin transporters by drugs like vortioxetine may also interfere with hemostasis. The co-administration of additional agents that may cause the same or similar effects (e.g. antiplatelet agents) may therefore result in additive antiplatelet activity and an increased risk of bleeding episodes. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Vortioxetine is indicated for the treatment of major depressive disorder (MDD). •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin by inhibition of the serotonin transporter (IC50=5.4 nM). Specifically, vortioxetine binds to 5­HT3 (Ki=3.7 nM), 5­HT1A (Ki=15 nM), 5­HT7 (Ki=19 nM), 5­HT1D (Ki=54 nM), and 5­HT1B (Ki=33 nM), receptors and is a 5­HT3, 5­HT1D, and 5­HT7 receptor antagonist, 5­HT1B receptor partial agonist, and 5­HT1A receptor agonist. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Vortioxetine is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonin transporter, while also acting as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. •Absorption (Drug A): No absorption available •Absorption (Drug B): The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): Following a single oral dose of [14C]­labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Mean terminal half­life is approximately 66 hours •Clearance (Drug A): No clearance available •Clearance (Drug B): No clearance available •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): The most commonly reported adverse effects during clinical trials were nausea, diarrhea, and dry mouth. The FDA label includes a blackbox warning for the following risks and complications: serotonin syndrome, especially when combined with other serotonergic agents; increased risk of abnormal bleeding, especially when combined with NSAIDs, aspirin, or other drugs that affect coagulation; activation of mania/hypomania; hyponatremia; and suicidal thoughts and behaviour in children, adolescents, and young adults. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Brintellix, Trintellix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Vortioxetine is a serotonin modulating antidepressant indicated for the treatment of major depressive disorder (MDD). Output: Prescribing information for vortioxetine states that its concomitant use with other drugs capable of interfering with hemostasis may lead to an increased risk of hemorrhage. Platelet aggregation - and consequently hemostasis - is mediated in part by serotonin, and for this reason the inhibition of serotonin transporters by drugs like vortioxetine may also interfere with hemostasis. The co-administration of additional agents that may cause the same or similar effects (e.g. antiplatelet agents) may therefore result in additive antiplatelet activity and an increased risk of bleeding episodes. The severity of the interaction is moderate.

Does Abciximab and Warfarin interact?

