Data from FDA - Curated by Toby Galbraith - Last updated 03 June 2017

Indication(s)

1 INDICATIONS AND USAGE Plavix is a P2Y12 platelet inhibitor indicated for: Acute coronary syndrome -For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], Plavix has been shown to reduce the rate of myocardial infarction (MI) and stroke. (1.1) -For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of MI and stroke. (1.1) Recent MI, recent stroke, or established peripheral arterial disease. Plavix has been shown to reduce the rate of MI and stroke. (1.2) 1.1 Acute Coronary Syndrome (ACS) Plavix is indicated to reduce the rate of myocardial infarction and stroke (MI) in 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. Plavix should be administered in conjunction with aspirin. Plavix is 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. Plavix 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 Plavix is indicated to reduce the rate of MI and stroke.

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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 Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Plavix is 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 (5.4)] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership at 1-800-633-1610 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. Plavix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below. Bleeding CURE In CURE, Plavix 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 Plavix (+ aspirin) Placebo (+ aspirin) (n=6259) (n=6303) Major bleeding Life-threatening and other 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 1.0 Other major bleeding 1.6 1.0 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2–3 units of blood 1.3 0.9 Minor bleeding Led to interruption of study medication. 5.1 2.4 COMMIT In COMMIT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2). Table 2: Incidence of Bleeding Events in COMMIT (% patients) Type of bleeding Plavix (+ aspirin) (n=22961) Placebo (+ aspirin) (n=22891) p-value MajorMajor bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. 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 (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Plavix vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix 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 Plavix compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the Plavix group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared Plavix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo. In CAPRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. 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 Plavix. 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 Plavix. 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 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: Myalgia, arthralgia, arthritis Nervous system disorders: Taste disorders, headache 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Acute coronary syndrome (2.1) -Initiate Plavix with a single 300-mg oral loading dose and then continue at 75 mg once daily -Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose (2.2) 2.1 Acute Coronary Syndrome In patients who need an antiplatelet effect within hours, initiate Plavix with a single 300-mg oral loading dose and then continue at 75 mg once daily. Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 75 mg once daily orally without a loading dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue drug or nursing. (8.3) 8.1 Pregnancy 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/m2 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, Plavix 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 Plavix were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Plavix were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with Plavix 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) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. (7.5) 7.1 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 Plavix with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of Plavix when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Plavix. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole or esomeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Coadministration of Plavix 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, coadministration of Plavix 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. 7.5 Repaglinide (CYP2C8 Substrates) The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Plavix can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose-adjustment and/or appropriate monitoring. Concomitant administration of Plavix with repaglinide significantly increases systemic exposures to repaglinide [see Clinical Pharmacology (12.3)]. When concomitant use is required in a patient maintained on clopidogrel, initiate repaglinide at 0.5 mg with each meal and titrate based on blood glucose levels. Do not exceed a total daily dose of 4 mg. If concomitant use of clopidogrel is required in a patient stabilized on higher doses of repaglinide, down titrate the dose of repaglinide based on blood glucose levels to not exceed a total daily dose of 4 mg.

More information

Category Value
Authorisation number NDA020839
Agency product number 08I79HTP27
Orphan designation No
Product NDC 63629-1598
Date Last Revised 22-05-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 213169
Marketing authorisation holder Bryant Ranch Prepack
Warnings WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE See full prescribing information for complete boxed warning. Effectiveness of Plavix depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1, 12.3) Tests are available to identify patients who are CYP2C19 poor metabolizers. (12.5) Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. (5.1) The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed "CYP2C19 poor metabolizers"). Tests are available to identify patients who are CYP2C19 poor metabolizers [see Clinical Pharmacology (12.5)]. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.