ntiate the risk of bleeding. as a 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 a reduction in platelet inhibition [see warnings and precautions (5.1) ] . omeprazole or esomeprazole avoid 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. a 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 a 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 other antiplatelet agents 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) ] . 7.8 repaglinide (cyp2c8 substrates) the acyl-?-glucuronide metabolite of clopidogrel is a 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 a total daily dose of 4 mg. increased frequency of glucose monitoring may be required during concomitant use.

lopidogrel 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. clopidogrel tablets should be administered in conjunction with aspirin. 1.2 recent mi, recent stroke, or established peripheral arterial disease 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.

because both significantly reduce the antiplatelet activity of clopidogrel bisulfate [see drug interactions (7.2) ] . 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 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. 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 a precaution, avoid concomitant use of strong cyp2c19 inducers [see drug interactions (7.1) and clinical pharmacology (12.3) ] . risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of nsaids) [see drug interactions (7.4 , 7.5 , 7.6 , 7.7) ] . 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 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 has 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) ] .

ed in trials comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below. bleeding cure in 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) event clopidogrel bisulfate (+ aspirin) (n=6259) placebo (+ aspirin) (n=6303) * life-threatening and other major bleeding. † led to interruption of study medication. major bleeding * 3.7 2.7 life-threatening bleeding 2.2 1.8 fatal 0.2 0.2 5 g/dl hemoglobin drop 0.9 0.9 requiring surgical intervention 0.7 0.7 hemorrhagic strokes 0.1 0.1 requiring inotropes 0.5 0.5 requiring transfusion (?4 units) 1.2 1 other major bleeding 1.6 1 significantly disabling 0.4 0.3 intraocular bleeding with significant loss of vision 0.05 0.03 requiring 2 to 3 units of blood 1.3 0.9 minor bleeding † 5.1 2.4 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) type of bleeding clopidogrel bisulfate (+ aspirin) (n=22961) placebo (+ aspirin) (n=22891) p-value * major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion. major* noncerebral or cerebral bleeding 0.6 0.5 0.59 major noncerebral 0.4 0.3 0.48 fatal 0.2 0.2 0.90 hemorrhagic stroke 0.2 0.2 0.91 fatal 0.2 0.2 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 a rate of 2% 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 events in 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 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 bisulfate. blood and lymphatic system disorders: agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (ttp), acquired hemophilia a 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

ntiate the risk of bleeding. as a 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 a reduction in platelet inhibition [see warnings and precautions (5.1) ] . omeprazole or esomeprazole avoid 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. a 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 a 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 other antiplatelet agents 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) ] . 7.8 repaglinide (cyp2c8 substrates) the acyl-?-glucuronide metabolite of clopidogrel is a 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 a total daily dose of 4 mg. increased frequency of glucose monitoring may be required during concomitant use.

vely. 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 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. 8.2 lactation 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 bisulfate and any potential adverse effects on the breastfed infant from clopidogrel bisulfate or from underlying maternal condition. 8.4 pediatric use 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. 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 1 and table 2 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) ] .

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 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel.

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 3 and day 7. at steady state, the average inhibition level observed with a 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 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 bisulfate 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 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 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 bisulfate can be administered with or without food. in a study in healthy male subjects when clopidogrel bisulfate 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 0-24 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 bisulfate 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-oxo-clopidogrel 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-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 bisulfate 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 c max 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 bisulfate 75 mg evaluated in dedicated drug interaction studies is presented in figure 1. pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole. opioids coadministration 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 coadministration. effect of clopidogrel bisulfate 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 bisulfate 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 bisulfate [see drug interactions (7.7) ] . figure 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 metabolizers have one but not two nonfunctional alleles. † ultrarapid metabolizers have at least one gain-of-function allele. ‡ inhibition of platelet aggregation with 5 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) c 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) 4 (1) 12 (5) 13 (7) 12 (6) 150 mg (day 5) 7 (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)

lic 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-oxo-clopidogrel 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-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 bisulfate 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 c max 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 bisulfate 75 mg evaluated in dedicated drug interaction studies is presented in figure 1. pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole. opioids coadministration 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 coadministration. effect of clopidogrel bisulfate 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 bisulfate 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 bisulfate [see drug interactions (7.7) ] . figure 1

w 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, a 20% relative risk reduction (95% ci of 10% to 28%; p <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 a 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 (+ aspirin)* (n=6259) placebo (+ aspirin)* (n=6303) relative risk reduction (%) (95% ci) primary outcome (cardiovascular death, mi, stroke) 582 (9.3%) 719 (11.4%) 20% (10.3, 27.9) p < 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, 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). figure 2: cardiovascular death, myocardial infarction, and stroke in the cure study the effect of clopidogrel 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. figure 3: hazard ratio for patient baseline characteristics and on-study concomitant medications/interventions for the cure study the use of clopidogrel bisulfate in cure was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel bisulfate group, 126 patients [2%] 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) (2253 patients [36%] in the clopidogrel bisulfate group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4%). commit in 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). 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 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 * 9 patients (2 clopidogrel and 7 placebo) suffered both a nonfatal stroke and a nonfatal mi. † nonfatal mi and nonfatal stroke exclude patients who died (of any cause). event clopidogrel bisulfate (+ aspirin) (n=22961) placebo (+ aspirin) (n=22891) odds ratio (95% ci) p-value composite endpoint: death, mi, or stroke* 2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0.002 death nonfatal mi † nonfatal stroke † 1726 (7.5%) 270 (1.2%) 127 (0.6%) 1845 (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 figure 4: cumulative event rates for death in the commit study* * all treated patients received aspirin. figure 5: cumulative event rates for the combined endpoint re-infarction, stroke or death in the commit study* * all treated patients received aspirin. 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. figure 6: effects of adding clopidogrel bisulfate to aspirin on the combined primary endpoint across baseline and concomitant medication subgroups for the commit study * ci is 95% for overall row only. figure 2: cardiovascular death, myocardial infarction, and stroke in the cure study figure-3 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 figure 6: effects of adding clopidogrel bisulfate to aspirin on the combined primary endpoint across baseline and concomitant medication subgroups for the commit study 14.2 recent myocardial infarction, recent stroke, or established peripheral arterial disease caprie the caprie trial was a 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 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 bisulfate n=9599 aspirin n=9586 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%) 1020 (10.6%) as shown in table 6, clopidogrel bisulfate was associated with a 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. figure 7: fatal or nonfatal vascular events in the caprie study the 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 a 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 a 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 a 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 figure 7: fatal or non-fatal vascular events in the caprie study figure 8: hazard ratio and 95% ci by baseline subgroups in the caprie study 14.3 no demonstrated benefit of clopidogrel bisulfate plus aspirin in patients with multiple risk factors or established vascular disease charisma the charisma trial was a 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 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 bisulfate group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). bleeding of all severities was more common in the subjects randomized to clopidogrel bisulfate.

zole or esomeprazole while taking clopidogrel bisulfate. dexlansoprazole, lansoprazole, and pantoprazole had less pronounced effects on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole [see drug interactions (7.2) ] . dispense with medication guide available at: www.aurobindousa.com/medication-guides distributed by: aurobindo pharma usa, inc. 279 princeton-hightstown road east windsor, nj 08520 manufactured by: aurobindo pharma limited hyderabad-500 032, india revised: 10/2022