•Drug A: Abciximab •Drug B: Warfarin •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Warfarin. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for: 1) Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism. 2) Prophylaxis and treatment of thromboembolism associated with atrial fibrillation. 3) Prophylaxis and treatment of thromboembolism associated with cardiac valve replacement. 4) Use as adjunct therapy to reduce mortality, recurrent myocardial infarction, and thromboembolic events post myocardial infarction. Off-label uses include: 1) Secondary prevention of stroke and transient ischemic attacks in patients with rheumatic mitral valve disease but without atrial fibrillation. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Warfarin is an anticoagulant, as such it disrupts the coagulation cascade to reduce frequency and extent of thrombus formation. In patients with deep vein thrombosis or atrial fibrillation there is an increased risk of thrombus formation due to the reduced movement of blood. For patients with cardiac valve disease or valve replacements this increased coagulability is due to tissue damage. Thrombi due to venous thrombosis can travel to the lungs and become pulmonary emboli, blocking circulation to a portion of lung tissue. Thrombi which form in the heart can travel to the brain and cause ischemic strokes. Prevention of these events is the primary goal of warfarin therapy. Limitation of thrombus formation is also a source of adverse effects. In patients with atheroscelotic plaques rupture typically results in thrombus formation. When these patients are anticoagulated plaque rupture can allow the escape of cholesterol from the lipid core in the form of atheroemboli or cholesterol microemboli. These emboli are smaller than thrombi and block smaller vessels, usually less than 200 μm in diameter. The consequences of this are varied and depend on the location of the blockage. Effects include visual disturbances, acute kidney injury or worsening of chronic kidney disease, central nervous system ischemia, and purple or blue toe syndrome. Blue toe syndrome can be reversed if it has not progressed to tissue necrosis but the other effects of microemboli are often permanent. Antocoagulation appears to mediate warfarin-related nephropathy, a seemingly spontaneous kidney injury or worsening of chronic kidney disease associated with warfarin therapy. Nephropathy in this case appears to be due to increased passage of red blood cells through the glomerulus and subsequent blockage of renal tubules with red blood cell casts. This is worsened or possibly triggered by pre-existing kidney damage. Increased risk of warfarin-related nephropathy occurs at INRs over 3.0 but risk does not increase as a function of INR beyond this point. Warfarin has been linked to the development of calciphylaxis. This is thought to be due to warfarin's inhibition of vitamin K recycling as VKA is needed for the carboxylation of matrix Gla protein. This protein is an anti-calcification factor and its inhibition through preventing the carboxylation step in its production leads to a shift in calcification balance in favor of calciphylaxis. Tissue necrosis can occur early on in warfarin therapy. This is attributable to half lives of the clotting factors impacted by inhibition of vitamin K recycling. Proteins C and S are anticoagulation factors with half lives of 8 and 24 hours respectively. The coagulation factors IX, X, VII, and thrombin (factor II) have half lives of 24, 36, 6, and 50 hours respectively. This means proteins C and S are inactivated sooner than pro-coagulation proteins, with the exception of factor VII, resulting in a pro-thrombotic state for the first few days of therapy. Thrombi which form in this time period can occlude arterioles in various locations, blocking blood flow and causing tissue necrosis due to ischemia. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH 2 is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH 2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K 1 by vitamin K epoxide reductase then back to vitamin KH 2 by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K 1. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K 2, functionally identical to vitamin K 1, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K 2 16 •Absorption (Drug A): No absorption available •Absorption (Drug B): Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vd of 0.14 L/kg. Warfarin has a distrubution phase lasting 6-12 hours. It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound primarily to albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Metabolism of warfarin is both stereo- and regio-selective. The major metabolic pathway is oxidation to various hydroxywarfarins, comprising 80-85% of the total metabolites. CYP2C9 is the major enzyme catalyzing the 6- and 7-hydroxylation of S-warfarin while 4'-hydroxylation occurs through CYP2C18 with minor contributions from CYP2C19. R-warfarin is metabolized to 4'-hydroxywarfarin by CYP2C8 with some contirbuting by CYP2C19, 6- and 8-hydroxywarfarin by CYP1A2 and CYP2C19, 7-hydroxywarfarin by CYP1A2 and CYP2C8, and lastly to 10-hydroxywarfarin by CYP3A4. The 10-hydroxywarfarin metabolite as well as a benzylic alcohol metabolite undergo an elimination step to form dehydrowarfarin. The minor pathway of metabolism is the reduction of the ketone group to warfarin alcohols, comprising 20% of the metabolites. Limited conjugation occurs with sulfate and gluronic acid groups but these metabolites have only been confirmed for R-hydroxywarfarins. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged. 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): R-warfarin is cleared more slowly than S-warfarin, at about half the rate. T 1/2 for R-warfarin is 37-89 hours. T 1/2 for S-warfarin is 21-43 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of warfarin varies depending on CYP2C9 genotype. The *2 and *3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the *5, *6, *9 and *11 alleles. Genotypes for which population clearance estimates have been found are listed below. *1/*1 = 0.065 mL/min/kg *1/*2, *1/*3 = 0.041 mL/min/kg *2/*2, *2/*3, *3/*3 = 0.020 mg/min/kg •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): LD 50 Values Mouse: 3 mg/kg (Oral), 165 mg/kg (IV), 750 mg/kg (IP) Rat: 1.6 mg/kg (Oral), 320 mg/kg (Inhaled), 1400 mg/kg (Skin) Rabbit: 800 mg/kg (Oral) Pig: 1 mg/kg (Oral) Dog: 3 mg/kg (Oral) Cat: 6 mg/kg (Oral) Chicken: 942 mg/kg (Oral) Guinea Pig: 180 mg/kg (Oral) Overdose Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans. Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system. Epistaxis, ecchymoses, as well as renal and hepatic bleeding are also associated. These symptoms become apparent within 2-4 days of overdose although increases in prothrombin time can be observed within 24 hours. Treatment for overdosed patients includes discontinuation of warfarin and administration of [vitamin K]. For more urgent reversal of anticoagulation prothrombin complex concentrate, blood plasma, or coagulation factor VIIa infusion can be used. Patients can be safely re-anticoagulated after reversal of the overdose. Carcinogenicity & Mutagenicity The carcinogenicity and mutagenicity of warfarin have not been thoroughly investigated. Reproductive Toxicity Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk. Fetal warfarin syndrome, attributed to exposure during the 1st trimester, is characterized by nasal hypoplasia with or without stippled epiphyses, possible failure of nasal septum development, and low birth weight. Either dorsal midline dysplasia or ventral midline dysplasia can occur. Dorsal midline dysplasia includes agenisis of the corpus callosum, Dandy-Walker malformations, midline cerebellar hypoplasia. Ventral midline dysplasia is characterized by eye anomalies which can potentially include optic atrophy, blindness, and microphthalmia. Exposure during the 2nd and 3rd trimester is associated with hypoplasia of the extremities, developmental retardation, microcephaly, hydrocephaly, schizencephaly, seizures, scoliosis, deafness, congenital heart malformations, and fetal death. The critical exposure period is estimated to be week 6-9 based on case reports. Effects noted in the Canadian product monograph include developing a single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, polydactyl malformations, corneal leukoma, diaphragm hernia, and cleft palate. Lactation Official product monographs mention a study in 15 women. Warfarin was not detected in the breast milk of any woman and 6 infants were documented as having normal prothrombin times. The remaining 9 infants were not tested. Another study in 13 women using doses of 2-12 mg also revealed no detectable warfarin in breast milk. A woman who mistakenly took 25 mg of warfarin for 7 days while breastfeeding presented to an emergency room with an INR of 10 and prothrombin time of over 100 s. Her infant had a normal INR of 1.0 and prothrombin time of 10.3. The infant in this case has an increased prothrombin time of 33.8 s three weeks previous but this was judged not to be due to warfarin exposure. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Coumadin, Jantoven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Coumafene Warfarin Warfarina Zoocoumarin •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Warfarin is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post myocardial infarction.

Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Question: Does Abciximab and Warfarin interact? Information: •Drug A: Abciximab •Drug B: Warfarin •Severity: MODERATE •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Warfarin. •Extended Description: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Indicated for: 1) Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism. 2) Prophylaxis and treatment of thromboembolism associated with atrial fibrillation. 3) Prophylaxis and treatment of thromboembolism associated with cardiac valve replacement. 4) Use as adjunct therapy to reduce mortality, recurrent myocardial infarction, and thromboembolic events post myocardial infarction. Off-label uses include: 1) Secondary prevention of stroke and transient ischemic attacks in patients with rheumatic mitral valve disease but without atrial fibrillation. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Warfarin is an anticoagulant, as such it disrupts the coagulation cascade to reduce frequency and extent of thrombus formation. In patients with deep vein thrombosis or atrial fibrillation there is an increased risk of thrombus formation due to the reduced movement of blood. For patients with cardiac valve disease or valve replacements this increased coagulability is due to tissue damage. Thrombi due to venous thrombosis can travel to the lungs and become pulmonary emboli, blocking circulation to a portion of lung tissue. Thrombi which form in the heart can travel to the brain and cause ischemic strokes. Prevention of these events is the primary goal of warfarin therapy. Limitation of thrombus formation is also a source of adverse effects. In patients with atheroscelotic plaques rupture typically results in thrombus formation. When these patients are anticoagulated plaque rupture can allow the escape of cholesterol from the lipid core in the form of atheroemboli or cholesterol microemboli. These emboli are smaller than thrombi and block smaller vessels, usually less than 200 μm in diameter. The consequences of this are varied and depend on the location of the blockage. Effects include visual disturbances, acute kidney injury or worsening of chronic kidney disease, central nervous system ischemia, and purple or blue toe syndrome. Blue toe syndrome can be reversed if it has not progressed to tissue necrosis but the other effects of microemboli are often permanent. Antocoagulation appears to mediate warfarin-related nephropathy, a seemingly spontaneous kidney injury or worsening of chronic kidney disease associated with warfarin therapy. Nephropathy in this case appears to be due to increased passage of red blood cells through the glomerulus and subsequent blockage of renal tubules with red blood cell casts. This is worsened or possibly triggered by pre-existing kidney damage. Increased risk of warfarin-related nephropathy occurs at INRs over 3.0 but risk does not increase as a function of INR beyond this point. Warfarin has been linked to the development of calciphylaxis. This is thought to be due to warfarin's inhibition of vitamin K recycling as VKA is needed for the carboxylation of matrix Gla protein. This protein is an anti-calcification factor and its inhibition through preventing the carboxylation step in its production leads to a shift in calcification balance in favor of calciphylaxis. Tissue necrosis can occur early on in warfarin therapy. This is attributable to half lives of the clotting factors impacted by inhibition of vitamin K recycling. Proteins C and S are anticoagulation factors with half lives of 8 and 24 hours respectively. The coagulation factors IX, X, VII, and thrombin (factor II) have half lives of 24, 36, 6, and 50 hours respectively. This means proteins C and S are inactivated sooner than pro-coagulation proteins, with the exception of factor VII, resulting in a pro-thrombotic state for the first few days of therapy. Thrombi which form in this time period can occlude arterioles in various locations, blocking blood flow and causing tissue necrosis due to ischemia. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH 2 is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH 2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K 1 by vitamin K epoxide reductase then back to vitamin KH 2 by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K 1. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K 2, functionally identical to vitamin K 1, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K 2 16 •Absorption (Drug A): No absorption available •Absorption (Drug B): Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Vd of 0.14 L/kg. Warfarin has a distrubution phase lasting 6-12 hours. It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound primarily to albumin. •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Metabolism of warfarin is both stereo- and regio-selective. The major metabolic pathway is oxidation to various hydroxywarfarins, comprising 80-85% of the total metabolites. CYP2C9 is the major enzyme catalyzing the 6- and 7-hydroxylation of S-warfarin while 4'-hydroxylation occurs through CYP2C18 with minor contributions from CYP2C19. R-warfarin is metabolized to 4'-hydroxywarfarin by CYP2C8 with some contirbuting by CYP2C19, 6- and 8-hydroxywarfarin by CYP1A2 and CYP2C19, 7-hydroxywarfarin by CYP1A2 and CYP2C8, and lastly to 10-hydroxywarfarin by CYP3A4. The 10-hydroxywarfarin metabolite as well as a benzylic alcohol metabolite undergo an elimination step to form dehydrowarfarin. The minor pathway of metabolism is the reduction of the ketone group to warfarin alcohols, comprising 20% of the metabolites. Limited conjugation occurs with sulfate and gluronic acid groups but these metabolites have only been confirmed for R-hydroxywarfarins. •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged. 