CLOPIDOGREL BISULFATE- clopidogrel bisulfate_tablet

Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 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 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. 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 max 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 max max Elimination Following an oral dose of 14 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. 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 Effect of clopidogrel tablets on other drugs In vitro 0-infinity [see Drug Interactions ( 7. 6 fig 1 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 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 * dagger double dagger section Values are mean (SD). Dose Poor (n=10) Intermediate * (n=10) Normal (n=10) Ultrarapid dagger (n=10) C max 300 mg (24 h) 11 (4) 23 (11) 32 (21) 24 (10) 600 mg (24 h) 17 (6) 39 (23) 44 (27) 36 (13) 75 mg (Day 5) 4 (1) 12 (5) 13 (7) 12 (6) 150 mg (Day 5) 7 (2) 18 (7) 19 (5) 16 (9) IPA (%) double dagger 300 mg (24 h) 24 (26) 37 (21) 39 (28) 40 (21) 600 mg (24 h) 32 (25) 56 (22) 49 (23) 51 (28) 75 mg (Day 5) 37 (23) 60 (18) 58 (19) 56 (13) 150 mg (Day 5) 61 (14) 74 (14) 73 (9) 68 (18) VASP-PRI (%) section 300 mg (24 h) 91 (12) 78 (12) 68 (16) 73 (12) 600 mg (24 h) 85 (14) 56 (26) 48 (20) 51 (20) 75 mg (Day 5) 83 (13) 50 (16) 39 (14) 40 (9) 150 mg (Day 5) 61 (18) 29 (11) 24 (10) 20 (10).

Clopidogrel tablets are P2Y 12 Acute coronary syndrome en dash For patients with nonen dashST-segment elevation ACS (unstable angina [UA]/nonen dashST-elevation myocardial infarction [NSTEMI]), clopidogrel tablets have been shown to reduce the rate of myocardial infarction (MI) and stroke. 1 en dash For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets have been shown to reduce the rate of MI and stroke. 1 Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel tablets have been shown to reduce the rate of MI and stroke. 2 Clopidogrel tablets are indicated to reduce the rate of myocardial infarction (MI) and stroke in patients with nonen dashST-segment elevation ACS (unstable angina [UA]/nonen dashST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. Clopidogrel tablets should be administered in conjunction with aspirin. Clopidogrel tablets are indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke clopidogrel tablets are indicated to reduce the rate of MI and stroke.

Acute coronary syndrome ( 2. 1 en dash Initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. en dash Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days. Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose. 2 In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology ( 12. 1 75 mg once daily orally without a loading dose [see Clinical Pharmacology ( 12.

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. 1 To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. The following serious adverse reactions are discussed below and elsewhere in the labeling: Bleeding [see Warnings and Precautions ( 5. 2 Thrombotic thrombocytopenic purpura [see Warnings and Precautions ( 5. 4 Because clinical trials are conducted under widely varying conditions and durations of follow-up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clopidogrel tablets has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing clopidogrel tablets plus aspirin to placebo plus aspirin and trials comparing clopidogrel tablets alone to aspirin alone are discussed below. Bleeding CURE In CURE, clopidogrel tablets use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0. 1%) and fatal bleeding (0. 2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise. The overall incidence of bleeding is described in Table 1. Table 1: CURE Incidence of Bleeding Complications (% patients) * dagger Event Clopidogrel tablets (+ aspirin) (n=6,259) Placebo (+ aspirin) (n=6,303) Major bleeding 3. 7 Life-threatening bleeding 2. 2 5 g/dL hemoglobin drop 0. 9 Requiring surgical intervention 0. 7 Hemorrhagic strokes 0. 1 Requiring inotropes 0. 5 Requiring transfusion (>=4 units) 1. 0 Other major bleeding 1. 0 Significantly disabling 0. 3 Intraocular bleeding with significant loss of vision 0. 03 Requiring 2 to 3 units of blood 1. 9 Minor bleeding dagger 5. 4 COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel tablets and placebo groups, both of which also received aspirin (see Table 2). Table 2: Incidence of Bleeding Events in COMMIT (% patients) * Type of Bleeding Clopidogrel tablets (+ aspirin) (n=22,961) Placebo (+ aspirin) (n=22,891) p-value Major* noncerebral or cerebral bleeding 0. 59 Other noncerebral bleeding (nonmajor) 3. 005 Any noncerebral bleeding 3. 004 CAPRIE (Clopidogrel tablets vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2. 0% in those taking clopidogrel tablets versus 2. 7% in those taking aspirin; bleeding requiring hospitalization occurred in 0. 1%, respectively. The incidence of intracranial hemorrhage was 0. 4% for clopidogrel tablets compared to 0. 5% for aspirin. Other bleeding events that were reported more frequently in the clopidogrel tablets group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared clopidogrel tablets plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel tablets and placebo. In CAPRIE, which compared clopidogrel tablets to aspirin, pruritus was more frequently reported in those taking clopidogrel tablets. No other difference in the rate of adverse events (other than bleeding) was reported. The following adverse reactions have been identified during postapproval use of clopidogrel tablets. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hemorrhages, including those with fatal outcome, have been reported in patients treated with clopidogrel tablets. Blood and lymphatic system disorders Gastrointestinal disorders General disorders and administration site condition Hepatobiliary disorders Immune system disorders Musculoskeletal, connective tissue and bone disorders Nervous system disorders Psychiatric disorders Respiratory, thoracic and mediastinal disorders Renal and urinary disorders Skin and subcutaneous tissue disorders Vascular disorders.

Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4. 1 Hypersensitivity to clopidogrel or any component of the product ( 4. 2 Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. Clopidogrel tablets are contraindicated in patients with hypersensitivity (e. , anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions ( 6.

Risk Summary Available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage [see Data] [see Clinical Considerations [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction and stroke are medical emergencies. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus. Labor or delivery Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage. Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma. When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade. Data Human data The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes. Animal data Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to 500 and 300 mg/kg/day, respectively, administered during organogenesis. These doses, corresponding to 65 and 78 times the recommended daily human dose, respectively, on a mg/m 2 Risk Summary There are no data on the presence of clopidogrel in human milk or the effects on milk production. No adverse effects on breastfed infants have been observed with maternal clopidogrel use during lactation in a small number of postmarketing cases. Studies in rats have shown that clopidogrel and/or its metabolites are present in the milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for clopidogrel tablets and any potential adverse effects on the breastfed infant from clopidogrel tablets or from underlying maternal condition. Safety and effectiveness in pediatric populations have not been established. A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin, and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population. Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel tablets were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel tablets were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with clopidogrel tablets plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions ( 6. 1 Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology ( 12. 2 No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology ( 12.

CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. 1 Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. 3 Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. 6 Other Antiplatelet Agents: Increases the risk of bleeding due to an additive effect. 7 Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. 8 Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Warnings and Precautions ( 5. 3 Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Warnings and Precautions ( 5. 1 Omeprazole or Esomeprazole Avoid concomitant use of clopidogrel tablets with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel tablets when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel tablets. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel tablets than did omeprazole or esomeprazole [see Warnings and Precautions ( 5. 3 As with other oral P2Y 12 [see Clinical Pharmacology ( 12. 3 Coadministration of clopidogrel tablets and NSAIDs increases the risk of gastrointestinal bleeding. Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel tablets with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitr Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding. Coadministration of antiplatelet agents increase the risk of bleeding due to an additive effect. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with other antiplatelet agents [see Warnings and Precautions (5. 2 The acyl-beta-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Clopidogrel tablets can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring. Clopidogrel tablets increased repaglinide exposures by 3. 9-fold to 5. 1-fold [see Clinical Pharmacology ( 12.

