ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.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)] Bleeding [see Warnings and Precautions 5.2)] Thrombotic thrombocytopenic purpura [see Warnings and Precautions 5.4)] 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions and durations of follow-up, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for year or more. The clinically important adverse reactions observed in trials comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.Bleeding CUREIn CURE, clopidogrel bisulfate 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) Life-threatening and other major bleeding. Led to interruption of study medication. Event Clopidogrel bisulfate (+ aspirin) (n=6,259) Placebo (+ aspirin) (n=6,303) Major bleeding 3.72.7 Life-threatening bleeding2.21.8 Fatal0.20.2 g/dL hemoglobin drop0.90.9 Requiring surgical intervention0.70.7 Hemorrhagic strokes0.10.1 Requiring inotropes0.50.5 Requiring transfusion (>=4 units)1.21.0Other major bleeding1.61.0 Significantly disabling0.40.3 Intraocular bleeding with significant loss of vision0.050.03 Requiring to units of blood1.30.9 Minor bleeding+5.12.4. COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin (see Table 2). Table 2: Incidence of Bleeding Events in COMMIT (% patients) Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion. Type of Bleeding Clopidogrel bisulfate (+ aspirin) (n=22,961) Placebo (+ aspirin) (n=22,891) p-value Major noncerebral or cerebral bleeding Major noncerebral Fatal Hemorrhagic stroke Fatal 0.6 0.4 0.2 0.2 0.2 0.5 0.3 0.2 0.2 0.2 0.59 0.48 0.90 0.91 0.81 Other noncerebral bleeding (nonmajor) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Clopidogrel bisulfate vs Aspirin)In CAPRIE, gastrointestinal hemorrhage occurred at rate of 2.0% in those taking clopidogrel bisulfate versus 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.Other Adverse EventsIn CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of clopidogrel bisulfate. Because these reactions are reported voluntarily from population of an unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hemorrhages, including those with fatal outcome, have been reported in patients treated with clopidogrel bisulfate.Blood and lymphatic system disorders Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia Gastrointestinal disorders Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea General disorders and administration site condition Fever Hepatobiliary disorders Acute liver failure, hepatitis (noninfectious), abnormal liver function test Immune system disorders Hypersensitivity reactions, anaphylactoid reactions, serum sickness, insulin autoimmune syndrome, which can lead to severe hypoglycemia Musculoskeletal, connective tissue and bone disorders Myalgia, arthralgia, arthritis Nervous system disorders Taste disorders, headache, ageusia Psychiatric disorders Confusion, hallucinations Respiratory, thoracic and mediastinal disorders Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Renal and urinary disorders Increased creatinine levels Skin and subcutaneous tissue disorders Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, lichen planus, generalized pruritus Vascular disorders Vasculitis, hypotension Blood and lymphatic system disorders Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia . Gastrointestinal disorders Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea General disorders and administration site condition Fever Hepatobiliary disorders Acute liver failure, hepatitis (noninfectious), abnormal liver function test Immune system disorders Hypersensitivity reactions, anaphylactoid reactions, serum sickness, insulin autoimmune syndrome, which can lead to severe hypoglycemia Musculoskeletal, connective tissue and bone disorders Myalgia, arthralgia, arthritis Nervous system disorders Taste disorders, headache, ageusia Psychiatric disorders Confusion, hallucinations Respiratory, thoracic and mediastinal disorders Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Renal and urinary disorders Increased creatinine levels Skin and subcutaneous tissue disorders Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, lichen planus, generalized pruritus Vascular disorders Vasculitis, hypotension.

CLINICAL PHARMACOLOGY SECTION.

