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 [see Boxed Warning] 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 [see Drug Interactions].
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.
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].
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 the pediatric population have not been established.
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 thrombotic events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figures 2 and 5 for the CURE and COMMIT trials, respectively [see Clinical Studies]. The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Tables 1 and 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].
No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology].