Data from FDA - Curated by Toby Galbraith - Last updated 12 July 2017

Indication(s)

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

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Advisory information

contraindications
4 CONTRAINDICATIONS •Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4.1) •Hypersensitivity to clopidogrel or any component of the product ( 4.2) 4.1 Active Bleeding Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)] .
Adverse reactions
6 ADVERSE REACTIONS 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 (5.5)] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clopidogrel has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below. Bleeding CURE In CURE, clopidogrel 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 (+ aspirin) Other standard therapies were used as appropriate. (n = 6,259) Placebo (+ aspirin) (n = 6,303) Major Bleeding Life-threatening and other major bleeding. 3.7 Major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin: < 100 mg = 2.6%; 100 mg to 200 mg = 3.5%; > 200 mg = 4.9% Major bleeding event rates for clopidogrel + aspirin by age were: < 65 years = 2.5%, ≥ 65 to < 75 years = 4.1%, ≥ 75 years = 5.9% 2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: < 100 mg = 2%; 100 mg to 200 mg = 2.3%; > 200 mg = 4% Major bleeding event rates for placebo + aspirin by age were: < 65 years = 2.1%, ≥ 65 to < 75 years = 3.1%, ≥ 75 years = 3.6% 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 Led to interruption of study medication. 5.1 2.4 Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel 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 (+ aspirin) (n = 22,961) Placebo (+ aspirin) (n = 22,891) p-value Major Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleeding The relative rate of major non-cerebral or cerebral bleeding was independent of age. Event rates for clopidogrel + aspirin by age were: < 60 years = 0.3%, ≥ 60 to < 70 years = 0.7%, ≥ 70 years = 0.8%. Event rates for placebo + aspirin by age were: < 60 years = 0.4%, ≥ 60 to < 70 years = 0.6%, ≥ 70 years = 0.7%. 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 (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Clopidogrel vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel vs. 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 compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo. In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel. 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 post-approval use of clopidogrel. 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. • Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A • Eye disorders: Eye (conjunctival, ocular, retinal) bleeding • Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea • General disorders and administration site condition: Fever, hemorrhage of operative wound • Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test • Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness • Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis • Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache • Psychiatric disorders: Confusion, hallucinations • Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, 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, skin bleeding, lichen planus, generalized pruritus • Vascular disorders: Vasculitis, hypotension

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Acute coronary syndrome ( 2.1) •UA/NSTEMI: 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75 mg to 325 mg once daily) •STEMI: 75 mg once daily, in combination with aspirin (75 mg to 325 mg once daily), with or without a loading dose •Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily ( 2.2) 2.1 Acute Coronary Syndrome Clopidogrel tablets can be administered with or without food [see Clinical Pharmacology (12.3)] . •For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 mg to 325 mg once daily) and continue in combination with clopidogrel tablets [see Clinical Studies (14.1)] . •For patients with STEMI, the recommended dose of clopidogrel tablets is 75 mg once daily orally, administered in combination with aspirin (75 mg to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets may be initiated with or without a loading dose [see Clinical Studies (14.1)] . 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease The recommended daily dose of clopidogrel tablets is 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3)] . 2.3 CYP2C19 Poor Metabolizers CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5)] , an appropriate dose regimen for this patient population has not been established. 2.4 Use with Proton Pump Inhibitors (PPI) Avoid using omeprazole or esomeprazole with clopidogrel tablets. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue drug or nursing. ( 8.3) 8.1 Pregnancy Teratogenic Effects. Pregnancy Category B Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (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. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 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 were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with clopidogrel 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)] .
Pregnancy and lactation
8.3 Nursing Mothers Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS •Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. ( 7.2, 7.3, 7.4) 7.1 CYP2C19 Inhibitors Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain 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) and Dosage and Administration (2.4)] . Proton Pump Inhibitors (PPI) Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . 7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Co-administration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding. 7.3 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, co-administration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. 7.4 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.

More information

Category Value
Authorisation number ANDA077665
Agency product number 08I79HTP27
Orphan designation No
Product NDC 55154-5388
Date Last Revised 29-06-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Cardinal Health
Warnings WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS The effectiveness of clopidogrel tablets is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)] . Clopidogrel tablets at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel tablets at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient’s CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)] . Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)] . WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS See full prescribing information for complete boxed warning. • Effectiveness of clopidogrel tablets depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. ( 5.1) • Poor metabolizers treated with clopidogrel tablets at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. ( 12.5) • Tests are available to identify a patient’s CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. ( 12.5) • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. ( 2.3, 5.1)