12 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 P2Y12 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 clopidogrels active metabolite are affected for the remainder of their lifespan (about 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 hours after single oral doses of clopidogrel bisulfate. Repeated doses of 75 mg clopidogrel bisulfate per day inhibit ADP induced platelet aggregation on the first day, and inhibition reaches steady state between Day and Day 7. At steady state, the average inhibition level observed with dose of 75 mg clopidogrel bisulfate per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 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 bisulfate per day, patients with severe renal impairment (creatinine clearance from 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 bisulfate 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 small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women. 12.3 Pharmacokinetics. Clopidogrel is prodrug and is metabolized to 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 foodClopidogrel bisulfate can be administered with or without food. In study in healthy male subjects when clopidogrel bisulfate 75 mg per day was given with standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC to 24 was unchanged in the presence of food, while there was 57% decrease in active metabolite max. Similar results were observed when clopidogrel bisulfate 300 mg loading dose was administered with 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 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxoclopidogrel intermediate metabolite results in formation of the active metabolite, 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 max of the active metabolite is twice as high following single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. 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 max and AUC, respectively. Elimination Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the days post dosing. After single, oral dose of 75 mg, clopidogrel has half-life of approximately hours. The half-life of the active metabolite is about 30 minutes. Drug Interactions Effect of other drugs on clopidogrelCYP2C19 inducersConcomitant 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 days with 600 mg loading dose of clopidogrel in healthy adults increased the mean AUC and Cmax of clopidogrels thiol metabolites by 3.8-fold. Mean inhibition of platelet aggregation at hours post-dose was 34% higher in the presence of rifampin compared to clopidogrel administered alone.CYP2C19 inhibitorsClopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and 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.Figure1:ExposuretoClopidogrelActiveMetaboliteFollowingMultipleDosesofclopidogreltablets75mgAloneorwithProtonPumpInhibitors(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 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and max of clopidogrels thiol metabolites by 34%. Mean platelet aggregation was higher up to to hours with morphine co-administration. Effect of clopidogrel on other drugsIn vitro studies have shown that the glucuronide metabolite of clopidogrel is strong inhibitor of CYP2C8. Concomitant administration of repaglinide with clopidogrel 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 of the maintenance dose (75 mg) of clopidogrel [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. 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 total of 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 metabolizers have one but not two nonfunctional alleles. Ultrarapid metabolizers have at least one gain-of-function allele. Inhibition of platelet aggregation with mcM ADP; larger value indicates greater platelet inhibition. Vasodilator-stimulated phosphoprotein platelet reactivity index; smaller value indicates greater platelet inhibition. Values are mean (SD). Dose Poor (n=10) Intermediate (n=10) Normal (n=10) Ultrarapid (n=10) max (ng/mL) 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) (1) 12 (5) 13 (7) 12 (6) 150 mg (Day 5) (2) 18 (7) 19 (5) 16 (9) IPA (%) 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 (%) 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).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Acute Coronary Syndrome. 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 or to at least twice the upper limit of normal. Patients were randomized to receive clopidogrel bisulfate (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 bisulfate-treated group and 719 (11.4%) in the placebo-treated group, 20% relative risk reduction (95% CI of 10% to 28%; <0.001) for the clopidogrel bisulfate-treated group (see Table 4). Table 4: Outcome Events in the CURE Primary Analysis Other standard therapies were used as appropriate. The individual components do not represent breakdown of the primary and coprimary outcomes, but rather the total number of subjects experiencing an event during the course of the study. Outcome Clopidogrel bisulfate Placebo (+ aspirin) (n=6,303) Relative Risk Reduction (%) (95% CI) (+ aspirin) (n=6,259) Primary outcome 582 (9.3%) 719 (11.4%) 20% (Cardiovascular death, MI, stroke) (10.3, 27.9) <0.001 All Individual Outcome Events: CV death 318 (5.1%) 345 (5.5%) 7% (-7.7, 20.6) MI 324 (5.2%) 419 (6.6%) 23% (11.0, 33.4) Stroke 75 (1.2%) 87 (1.4%) 14% (-17.7, 36.6) Most of the benefit of clopidogrel bisulfate 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). Figure2:CardiovascularDeath, MyocardialInfarction, andStrokeintheCUREStudyThe effect of clopidogrel bisulfate did not differ significantly in various subgroups, as shown in Figure 3. The benefits associated with clopidogrel bisulfate 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 bisulfate 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.The use of clopidogrel bisulfate in CURE was associated with decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel bisulfate 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 bisulfate group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel bisulfate 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 bisulfate group, 2,324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).COMMITIn patients with STEMI, the safety and efficacy of clopidogrel bisulfate 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.