OVERDOSAGE
Platelet inhibition by clopidogrel tablets is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1,500 or 2,000 mg/kg was lethal to mice and to rats and at 3,000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals. Based on biological plausibility, platelet transfusion may restore clotting ability.
NONCLINICAL TOXICOLOGY
There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg. Clopidogrel was not genotoxic in four in vitro in vivo Clopidogrel was found to have no effect on fertility of male and female rats treated prior to pairing and throughout gestationat oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m 2
CLINICAL STUDIES
CURE The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomized to receive clopidogrel tablets (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization. The patient population was largely White (82%) and included 38% women, and 52% age >=65 years of age. Only about 20% of patients underwent revascularization during the initial hospitalization and few underwent emergent or urgent revascularization. The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9. 3%) in the clopidogrel tablets-treated group and 719 (11. 4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p <0. 001) for the clopidogrel tablets-treated group (see Table 4). Table 4: Outcome Events in the CURE Primary Analysis * dagger Outcome Clopidogrel Placebo (+ aspirin) * (n=6,303) Relative Risk Reduction (%) (95% CI) tablets (+ aspirin) * (n=6,259) Primary outcome 582 (9. 3%) 719 (11. 4%) 20% (Cardiovascular death, MI, stroke) (10. 9) All Individual Outcome Events: dagger CV death 318 (5. 6) MI 324 (5. 6%) 23% (11. 4) Stroke 75 (1. 4%) 14% (-17. 6) Most of the benefit of clopidogrel tablets occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 2). Figure 2: Cardiovascular Death Myocardial Infarction and Stroke in the CURE Study The effect of clopidogrel tablets did not differ significantly in various subgroups, as shown in Figure 3. The benefits associated with clopidogrel tablets were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE inhibitors. The efficacy of clopidogrel tablets was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, nonstudy antiplatelet drugs, and chronic NSAIDs was not allowed in CURE. Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study (continued) The use of clopidogrel tablets in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1. 1%] in the clopidogrel tablets group, 126 patients [2. 0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5. 9%] in the clopidogrel tablets group, 454 patients [7. 2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel tablets in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting) (2,253 patients [36. 0%] in the clopidogrel tablets group, 2,324 patients [36. 9%] in the placebo group; relative risk reduction of 4. COMMIT In patients with STEMI, the safety and efficacy of clopidogrel tablets were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i. , ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel tablets (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first. The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The patient population was 28% women and 58% age >=60 years (26% age >=70 years). Fifty-five percent (55%) of patients received thrombolytics and only 3% underwent PCI. As shown in Table 5 and Figure 4 and Figure 5 below, clopidogrel tablets significantly reduced the relative risk of death from any cause by 7% (p=0. 029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0. Table 5: Outcome Events in COMMIT * dagger Event Clopidogrel tablets (+ aspirin) (N=22,961) Placebo (+ aspirin) (N=22,891) Odds ratio (95% CI) p-value Composite endpoint: Death MI or Stroke * 2,121 (9. 2%) 2,310 (10. 002 Death dagger dagger 1,726 (7. 5%) 1,845 (8. 029 Figure 4: Cumulative Event Rates for Death in the COMMIT Study * Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction Stroke or Death in the COMMIT Study * The effect of clopidogrel tablets did not differ significantly in various prespecified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously. Figure 6: Effects of Adding Clopidogrel Tablets to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study fig 2 fig 3 fig3-a fig 4 fig 5 fig 6 CAPRIE The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing clopidogrel tablets (75 mg daily) to aspirin (325 mg daily). To be eligible to enroll, patients had to have: 1) recent history of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; and/or 3) established peripheral arterial disease (PAD). Patients received randomized treatment for an average of 1. 6 years (maximum of 3 years). The trial''s primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular. Table 6: Outcome Events in the CAPRIE Primary Analysis Patients Clopidogrel tablets Aspirin n=9,599 n=9,586 Ischemic stroke (fatal or not) 438 (4. 8%) MI (fatal or not) 275 (2. 5%) Other vascular death 226 (2. 4%) Total 939 (9. 8%) 1,020 (10. 6%) As shown in Table 6, clopidogrel tablets was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6. In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel tablets group. The curves showing the overall event rate are shown in Figure 7. The event curves separated early and continued to diverge over the 3-year follow-up period. Figure 7: Fatal or Nonfatal Vascular Events in the CAPRIE Study The statistical significance favoring clopidogrel tablets over aspirin was marginal (p=0. However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel tablets is substantial. The CAPRIE trial enrolled a population that had recent MI, recent stroke, or PAD. The efficacy of clopidogrel tablets relative to aspirin was heterogeneous across these subgroups (p=0. 043) (see Figure 8). Nonetheless, this difference may be a chance occurrence because the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel tablets over aspirin in the individual patient subgroups. The benefit was most apparent in patients who were enrolled because of peripheral arterial disease and less apparent in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel tablets was not numerically superior to aspirin. Figure 8: Hazard Ratio and 95% CI by Baseline Subgroups in the CAPRIE Study fig 8 fig 5 CHARISMA The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel tablets (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6. 9%) patients in the clopidogrel tablets group versus 573 (7. 4%) patients in the placebo group experienced a primary outcome event (p=0. Bleeding of all severities was more common in the subjects randomized to clopidogrel tablets.

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CLOPIDOGREL BISULFATE- clopidogrel bisulfate_tablet Product manual source documgent