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U.S. Department of Health and Human Services

Safety

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Plavix (clopidogrel bisulfate) tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – March 2010

 

Summary View

 

BOXED WARNING

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
  • The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Plavix 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 Plavix 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. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

WARNINGS AND PRECAUTIONS

Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function
  • Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. Avoid concomitant use of Plavix and drugs that inhibit CYP2C19 activity. Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart.
General Risk of Bleeding
  • Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix 5 days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event
    rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin. Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. 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.
Discontinuation of Plavix
  • Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as possible. Premature discontinuation of Plavix may increase the risk of cardiovascular events.

DRUG INTERACTIONS

CYP2C19 Inhibitors

Omeprazole

  • In a crossover clinical study, 72 healthy subjects were administered Plavix (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as Plavix) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when Plavix and omeprazole were administered together. Mean inhibition of platelet aggregation was diminished by 47% (24 hours) and 30% (Day 5) when Plavix and omeprazole were administered together.
  • In another study, 72 healthy subjects were given the same doses of Plavix and omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering Plavix and omeprazole at different times does not prevent their interaction.
Warfarin (CYP2C9 Substrates)
  • Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfain therapy, coadministration of Plavix with warfarin increases the risk of bleeding because of independent effects on hemostasis.

USE IN SPECIFIC POPULATIONS

Renal Impairment
  • Experience is limited in patients with severe and moderate renal impairment.

PATIENT COUNSELING INFORMATION

Benefits and Risks
  • Summarize the effectiveness features and potential side effects of Plavix.
  • Tell patients to take Plavix exactly as prescribed.
  • Remind patients not to discontinue Plavix without first discussing it with the physician who prescribed Plavix.
Bleeding
Inform patients that they:
  • will bruise and bleed more easily.
  • will take longer than usual to stop bleeding.
  • should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine.
Other Signs and Symptoms Requiring Medical Attention
  • Inform patients that TTP is a rare but serious condition that has been reported with Plavix and other drugs in this class of drugs.
  • Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes.
Invasive Procedures

Instruct patients to:

  • inform physicians and dentists that they are taking Plavix before any invasive procedure is scheduled.
  • tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Plavix.
Concomitant Medications
  • Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take, including prescription or over-the-counter omeprazole, so the physician knows about other treatments that may affect how Plavix works (e.g., warfarin and NSAIDs).