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel bisulfate (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). Fiftyfive percent (55%) of patients received thrombolytics and only 3% underwent PCI.As shown in Table and Figure and Figure below, clopidogrel bisulfate 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=0.002). Table 5: Outcome Events in COMMIT patients (2 clopidogrel and placebo) suffered both nonfatal stroke and nonfatal MI. Nonfatal MI and nonfatal stroke exclude patients who died (of any cause). Event Clopidogrel bisulfate (+ 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 (10.1%) 0.91 (0.86, 0.97) 0.002 Death Nonfatal MI Nonfatal Stroke 1,726 (7.5%) 270 (1.2%) 127 (0.6%) 1,845 (8.1%) 330 (1.4%) 142 (0.6%) 0.93 (0.87, 0.99) 0.81 (0.69, 0.95) 0.89 (0.70, 1.13) 0.029 0.011 0.33 Figure5:CumulativeEventRatesfortheCombinedEndpointRe-Infarction, StrokeorDeathintheCOMMITStudy The effect of clopidogrel bisulfate 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.. fig 2. fig 3. fig2. fig 4. fig 5. fig 6. 14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease. CAPRIEThe CAPRIE trial was 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing clopidogrel bisulfate (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 months) with at least 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 years).The trials 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 PatientsClopidogrel bisulfateAspirin n=9,599 n=9,586 Ischemic stroke (fatal or not) 438 (4.6%) 461 (4.8%) MI (fatal or not) 275 (2.9%) 333 (3.5%) Other vascular death 226 (2.4%) 226 (2.4%) Total 939 (9.8%) 1,020 (10.6%) As shown in Table 6, clopidogrel bisulfate was associated with lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel bisulfate 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.Figure7:FatalorNonfatalVascularEventsintheCAPRIEStudyThe statistical significance favoring clopidogrel bisulfate over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel bisulfate is substantial. The CAPRIE trial enrolled population that had recent MI, recent stroke, or PAD. The efficacy of clopidogrel bisulfate relative to aspirin was heterogeneous across these subgroups (p=0.043) (see Figure 8). Nonetheless, this difference may be chance occurrence because the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel bisulfate 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 recent myocardial infarction, clopidogrel bisulfate was not numerically superior to aspirin.Figure 8: Hazard Ratio and 95% CI by Baseline Subgroups in the CAPRIE Study. fig 8. fig 5. 14.3 No Demonstrated Benefit of clopidogrel bisulfate plus Aspirin in Patients withMultiple Risk Factors or Established Vascular Disease. CHARISMA The CHARISMA trial was 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel bisulfate (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 reduction in the occurrence of the primary endpoint, composite of CV death, MI, or stroke. total of 534 (6.9%) patients in the clopidogrel bisulfate group versus 573 (7.4%) patients in the placebo group experienced primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel bisulfate.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. 7.1) Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. 7.2) Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. 7.4, 7.5, 7.6) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. 7.7) CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. 7.1) Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. 7.2) Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. 7.4, 7.5, 7.6) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. 7.7) 7.1 CYP2C19 Inducers. 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 precaution, avoid concomitant use of strong CYP2C19 inducers [see Warnings and Precautions 5.1) and Clinical Pharmacology 12.3)]. 7.2 CYP2C19 Inhibitors. 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 reduction in platelet inhibition [see Warnings and Precautions 5.1)] Omeprazole or EsomeprazoleAvoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel bisulfate when given concomitantly or 12 hours apart. similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel bisulfate. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole [see Warnings and Precautions 5.1) and Clinical Pharmacology 12.3)]. 7.3 Opioids. As with other oral P2Y 12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to its metabolites [see Clinical Pharmacology 12.3)] Consider the use of parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists. 7.4 Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Coadministration of clopidogrel bisulfate and NSAIDs increases the risk of gastrointestinal bleeding. 7.5 Warfarin (CYP2C9 Substrates). 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 bisulfate with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. 7.6 SSRIs and SNRIs. 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.. 7.7 Repaglinide (CYP2C8 Substrates). The acyl--glucuronide metabolite of clopidogrel is strong inhibitor of CYP2C8. Clopidogrel bisulfate can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring.Clopidogrel bisulfate increased repaglinide exposures by 3.9-fold to 5.1-fold [see Clinical Pharmacology 12.3)]. Avoid concomitant use of repaglinide with clopidogrel bisulfate. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed total daily dose of mg. Increased frequency of glucose monitoring may be required during concomitant use.

SPL MEDGUIDE SECTION.