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): R-warfarin is cleared more slowly than S-warfarin, at about half the rate. T 1/2 for R-warfarin is 37-89 hours. T 1/2 for S-warfarin is 21-43 hours. •Clearance (Drug A): No clearance available •Clearance (Drug B): Clearance of warfarin varies depending on CYP2C9 genotype. The *2 and *3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the *5, *6, *9 and *11 alleles. Genotypes for which population clearance estimates have been found are listed below. *1/*1 = 0.065 mL/min/kg *1/*2, *1/*3 = 0.041 mL/min/kg *2/*2, *2/*3, *3/*3 = 0.020 mg/min/kg •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): LD 50 Values Mouse: 3 mg/kg (Oral), 165 mg/kg (IV), 750 mg/kg (IP) Rat: 1.6 mg/kg (Oral), 320 mg/kg (Inhaled), 1400 mg/kg (Skin) Rabbit: 800 mg/kg (Oral) Pig: 1 mg/kg (Oral) Dog: 3 mg/kg (Oral) Cat: 6 mg/kg (Oral) Chicken: 942 mg/kg (Oral) Guinea Pig: 180 mg/kg (Oral) Overdose Doses of 1-2 mg/kg/day over a period of 15 days have been fatal in humans. Warfarin overdose is primarily associated with major bleeding particularly from the mucous membranes, gastrointestinal tract, and genitourinary system. Epistaxis, ecchymoses, as well as renal and hepatic bleeding are also associated. These symptoms become apparent within 2-4 days of overdose although increases in prothrombin time can be observed within 24 hours. Treatment for overdosed patients includes discontinuation of warfarin and administration of [vitamin K]. For more urgent reversal of anticoagulation prothrombin complex concentrate, blood plasma, or coagulation factor VIIa infusion can be used. Patients can be safely re-anticoagulated after reversal of the overdose. Carcinogenicity & Mutagenicity The carcinogenicity and mutagenicity of warfarin have not been thoroughly investigated. Reproductive Toxicity Warfarin is known to be a teratogen and its use during pregnancy is contraindicated in the absence of high thrombotic risk. Fetal warfarin syndrome, attributed to exposure during the 1st trimester, is characterized by nasal hypoplasia with or without stippled epiphyses, possible failure of nasal septum development, and low birth weight. Either dorsal midline dysplasia or ventral midline dysplasia can occur. Dorsal midline dysplasia includes agenisis of the corpus callosum, Dandy-Walker malformations, midline cerebellar hypoplasia. Ventral midline dysplasia is characterized by eye anomalies which can potentially include optic atrophy, blindness, and microphthalmia. Exposure during the 2nd and 3rd trimester is associated with hypoplasia of the extremities, developmental retardation, microcephaly, hydrocephaly, schizencephaly, seizures, scoliosis, deafness, congenital heart malformations, and fetal death. The critical exposure period is estimated to be week 6-9 based on case reports. Effects noted in the Canadian product monograph include developing a single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, polydactyl malformations, corneal leukoma, diaphragm hernia, and cleft palate. Lactation Official product monographs mention a study in 15 women. Warfarin was not detected in the breast milk of any woman and 6 infants were documented as having normal prothrombin times. The remaining 9 infants were not tested. Another study in 13 women using doses of 2-12 mg also revealed no detectable warfarin in breast milk. A woman who mistakenly took 25 mg of warfarin for 7 days while breastfeeding presented to an emergency room with an INR of 10 and prothrombin time of over 100 s. Her infant had a normal INR of 1.0 and prothrombin time of 10.3. The infant in this case has an increased prothrombin time of 33.8 s three weeks previous but this was judged not to be due to warfarin exposure. •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Coumadin, Jantoven •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Coumafene Warfarin Warfarina Zoocoumarin •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Warfarin is a vitamin K antagonist used to treat venous thromboembolism, pulmonary embolism, thromboembolism with atrial fibrillation, thromboembolism with cardiac valve replacement, and thromboembolic events post myocardial infarction. Output: Both antiplatelet agents and anticoagulants are associated with a risk of bleeding when administered alone. The concomitant use of these agents may further increase the risk for fatal and non-fatal bleeding events, including gastrointestinal hemorrhage. The severity of the interaction is moderate.

