National Geographic : 2006 Aug
PLAVIX® Rxonly clopidogrel bisulfate tablets INDICATIONSANDUSAGE PLAVIX(clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events as follows: * Recent MI, Recent Stroke or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (Ml), recent stroke, or estab lished peripheral arterial disease, PLAVIXhas 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. * Acute Coronary Syndrome For patients with acute coronary syndrome (unstable angina/non-Q-wave MI)including patients who are to be managed medically and those who are to be managed with per cutaneous coronary intervention (with or without stent) or CABG,PLAVIXhas been shown to decrease the rate of a combined endpoint of cardiovascular death, MI,or stroke as well as the rate of a combined endpoint of cardiovascular death, MI,stroke, or refractory ischemia. CONTRAINDICATIONS The use of PLAVIXis contraindicated in the following conditions: * Hypersensitivity to the drug substance or any component of the product. * Active pathological bleeding such as peptic ulcer or intracranial hemorrhage. WARNINGS Thrombotic thrombocytopenic purpura (TTP): TTP has been reported rarely following use of PLAVIX,sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and 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 ADVERSEREACTIONS.) PRECAUTIONS General PLAVIXprolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological condi tions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, PLAVIXshould be discontinued 5 days prior to surgery. Due to the risk of bleeding and undesirable hematological effects, blood cell count determi nation and/or other appropriate testing should be promptly considered, whenever such sus pected clinical symptoms arise during the course of treatment (see ADVERSEREACTIONS). In patients with recent TIAor stroke who are at high risk for recurrent ischemic events, the combination of aspirin and PLAVIXhas not been shown to be more effective than PLAVIX alone, but the combination has been shown to increase major bleeding. GIBleeding: In CAPRIE,PLAVIXwas associated with a rate of gastrointestinal bleeding of 2.0%,vs. 2 .7% on aspirin. In CURE,the incidence of major gastrointestinal bleeding was 1.3% vs 0.7% (PLAVIX+ aspirin vs. placebo + aspirin, respectively). PLAVIXshould be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking PLAVIX. Use in Hepatically Impaired Patients: Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. PLAVIXshould be used with caution in this population. Use in Renally-impaired Patients: Experience is limited in patients with severe renal impairment. PLAVIXshould be used with caution in this population. Information for Patients Patients should be told it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they take PLAVIXor PLAVIXcombined with aspirin, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking PLAVIXand/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken. Drug Interactions Study of specific drug interactions yielded the following results: Aspirin: Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by PLAVIX.PLAVIXpoten tiated the effect of aspirin on collagen-induced platelet aggregation. PLAVIXand aspirin have been administered together for up to one year. Heparin: In a study in healthy volunteers, PLAVIXdid not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by PLAVIX. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):In healthy volunteers receiving naproxen, concomitant administration of PLAVIXwas associated with increased occult gastrointestinal blood loss. NSAIDsand PLAVIXshould be coadministered with caution. Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with PLAVIXshould be undertaken with caution. (See PRECAUTIONS-General.) Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when PLAVIXwas coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of PLAVIXwas also not significantly influ enced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline were not modified by the coadminis tration of PLAVIX(clopidogrel bisulfate). At high concentrations in vitro, clopidogrel inhibits P450(2C9).Accordingly, PLAVIXmay interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with PLAVIX. In addition to the above specific interaction studies, patients entered into clinical trials with PLAVIXreceived a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy, heparins (unfractionated and LMWH)and GPIIb/llla antagonists without evidence of clinically significant adverse inter actions. The use of oral anticoagulants, non-study anti-platelet drug and chronic NSAIDs was not allowed in CUREand there are no data on their concomitant use with clopidogrel. Drug/Laboratory Test Interactions None known. 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 hepa tocytes, 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/m 2 basis). 