SPL MEDGUIDE. Medication Guide Clopidogrel (kloe PID oh grel) Tablets, USPRead this Medication Guide before you start taking clopidogrel tablets and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.What is the most important information should know about clopidogrel tablets 1. Clopidogrel tablets may not work as well in people who: have certain genetic factors that affect how the body breaks down clopidogrel tablets. Your doctor may do genetic tests to make sure clopidogrel tablets are right for you. take certain medicines, especially omeprazole (Prilosec(R)) or esomeprazole (Nexium(R)). Your doctor may change the medicine you take for stomach acid problems while you take clopidogrel tablets. 2. Clopidogrel tablets can cause bleeding which can be serious and can sometimes lead to death. Clopidogrel tablets are blood thinner medicine that lowers the chance of blood clots forming in your body. While you take clopidogrel tablets: you may bruise and bleed more easilyyou are more likely to have nose bleedsit will take longer for any bleeding to stopCall your doctor right away if you have any of these signs or symptoms of bleeding:unexpected bleeding or bleeding that lasts long timeblood in your urine (pink, red or brown urine)red or black stools (looks like tar)bruises that happen without known cause or get largercough up blood or blood clotsvomit blood or your vomit looks like coffee groundsDo not stop taking clopidogrel tablets without talking to the doctor who prescribes it for you. People who stop taking clopidogrel tablets too soon have higher risk of having heart attack or dying. If you must stop clopidogrel tablets because of bleeding, your risk of heart attack may be higher.What are clopidogrel tablets Clopidogrel tablets are prescription medicine used to treat people who have any of the following:chest pain due to heart problemspoor circulation in their legs (peripheral arterial disease)a heart attacka strokeClopidogrel tablets are used alone or with aspirin to lower your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clot that can lead to death.Platelets are blood cells that help your blood clot normally. Clopidogrel tablets help to prevent platelets from sticking together and forming clot that can block an artery.It is not known if clopidogrel tablets are safe and effective in children.Who should not take clopidogrel tablets Do not take clopidogrel tablets if you:currently have condition that causes bleeding, such as stomach ulcerare allergic to clopidogrel or other ingredients in clopidogrel tablets. See the end of this leaflet for complete list of ingredients in clopidogrel tablets.What should tell my doctor before taking clopidogrel tablets Before you take clopidogrel tablets, tell your doctor if you:have history of bowel (gastrointestinal) or stomach ulcershave history of bleeding problemsplan to have surgery or dental procedure. See How should take clopidogrel tablets are pregnant or plan to become pregnant. It is not known if clopidogrel tablets will harm your unborn babyare breastfeeding or plan to breastfeed. It is not known if clopidogrel bisulfate passes into your breast milk. decision should be made with your healthcare provider to avoid or discontinue breastfeeding when continuing clopidogrel tablets is needed.have had an allergy or reaction to any medicine used to treat your disease.Tell all of your doctors and your dentist that you are taking clopidogrel tablets. They should talk to the doctor who prescribed clopidogrel tablets for you before you have any surgery or invasive procedure.Tell your doctor about all the medicines you take, including prescription, non-prescription medicines, vitamins and herbal supplements. Clopidogrel tablets may affect the way other medicines work, and other medicines may affect how clopidogrel tablets work. See What is the most important information should know about clopidogrel tablets Clopidogrel tablets may increase blood levels of other medicines such as repaglinide (Prandin (R)). Taking clopidogrel tablets with certain other medicines may increase your risk of bleeding. Especially tell your doctor if you take: aspirin, especially if you have had stroke. Always talk to your doctor about whether you should take aspirin along with clopidogrel tablets to treat your condition.Non-steroidal anti-inflammatory drugs (NSAIDs). Ask your doctor or pharmacist for list of NSAID medicines if you are not sure.warfarin (Coumadin (R), Jantoven (R)). selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Ask your doctor or pharmacist for list of SSRI or SNRI medicines if you are not sure.rifampin (used to treat severe infections)Know the medicines you take. Keep list of them to show your doctor or pharmacist when you get new medicine.How should take clopidogrel tablets .Take clopidogrel tablets exactly as your doctor tells you.Do not change your dose or stop taking clopidogrel tablets without talking to your doctor first. Stopping clopidogrel tablets may increase your risk of heart attack or stroke.Take clopidogrel tablets with aspirin as instructed by your doctor.If you miss dose, take clopidogrel tablets as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose at your regular time. Do not take doses of clopidogrel tablets at the same time unless your doctor tells you to.If you take too much clopidogrel tablets, call your doctor or go to the nearest emergency room right away.Talk with your doctor about stopping your clopidogrel tablets before you have surgery. Your