clopidogrel 75 MG Oral Tablet [Plavix]

INDICATIONS AND USAGE Clopidogrel tablets USP are a P2Y 12 platelet inhibitor indicated for: • Acute coronary syndrome • For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], clopidogrel tablets USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. ( 1.1 ) • For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary PCI is unknown. ( 1.1 ) • Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel tablets USP have been shown to reduce the combined endpoint of new ischemic stroke, new MI, and other vascular death. ( 1.2 ) 1.1 Acute Coronary Syndrome (ACS) • For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel tablets USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. • For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown. The optimal duration of clopidogrel tablet USP therapy in ACS is unknown. 1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel tablets USP have been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

DOSAGE AND ADMINISTRATION • Acute coronary syndrome ( 2.1 ) • UA/NSTEMI: 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75 to 325 mg once daily) • STEMI: 75 mg once daily, in combination with aspirin (75 to 325 mg once daily), with or without a loading dose • Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily ( 2.2 ) 2.1 Acute Coronary Syndrome Clopidogrel tablets can be administered with or without food [ see Clinical Pharmacology ( 12.3 ) ]. • For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 to 325 mg once daily) and continue in combination with clopidogrel tablets [ see Clinical Studies ( 14.1 ) ]. • For patients with STEMI, the recommended dose of clopidogrel tablets is 75 mg once daily orally, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets may be initiated with or without a loading dose [ see Clinical Studies ( 14.1 ) ]. 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease The recommended daily dose of clopidogrel tablets is 75 mg once daily orally, with or without food [ see Clinical Pharmacology ( 12.3 ) ]. 2.3 CYP2C19 Poor Metabolizers CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response [ see Clinical Pharmacology ( 12.5 ) ], an appropriate dose regimen for this patient population has not been established. 2.4 Use With Proton Pump Inhibitors (PPI) Avoid using omeprazole or esomeprazole with clopidogrel tablets. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel tablets. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite [ see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 ) ].

WARNINGS AND PRECAUTIONS CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. (5.1) Bleeding: Clopidogrel bisulfate increases risk of bleeding. (5.2) Discontinuation: Premature discontinuation increases risk of cardiovascular events. Discontinue 5 days prior to elective surgery that has a major risk of bleeding. ( 5.3 ) Thrombotic thrombocytopenic purpura (TTP) has been reported. ( 5.4 ) Cross-reactivity among thienopyridines has been reported. ( 5.5 ) 5.1 Diminished Antiplatelet Activity in Patients with Impaired CYP2C19 Function Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 . The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel bisulfate . Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 [see Boxed Warning ] . The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel bisulfate [see Drug Interactions (7.1) ] . 5.2 General Risk of Bleeding Thienopyridines, including clopidogrel bisulfate, increase risk of bleeding. Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days). Because the half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. Thienopyridines, including clopidogrel bisulfate, increase the risk of bleeding. Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days). Because the half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. 5.3 Discontinuation of Clopidogrel Bisulfate Discontinuation of clopidogrel bisulfate increases the risk of cardiovascular events. If clopidogrel bisulfate must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding), restart it as soon as possible. When possible, interrupt therapy clopidogrel bisulfate for five days prior to such surgery. Resume clopidogrel bisulfate as soon as hemostasis is achieved. Discontinuation of clopidogrel bisulfate increases the risk of cardiovascular events. If clopidogrel bisulfate must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding), restart it as soon as possible. When possible, interrupt therapy with clopidogrel bisulfate for five days prior to such surgery. Resume clopidogrel bisulfate as soon as hemostasis is achieved. 5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions (6.2) ]. 5.5 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel bisulfate, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications (4.2) and Adverse Reactions (6.2) ] .

CONTRAINDICATIONS • Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4.1 ) • Hypersensitivity to clopidogrel or any component of the product ( 4.2 ) 4.1 Active Bleeding Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions ( 6.2 )] .

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets. 12.2 Pharmacodynamics Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel tablets. Repeated doses of 75 mg clopidogrel tablets per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel tablets per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Geriatric Patients Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation. Renally Impaired Patients After repeated doses of 75 mg clopidogrel tablets per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation. Hepatically Impaired Patients After repeated doses of 75 mg clopidogrel tablets per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. Gender In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women. 12.3 Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites. Absorption After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Effect of food Clopidogrel tablets can be administered with or without food. In a study in healthy male subjects when clopidogrel tablets 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC 0to24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max . Similar results were observed when a clopidogrel tablets 300 mg loading dose was administered with a high-fat breakfast. Metabolism Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxoclopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet. The C max of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. C max occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the C max and AUC, respectively. Elimination Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes. Drug Interactions Effect of other drugs on clopidogrel tablets Clopidogrel is metabolized to its active metabolite in part by CYP2C19. CYP2C19 inducers Concomitant use of strong inducers of CYP2C19 results in increased plasma concentration of the active metabolite of clopidogrel and an increase in platelet inhibition. Rifampin: Coadministration of rifampin 300 mg twice daily for 7 days with 600 mg loading dose of clopidogrel in healthy adults increased the mean AUC and Cmax of clopidogrel’s thiol metabolites by 3.8-fold. Mean inhibition of platelet aggregation at 4 hours post dose was 34% higher in the presence of rifampin compared to clopidogrel administered alone. CYP2C19 inhibitors Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Proton pump inhibitors (PPI) The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel tablets 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1. Figure 1: Exposure to Clopidogrel Active Metabolite Following Multiple Doses of clopidogrel tablets 75 mg Alone or with Proton Pump Inhibitors (PPIs) Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole. Opioids Co-administration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and C max of clopidogrel's thiol metabolites by 34%. Mean platelet aggregation was higher up to 2 to 4 hours with morphine co-administration. Effect of clopidogrel tablets on other drugs In vitro studies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Concomitant administration of repaglinide with clopidogrel tablets increased the systemic exposure to repaglinide (AUC 0-∞ ) by 5.1-fold following the loading dose (300 mg) and by 3.9- fold on day 3 of the maintenance dose (75 mg) of clopidogrel tablets [see Drug Interactions ( 7.6 )] . fig 1 12.5 Pharmacogenomics CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed "CYP2C19 poor metabolizers." Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to identify patients who are CYP2C19 poor metabolizers. A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19 Metabolizer Status * Intermediate metaboliz