Does Abciximab and Zidovudine interact?

•Drug A: Abciximab •Drug B: Zidovudine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Zidovudine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used in combination with other antiretroviral agents for the treatment of human immunovirus (HIV) infections. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ. •Absorption (Drug A): No absorption available •Absorption (Drug B): Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 30-38% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age] 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age] 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD 50 is 3084 mg/kg (orally in mice). •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Combivir, Retrovir, Trizivir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azidothymidine Zidovudina Zidovudine Zidovudinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Zidovudine is a dideoxynucleoside used in the treatment of HIV infection.

As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Question: Does Abciximab and Zidovudine interact? Information: •Drug A: Abciximab •Drug B: Zidovudine •Severity: MINOR •Description: The risk or severity of bleeding can be increased when Abciximab is combined with Zidovudine. •Extended Description: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. •Indication (Drug A): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Indication (Drug B): Used in combination with other antiretroviral agents for the treatment of human immunovirus (HIV) infections. •Pharmacodynamics (Drug A): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Pharmacodynamics (Drug B): Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. •Mechanism of action (Drug A): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Mechanism of action (Drug B): Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ. •Absorption (Drug A): No absorption available •Absorption (Drug B): Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption. •Volume of distribution (Drug A): No volume of distribution available •Volume of distribution (Drug B): Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 30-38% •Metabolism (Drug A): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Metabolism (Drug B): Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT). •Route of elimination (Drug A): No route of elimination available •Route of elimination (Drug B): As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV. •Half-life (Drug A): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Half-life (Drug B): Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours) •Clearance (Drug A): No clearance available •Clearance (Drug B): 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age] 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age] 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine. •Toxicity (Drug A): No toxicity available •Toxicity (Drug B): Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD 50 is 3084 mg/kg (orally in mice). •Brand Names (Drug A): No brand names available •Brand Names (Drug B): Combivir, Retrovir, Trizivir •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azidothymidine Zidovudina Zidovudine Zidovudinum •Summary (Drug A): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. •Summary (Drug B): Zidovudine is a dideoxynucleoside used in the treatment of HIV infection. Output: As their name suggested, myelosuppressive agents can decrease the production of cells found in the bone marrow, including thrombocytes.5,1 Low levels of thrombocytes, or thrombocytopenia, can increase the risk of bleeding due to the inability to form blood clots. Therefore, concomitant administration of agents that prevent thrombotic events such as antiplatelet agents can further exacerbate this risk into abnormal bleeding. The severity of the interaction is minor.

Does Adalimumab and Abatacept interact?

•Drug A: Adalimumab •Drug B: Abatacept •Severity: MODERATE •Description: The risk or severity of infection can be increased when Adalimumab is combined with Abatacept. •Extended Description: Since adalimumab and abatacept are both immunosuppressants, co-administration of adalimumab and abatacept can increase the risk of infection. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Kidney and liver •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Orencia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease.

Since adalimumab and abatacept are both immunosuppressants, co-administration of adalimumab and abatacept can increase the risk of infection. The severity of the interaction is moderate.

Question: Does Adalimumab and Abatacept interact? Information: •Drug A: Adalimumab •Drug B: Abatacept •Severity: MODERATE •Description: The risk or severity of infection can be increased when Adalimumab is combined with Abatacept. •Extended Description: Since adalimumab and abatacept are both immunosuppressants, co-administration of adalimumab and abatacept can increase the risk of infection. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Kidney and liver •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Orencia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. Output: Since adalimumab and abatacept are both immunosuppressants, co-administration of adalimumab and abatacept can increase the risk of infection. The severity of the interaction is moderate.

Does Adalimumab and Abciximab interact?

•Drug A: Adalimumab •Drug B: Abciximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Abciximab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Abciximab interact? Information: •Drug A: Adalimumab •Drug B: Abciximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Abciximab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0.25 - 0.30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Abemaciclib interact?

