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Revision as of 16:47, 27 September 2011
List of precautions
General
GI Bleeding
Information for Patients
Drug Interactions
Drug/Laboratory Test Interactions
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Nursing Mothers
Pediatric Use
Geriatric Use
General
Plavix prolongs 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 conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, Plavix should be discontinued 5 days prior to surgery.
Due to the risk of bleeding and undesirable hematological effects, blood cell count determination and/or other appropriate testing should be promptly considered, whenever such suspected clinical symptoms arise during the course of treatment (see ADVERSE REACTIONS).
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.
GI Bleeding
In CAPRIE, Plavix was 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). Plavix should 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. Plavix should be used with caution in this population.
Use in Renally-impaired Patients
Experience is limited in patients with severe renal impairment. Plavix should be used with caution in this population.
Information for Patients
Patients should be told that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they take Plavix or Plavix combined with aspirin, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking Plavix and/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. Plavix potentiated the effect of aspirin on collagen-induced platelet aggregation. Plavix and aspirin have been administered together for up to one year.
Heparin
In a study in healthy volunteers, Plavix did 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 Plavix was associated with increased occult gastrointestinal blood loss. NSAIDs and Plavix should be coadministered with caution.
Warfarin
Because of the increased risk of bleeding, the concomitant administration of warfarin with Plavix should be undertaken with caution. (See PRECAUTIONS–General.)
Other Concomitant Therapy
No clinically significant pharmacodynamic interactions were observed when Plavix was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Plavix was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of Plavix (clopidogrel bisulfate).
At high concentrations in vitro, clopidogrel inhibits P450 (2C9). Accordingly, Plavix may 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 Plavix received 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/IIIa antagonists without evidence of clinically significant adverse interactions. The use of oral anticoagulants, non-study anti-platelet drug and chronic NSAIDs was not allowed in CURE and 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 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).
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 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.
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, 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
Of the total number of subjects in controlled clinical studies, approximately 50% of patients treated with Plavix were 65 years of age and over. Approximately 16% of patients treated with Plavix were 75 years of age and over.
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Adapted from the FDA Package Insert.