doctor may tell you to stop taking clopidogrel tablets at least days before you have surgery to avoid excessive bleeding during surgery.What are the possible side effects of clopidogrel tablets Clopidogrel tablets can cause serious side effects including: See What is the most important information should know about clopidogrel tablets blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can happen with clopidogrel tablets, sometimes after short time (less than weeks). TTP is blood clotting problem where blood clots form in blood vessels; and can happen anywhere in the body. TTP needs to be treated in hospital right away, because it may cause death. Get medical help right away if you have any of these symptoms and they can not be explained by another medical condition: purplish spots (called purpura) on the skin or in the mouth (mucous membranes) due to bleeding under the skinyour skin or the whites of your eyes are yellow (jaundice)you feel tired or weakyour skin looks very palefeverfast heart rate or feeling short of breathheadachespeech changesconfusioncomastrokeseizurelow amount of urine, or urine that is pink or has blood in itstomach area (abdominal) painnausea, vomiting, or diarrheavision changes.persistent low blood sugar symptomsTell your doctor if you have any side effect that bothers you or that does not go away. Tell your doctor if you develop an allergic reaction including skin reactions while taking clopidogrel tablets.These are not all the possible side effects of clopidogrel tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store clopidogrel tablets Store clopidogrel tablets at 20 to 25 (68 to 77 F); excursions permitted to 15 to 30 (59 to 86 F) [See USP Controlled Room Temperature].Keep clopidogrel tablets and all medicines out of the reach of children. General information about clopidogrel tablets Medicines are sometimes used for purposes other than those listed in Medication Guide. Do not take clopidogrel tablets for condition for which they were not prescribed. Do not give clopidogrel tablets to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about clopidogrel tablets. If you would like more information, talk to your doctor. Ask your doctor or pharmacist for information about clopidogrel tablets that was written for healthcare professionals.For more information, call Torrent Pharma Inc. at 1-800-912-9561.What are the ingredients in clopidogrel tablets Active ingredient: clopidogrel bisulfate, USP Inactive ingredients: Tablet: colloidal silicon dioxide, hydrogenated castor oil, lactose monohydrate, low substituted hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose and polyethylene glycol 6000Film coating: ferric oxide red, hypromellose 2910, and titanium dioxideThis Medication Guide has been approved by the U.S. Food and Drug Administration.Trade marks are the property of their respective owners.Manufactured by:TORRENT PHARMACEUTICALS LTD., INDIA.Manufactured for:TORRENT PHARMA INC., Levittown, PA 19057.8083249 Revised August 2021. have certain genetic factors that affect how the body breaks down clopidogrel tablets. Your doctor may do genetic tests to make sure clopidogrel tablets are right for you. take certain medicines, especially omeprazole (Prilosec(R)) or esomeprazole (Nexium(R)). Your doctor may change the medicine you take for stomach acid problems while you take clopidogrel tablets. you may bruise and bleed more easily. you are more likely to have nose bleeds. it will take longer for any bleeding to stop. unexpected bleeding or bleeding that lasts long time. blood in your urine (pink, red or brown urine). red or black stools (looks like tar). bruises that happen without known cause or get larger. cough up blood or blood clots. vomit blood or your vomit looks like coffee grounds. chest pain due to heart problems. poor circulation in their legs (peripheral arterial disease). heart attack. stroke. currently have condition that causes bleeding, such as stomach ulcer. are allergic to clopidogrel or other ingredients in clopidogrel tablets. See the end of this leaflet for complete list of ingredients in clopidogrel tablets.. have history of bowel (gastrointestinal) or stomach ulcers. have history of bleeding problems. plan to have surgery or dental procedure. See How should take clopidogrel tablets . are pregnant or plan to become pregnant. It is not known if clopidogrel tablets will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if clopidogrel bisulfate passes into your breast milk. decision should be made with your healthcare provider to avoid or discontinue breastfeeding when continuing clopidogrel tablets is needed.. have had an allergy or reaction to any medicine used to treat your disease.. aspirin, especially if you have had stroke. Always talk to your doctor about whether you should take aspirin along with clopidogrel tablets to treat your condition.. Non-steroidal anti-inflammatory drugs (NSAIDs). Ask your doctor or pharmacist for list of NSAID medicines if you are not sure.. warfarin (Coumadin (R), Jantoven (R)). selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Ask your doctor or pharmacist for list of SSRI or SNRI medicines if you are not sure.. rifampin (used to treat severe infections). Take clopidogrel tablets exactly as your doctor tells you.. Do not change your dose or stop taking clopidogrel tablets without talking to your doctor first. Stopping clopidogrel tablets may increase your risk of heart attack or stroke.. Take clopidogrel tablets with aspirin as instructed by your doctor.. If you miss dose, take clopidogrel tablets as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose at your regular time. Do not take doses of clopidogrel tablets at the same time unless your doctor tells you to.. If you take too much clopidogrel tablets, call your doctor or go to the nearest emergency room right away.. Talk with your doctor about stopping your clopidogrel tablets before you have surgery. Your doctor may tell you to stop taking clopidogrel tablets at least days before you have surgery to avoid excessive bleeding during surgery.. See What is the most important information should know about clopidogrel tablets A blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can happen with clopidogrel tablets, sometimes after short time (less than weeks). TTP is blood clotting problem where blood clots form in blood vessels; and can happen anywhere in the body. TTP needs to be treated in hospital right away, because it may cause death. Get medical help right away if you have any of these symptoms and they can not be explained by another medical condition: purplish spots (called purpura) on the skin or in the mouth (mucous membranes) due to bleeding under the skin. your skin or the whites of your eyes are yellow (jaundice). you feel tired or weak. your skin looks very pale. fever. fast heart rate or feeling short of breath. headache. speech changes. confusion. coma. stroke. seizure. low amount of urine, or urine that is pink or has blood in it. stomach area (abdominal) pain. nausea, vomiting, or diarrhea. vision changes.. persistent low blood sugar symptoms. Store clopidogrel tablets at 20 to 25 (68 to 77 F); excursions permitted to 15 to 30 (59 to 86 F) [See USP Controlled Room Temperature].. 1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable 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].There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke [see Clinical Considerations]. No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defects, loss, or other adverse outcomes. In the U.S. 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 ConsiderationsDisease-associated maternal and/or embryo/fetal riskMyocardial 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 deliveryClopidogrel 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 to days prior to labor, delivery, or neuraxial blockade.DataHuman dataThe 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 dataEmbryo-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 mg/m basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. 8.2 Lactation. Risk SummaryThere 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 small number of postmarketing cases. Studies in rats have shown that clopidogrel and/or its metabolites are present in the milk. When 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 mothers clinical need for clopidogrel and any potential adverse effects on the breastfed infant from clopidogrel or from underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in the pediatric population have not been established. randomized, placebo-controlled trial (CLARINET) did not demonstrate clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with 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 trial with different design would demonstrate clinical benefit in this patient population.. 8.5 Geriatric Use. Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel bisulfate were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel bisulfate were 60 years and older, 26% of whom were 70 years and older.The observed risk of bleeding events with clopidogrel bisulfate plus aspirin versus placebo plus aspirin by age category is provided in Table and Table for the CURE and COMMIT trials, respectively [see Adverse Reactions 6.1)] No dosage adjustment is necessary in elderly patients. 8.6 Renal Impairment. Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology 12.2)]. 8.7 Hepatic Impairment. No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology 12.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. CYP2C19 function: 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 days prior to elective surgery that has major risk of bleeding. 5.3) Thrombotic thrombocytopenic purpura (TTP) has been reported 5.4) Cross-reactivity among thienopyridines has been reported. 5.5) CYP2C19 function: 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 days prior to elective surgery that has 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 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. P2Y12 inhibitors (Thienopyridines), including clopidogrel bisulfate, increase the risk of bleeding.P2Y12 inhibitors (Thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days). Because the half-life of clopidogrels active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within hours of the loading dose or hours of the maintenance dose may be less effective.Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As precaution, avoid concomitant use of strong CYP2C19 inducers [see Drug Interactions 7.1) and Clinical Pharmacology 12.3)]. 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 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 short exposure (<2 weeks). TTP is 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 has been reported in patients receiving clopidogrel bisulfate, including patients with history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications 4.2) and Adverse Reactions 6.2)].