•Drug A: Adalimumab •Drug B: Abemaciclib •Severity: MAJOR •Description: The metabolism of Abemaciclib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19.7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8.6 months after treatment. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models. In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg, but may range up to 24 hours. The absolute bioavailability of the drug is reported to be 45%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated in vitro binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93.4%, 96.8% and 97.8%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Verzenio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abemaciclib is a medication used to treat HR+ HER2- advanced or metastatic breast cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Abemaciclib interact? Information: •Drug A: Adalimumab •Drug B: Abemaciclib •Severity: MAJOR •Description: The metabolism of Abemaciclib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19.7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8.6 months after treatment. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models. In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg, but may range up to 24 hours. The absolute bioavailability of the drug is reported to be 45%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated in vitro binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93.4%, 96.8% and 97.8%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Verzenio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abemaciclib is a medication used to treat HR+ HER2- advanced or metastatic breast cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Abrocitinib interact?

•Drug A: Adalimumab •Drug B: Abrocitinib •Severity: MODERATE •Description: The metabolism of Abrocitinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. In the US, it is indicated to treat refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when the use of those therapies is inadvisable. Abrocitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Abrocitinib mediates anti-inflammatory effects by blocking the signalling of pro-inflammatory cytokines implicated in atopic dermatitis. It dose-dependently reduces the serum markers of inflammation in atopic dermatitis, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31), and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within four weeks following drug discontinuation. At two weeks of treatment, the mean absolute lymphocyte count increased, which returned to baseline by nine months of treatment. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts: the clinical significance of these changes is unknown. Treatment with 200 mg abrocitinib once-daily was associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days. Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Janus kinases (JAKs) are a family consisting of four receptor-associated kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Upon ligand binding and subsequent dimerization of cytokine and hormone receptors, receptor-associated JAKs are activated and phosphorylated. This allows the binding of Signal Transducers and Activators of Transcription (STATs), which are transcription factors. STAT binds to the receptor, and JAK phosphorylates and activates STAT to create a STAT dimer. The STAT dimer translocates to the nucleus to upregulate the gene transcription of pro-inflammatory cytokines and growth factors implicated in atopic dermatitis. Blocking the JAK-STAT pathway is advantageous, as it is an intracellular signalling pathway where many pro-inflammatory pathways converge. Each JAK plays a role in the signalling and regulation of different cytokines and immune cells. In atopic dermatitis, JAK1 is the therapeutic target of focus as it is involved in the signalling of the γc family of cytokines involved in immune responses and disease pathophysiology, including IL-2, IL-4, IL-7, IL-9, and IL-15. Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. Biochemical assays demonstrate that abrocitinib is selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. Similarly, in cellular settings, abrocitinib preferentially inhibited cytokine-induced STAT phosphorylation by signalling pairs involving JAK1, while sparing signalling by JAK2/JAK2, or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to the drug's therapeutic effectiveness is currently unknown. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within one hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once-daily administration. Both C max and AUC of abrocitinib increased dose proportionally up to 200 mg. A high-fat meal, high-calorie meal increased AUC by 26% and C max by 29%, and prolongs T max by two hours; however, there are ultimately no clinically relevant effect on abrocitinib exposures. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): After intravenous administration, the volume of distribution of abrocitinib was approximately 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Abrocitinib undergoes CYP-mediated oxidative metabolism. CYP2C19 is the predominant enzyme, accounting for about 53% of drug metabolism. CYP2C9 is responsible for 30% of drug metabolism. About 11% and 6% of the drug is metabolized by CYP3A4 and CYP2B6, respectively. In a human radiolabeled study, the parent drug was the most prevalent circulating species. Polar mono-hydroxylated metabolites of abrocitinib - M1 (3-hydroxypropyl; PF-06471658), M2 (2-hydroxypropyl; PF-07055087), and M4 (pyrrolidinone pyrimidine; PF-07054874) - were also identified in the systemic circulation. M2 has a chiral center, thus has an enantiomer M3 (PF-07055090). At steady state, M2 and M4 are major metabolites and M1 is a minor metabolite. M2 has a pharmacological activity comparable to abrocitinib while M1 is less pharmacologically active than abrocitinib. M3 and M4 are inactive metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of the parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in the systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose being excreted in urine as an unchanged parent drug. The metabolites of abrocitinib are excreted predominantly in urine. Pharmacokinetics data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range from three to five hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): There is no information available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is no experience regarding human overdosage with abrocitinib. In clinical trials, there were no specific toxicities observed when abrocitinib was administered in single oral doses of 800 mg and 400 mg daily for 28 days. An overdose should be responded with symptomatic and supportive treatment, as there is no specific antidote for overdose with abrocitinib. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abrocitinib is a kinase inhibitor used to treat moderate-to-severe atopic dermatitis in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Abrocitinib interact? Information: •Drug A: Adalimumab •Drug B: Abrocitinib •Severity: MODERATE •Description: The metabolism of Abrocitinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. In the US, it is indicated to treat refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when the use of those therapies is inadvisable. Abrocitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Abrocitinib mediates anti-inflammatory effects by blocking the signalling of pro-inflammatory cytokines implicated in atopic dermatitis. It dose-dependently reduces the serum markers of inflammation in atopic dermatitis, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31), and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within four weeks following drug discontinuation. At two weeks of treatment, the mean absolute lymphocyte count increased, which returned to baseline by nine months of treatment. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts: the clinical significance of these changes is unknown. Treatment with 200 mg abrocitinib once-daily was associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days. Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Janus kinases (JAKs) are a family consisting of four receptor-associated kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Upon ligand binding and subsequent dimerization of cytokine and hormone receptors, receptor-associated JAKs are activated and phosphorylated. This allows the binding of Signal Transducers and Activators of Transcription (STATs), which are transcription factors. STAT binds to the receptor, and JAK phosphorylates and activates STAT to create a STAT dimer. The STAT dimer translocates to the nucleus to upregulate the gene transcription of pro-inflammatory cytokines and growth factors implicated in atopic dermatitis. Blocking the JAK-STAT pathway is advantageous, as it is an intracellular signalling pathway where many pro-inflammatory pathways converge. Each JAK plays a role in the signalling and regulation of different cytokines and immune cells. In atopic dermatitis, JAK1 is the therapeutic target of focus as it is involved in the signalling of the γc family of cytokines involved in immune responses and disease pathophysiology, including IL-2, IL-4, IL-7, IL-9, and IL-15. Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. Biochemical assays demonstrate that abrocitinib is selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. Similarly, in cellular settings, abrocitinib preferentially inhibited cytokine-induced STAT phosphorylation by signalling pairs involving JAK1, while sparing signalling by JAK2/JAK2, or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to the drug's therapeutic effectiveness is currently unknown. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within one hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once-daily administration. Both C max and AUC of abrocitinib increased dose proportionally up to 200 mg. A high-fat meal, high-calorie meal increased AUC by 26% and C max by 29%, and prolongs T max by two hours; however, there are ultimately no clinically relevant effect on abrocitinib exposures. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): After intravenous administration, the volume of distribution of abrocitinib was approximately 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Abrocitinib undergoes CYP-mediated oxidative metabolism. CYP2C19 is the predominant enzyme, accounting for about 53% of drug metabolism. CYP2C9 is responsible for 30% of drug metabolism. About 11% and 6% of the drug is metabolized by CYP3A4 and CYP2B6, respectively. In a human radiolabeled study, the parent drug was the most prevalent circulating species. Polar mono-hydroxylated metabolites of abrocitinib - M1 (3-hydroxypropyl; PF-06471658), M2 (2-hydroxypropyl; PF-07055087), and M4 (pyrrolidinone pyrimidine; PF-07054874) - were also identified in the systemic circulation. M2 has a chiral center, thus has an enantiomer M3 (PF-07055090). At steady state, M2 and M4 are major metabolites and M1 is a minor metabolite. M2 has a pharmacological activity comparable to abrocitinib while M1 is less pharmacologically active than abrocitinib. M3 and M4 are inactive metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of the parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in the systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose being excreted in urine as an unchanged parent drug. The metabolites of abrocitinib are excreted predominantly in urine. Pharmacokinetics data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range from three to five hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): There is no information available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is no experience regarding human overdosage with abrocitinib. In clinical trials, there were no specific toxicities observed when abrocitinib was administered in single oral doses of 800 mg and 400 mg daily for 28 days. An overdose should be responded with symptomatic and supportive treatment, as there is no specific antidote for overdose with abrocitinib. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Abrocitinib is a kinase inhibitor used to treat moderate-to-severe atopic dermatitis in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Adalimumab and Acalabrutinib interact?

