"March 11, 2010 - The FDA has put a new "black box" warning on the anti-clotting drug Plavix, the second best-selling drug in the world.
The new label warns that normal doses of Plavix have a potentially deadly lack of effect in 2% "...
Diminished Antiplatelet Activity Due To Impaired CYP2C19 Function
Clopidogrel is a 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] and by concomitant medications that interfere with CYP2C19.
Proton Pump Inhibitors
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 five 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.
Patients with Recent Transient Ischemic Attack (TIA) Or Stroke
In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.
Thrombotic Thrombocytopenic Purpura (TTP)
TTP, sometimes fatal, has been reported following use of Plavix, 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].
Cross-Reactivity Among Thienopyridines
Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving Plavix, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see CONTRAINDICATIONS and ADVERSE REACTIONS].
Patient Counseling Information
[See Medication Guide]
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.
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.
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.
Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m² basis).
Use In Specific Populations
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.
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.
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.
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]. No dosage adjustment is necessary in elderly patients.
Experience is limited in patients with severe and moderate renal impairment [see CLINICAL PHARMACOLOGY].
Prescribing Document Revised: December 2013This monograph has been modified to include the generic and brand name in many instances.
Additional Plavix Information
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