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 on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopido grel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, PLAVIXshould be used during pregnancy only if clearly needed. 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 nurs ing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman. Pediatric Use Safety and effectiveness in the pediatric population have not been established. Geriatric Use Ofthe total number of subjects in controlled clinical studies, approximately 50%of patients treated with PLAVIXwere 65 years of age and over. Approximately 16% of patients treated with PLAVIXwere 75 years of age and over. The observed difference in risk of thrombotic events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figure 3 (see CLINICALSTUDIES).The observed difference in risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 3 (see ADVERSEREACTIONS). ADVERSEREACTIONS PLAVIXhas been evaluated for safety in more than 17,500 patients, including over 9,000 patients treated for 1 year or more. The overall tolerability of PLAVIXin CAPRIEwas similar to that of aspirin regardless of age, gender and race, with an approximately equal incidence (13%)of patients withdrawing from treatment because of adverse reactions. The clinically important adverse events observed in CAPRIEand CUREare discussed below. Hemorrhagic: In CAPRIEpatients receiving PLAVIX,gastrointestinal hemorrhage occurred at a rate of 2.0%,and required hospitalization in 0.7%. In patients receiving aspirin, the cor responding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemor rhage was 0.4% for PLAVIXcompared to 0.5% for aspirin. In CURE,PLAVIXuse with aspirin was associated with an increase in bleeding compared to placebo with aspirin (see Table 3). There was an excess in major bleeding in patients receiv ing PLAVIXplus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidence of intracranial hemorrhage (0.1%),and fatal bleeding (0.2%),were the same in both groups. The overall incidence of bleeding is described in Table 3 for patients receiving both PLAVIXand aspirin in CURE, Table 3: CUREIncidence of bleeding complications (%patients) Event PLAVIX Placebo P-value (+ aspirin)* (+ aspirin)* (n=6259) (n=6303 Major bleeding t 3.7 : 2.7 § 0.001 Life-threatening bleeding 2.2 1.8 0.13 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 (a4 units) 1.2 1.0 Other major bleeding 1.6 1.0 0.005 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 5.1 2.4 <0.001 * Other standard therapies were usedas appropriate. t Lifethreatening and other major bleeding. t Majorbleeding event rate for PLAVIX+ aspirin was dose-dependent on aspirin: <100 mg=2.6%; 100-200mg= 3.5%;>200 mg=4.9% Major bleeding event rates for PLAVIX+ aspirin by age were: <65 years = 2.5%, a65 to <75 years = 4.1%,a75 years 5.9% § Majorbleeding event rate forplacebo + aspirin wasdose-dependent onaspirin: <100 mg=2.0%; 100-200mg= 2.3%;>200 mg=4.0% Majorbleeding event rates for placebo + aspirin by age were: <65 years = 2.1%,a65 to <75 years = 3.1%,275 years3.6% Ledto interruption of study medication. Ninety-two percent (92%)of the patients in the CUREstudy received heparin/LMWH, and the rate of bleeding in these patients was similar to the overall results. There was no excess in major bleeds within seven days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (event rate 4.4% PLAVIX+ aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for PLAVIX+ aspirin, and 6.3% for placebo + aspirin. Neutropenia/agranulocytosis: Ticlopidine, a drug chemically similar to PLAVIX,is associat ed with a 0.8% rate of severe neutropenia (less than 450 neutrophils/pL). In CAPRIEsevere neutropenia was observed in six patients, four on PLAVIXand two on aspirin. Two of the 9599 patients who received PLAVIXand none of the 9586 patients who received aspirin had neutrophil counts of zero. One of the four PLAVIXpatients in CAPRIEwas receiving cytotoxic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with PLAVIX(clopidogrel bisulfate). In CURE,the numbers of patients with thrombocytopenia (19 PLAVIX+ aspirin vs. 24 placebo + aspirin) or neutro penia (3vs. 3) were similar. Although the risk of myelotoxicity with PLAVIX(clopidogrel bisulfate) thus appears to be quite low, this possibility should be considered when a patient receiving PLAVIXdemon strates fever or other sign of infection. Gastrointestinal: Overall, the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving PLAVIX(clopidogrel bisulfate) was 27.1%, compared to 29.8% in those receiving aspirin in the CAPRIEtrial. In the CURE trial the incidence of these gastrointestinal events for patients receiving PLAVIX+ aspirin was 11.7% compared to 12.5% for those receiving placebo + aspirin. In the CAPRIEtrial, the incidence of peptic, gastric or duodenal ulcers was 0.7% for PLAVIX (clopidogrel bisulfate) and 1.2%for aspirin. In the CUREtrial the incidence of peptic, gastric or duodenal ulcers was 0.4% for PLAVIX+ aspirin and 0.3% for placebo + aspirin.