•Drug A: Adalimumab •Drug B: Acalabrutinib •Severity: MAJOR •Description: The metabolism of Acalabrutinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The mean steady-state volume of distribution is approximately 34 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Reversible binding of acalabrutinib to human plasma protein is approximately 97.5%. The in vitro mean blood-to-plasma ratio is about 0.7. In vitro experiments at physiologic concentrations show that acalabrutinib can be 93.7% bound to human serum albumin and 41.1% bound to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours. The half-life of the active metabolite, ACP-5862, is about 6.9 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding the toxicity of acalabrutinib is not readily available. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Calquence •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Acalabrutinib is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Acalabrutinib interact? Information: •Drug A: Adalimumab •Drug B: Acalabrutinib •Severity: MAJOR •Description: The metabolism of Acalabrutinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The mean steady-state volume of distribution is approximately 34 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Reversible binding of acalabrutinib to human plasma protein is approximately 97.5%. The in vitro mean blood-to-plasma ratio is about 0.7. In vitro experiments at physiologic concentrations show that acalabrutinib can be 93.7% bound to human serum albumin and 41.1% bound to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours. The half-life of the active metabolite, ACP-5862, is about 6.9 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding the toxicity of acalabrutinib is not readily available. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Calquence •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Acalabrutinib is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Acebutolol interact?

•Drug A: Adalimumab •Drug B: Acebutolol •Severity: MODERATE •Description: The metabolism of Acebutolol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the management of hypertension and ventricular premature beats in adults. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. In general, beta-blockers reduce the work the heart has to do and allow it to beat more regularly. Acebutolol has less antagonistic effects on peripheral vascular ß2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Low doses of acebutolol produce less evidence of bronchoconstriction than nonselective agents like propranolol but more than atenolol. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 26% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The plasma elimination half-life is approximately 3 to 4 hours. The half-life of its metabolite, diacetolol, is 8 to 13 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include extreme bradycardia, advanced atrioventricular block, intraventricular conduction defects, hypotension, severe congestive heart failure, seizures, and in susceptible patients, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Sectral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acebutolol Acebutololum Acetobutolol •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Acebutolol interact? Information: •Drug A: Adalimumab •Drug B: Acebutolol •Severity: MODERATE •Description: The metabolism of Acebutolol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the management of hypertension and ventricular premature beats in adults. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. In general, beta-blockers reduce the work the heart has to do and allow it to beat more regularly. Acebutolol has less antagonistic effects on peripheral vascular ß2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Low doses of acebutolol produce less evidence of bronchoconstriction than nonselective agents like propranolol but more than atenolol. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 26% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The plasma elimination half-life is approximately 3 to 4 hours. The half-life of its metabolite, diacetolol, is 8 to 13 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include extreme bradycardia, advanced atrioventricular block, intraventricular conduction defects, hypotension, severe congestive heart failure, seizures, and in susceptible patients, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Sectral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acebutolol Acebutololum Acetobutolol •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Acenocoumarol interact?

•Drug A: Adalimumab •Drug B: Acenocoumarol •Severity: MAJOR •Description: The metabolism of Acenocoumarol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment and prevention of thromboembolic diseases. More specifically, it is indicated for the prevention of cerebral embolism, deep vein thrombosis, pulmonary embolism, thromboembolism in infarction and transient ischemic attacks. It is used for the treatment of deep vein thrombosis and myocardial infarction. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by acenocoumarol. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Acenocoumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent clotting factors, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98.7% protein bound, mainly to albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Mostly via the kidney as metabolites •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 8 to 11 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdosage, and the duration of treatment. Bleeding is the major sign of toxicity with oral anticoagulant drugs. The most frequent symptoms observed are: cutaneous bleeding (80%), haematuria (with renal colic) (52%), haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and bleeding into the joints. Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acenocoumarin Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Acenocoumarol is an anticoagulant drug used in the prevention of thromboembolic diseases in infarction and transient ischemic attacks, as well as management of deep vein thrombosis and myocardial infarction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Acenocoumarol interact? Information: •Drug A: Adalimumab •Drug B: Acenocoumarol •Severity: MAJOR •Description: The metabolism of Acenocoumarol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment and prevention of thromboembolic diseases. More specifically, it is indicated for the prevention of cerebral embolism, deep vein thrombosis, pulmonary embolism, thromboembolism in infarction and transient ischemic attacks. It is used for the treatment of deep vein thrombosis and myocardial infarction. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by acenocoumarol. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Acenocoumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent clotting factors, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98.7% protein bound, mainly to albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Mostly via the kidney as metabolites •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 8 to 11 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdosage, and the duration of treatment. Bleeding is the major sign of toxicity with oral anticoagulant drugs. The most frequent symptoms observed are: cutaneous bleeding (80%), haematuria (with renal colic) (52%), haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and bleeding into the joints. Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acenocoumarin Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Acenocoumarol is an anticoagulant drug used in the prevention of thromboembolic diseases in infarction and transient ischemic attacks, as well as management of deep vein thrombosis and myocardial infarction. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.