FDA label d23a7219-c75a-41ba-8be3-e2c81004d140

WARNINGS Reduced effectiveness due to impaired CYP2C19 function The inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. Clopidogrel is metabolized to this active metabolite in part by CYP2C19. This metabolism can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. Avoid use of PLAVIX in patients with impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity. Genetic variations Patients with genetically reduced CYP2C19 function have diminished antiplatelet responses and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function (see CLINICAL PHARMACOLOGY: Pharmacogenetics ). Drug interactions 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. There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers (except cimetidine, which is a CYP2C19 inhibitor) or antacids interfere with the antiplatelet activity of clopidogrel (see PRECAUTIONS: Drug Interactions ). Thrombotic thrombocytopenic purpura (TTP) TTP has been reported rarely following use of PLAVIX, sometimes after a short exposure (less than 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 ADVERSE REACTIONS .) PRECAUTIONS 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 of 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.

ADVERSE REACTIONS PLAVIX has been evaluated for safety in more than 42,000 patients, including over 9,000 patients treated for 1 year or more. The clinically important adverse events observed in CAPRIE, CURE, CLARITY and COMMIT are discussed below. The overall tolerability of PLAVIX in CAPRIE was 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. Hemorrhagic In CAPRIE patients receiving PLAVIX, gastrointestinal hemorrhage occurred at a rate of 2.0%, and required hospitalization in 0.7%. In patients receiving aspirin, the corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for PLAVIX compared to 0.5% for aspirin. In CURE, PLAVIX use with aspirin was associated with an increase in bleeding compared to placebo with aspirin (see Table 6 ). There was an excess in major bleeding in patients receiving PLAVIX plus 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 6 for patients receiving both PLAVIX and aspirin in CURE. Ninety-two percent (92%) of the patients in the CURE study 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. In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin great than 5 g/dL) was similar between groups (1.3% versus 1.1% in the PLAVIX + aspirin and in the placebo + aspirin groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the PLAVIX + aspirin and in the placebo + aspirin groups, respectively) and intracranial hemorrhage (0.5% versus 0.7%, respectively) was low and similar in both groups. The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups as shown in Table 7 below Adverse events occurring in greater than or equal to 2.5% of patients on PLAVIX in the CAPRIE controlled clinical trial are shown below regardless of relationship to PLAVIX. The median duration of therapy was 20 months, with a maximum of 3 years No additional clinically relevant events to those observed in CAPRIE with a frequency greater than or equal to 2.5%, have been reported during the CURE and CLARITY controlled studies. COMMIT collected only limited safety data. Other adverse experiences of potential importance occurring in 1% to 2.5% of patients receiving PLAVIX (clopidogrel bisulfate) in the controlled clinical trials are listed below regardless of relationship to PLAVIX. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in the other clinical trials). Autonomic Nervous System Disorders : Syncope, Palpitation. Body as a Whole-general disorders: Asthenia, Fever, Hernia. Cardiovascular disorders: Cardiac failure. Central and peripheral nervous system disorders: Cramps legs, Hypoaesthesia, Neuralgia, Paraesthesia, Vertigo. Gastrointestinal system disorders: Constipation, Vomiting. Heart rate and rhythm disorders: Fibrillation atrial. Liver and biliary system disorders: Hepatic enzymes increased. Metabolic and nutritional disorders: Gout, hyperuricemia, non-protein nitrogen (NPN) increased. Musculo-skeletal system disorders: Arthritis, Arthrosis. Platelet, bleeding and clotting disorders: GI hemorrhage, hematoma, platelets decreased. Psychiatric disorders: Anxiety, Insomnia. Red blood cell disorders: Anemia. Respiratory system disorders: Pneumonia, Sinusitis. Skin and appendage disorders: Eczema, Skin ulceration. Urinary system disorders: Cystitis. Vision disorders: Cataract, Conjunctivitis. Other potentially serious adverse events which may be of clinical interest but were rarely reported (less than 1%) in patients who received PLAVIX in the controlled clinical trials are listed below regardless of relationship to PLAVIX. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in the other clinical trials). Body as a whole: Allergic reaction, necrosis ischemic. Cardiovascular disorders: Edema generalized. Gastrointestinal system disorders: Peptic, gastric or duodenal ulcer, gastritis, gastric ulcer perforated, gastritis hemorrhagic, upper GI ulcer hemorrhagic. Liver and Biliary system disorders: Bilirubinemia, hepatitis infectious, liver fatty. Platelet, bleeding and clotting disorders: hemarthrosis, hematuria, hemoptysis, hemorrhage intracranial, hemorrhage retroperitoneal, hemorrhage of operative wound, ocular hemorrhage, pulmonary hemorrhage, purpura allergic, thrombocytopenia. Red blood cell disorders: Anemia aplastic, anemia hypochromic. Reproductive disorders, female: Menorrhagia. Respiratory system disorders: Hemothorax. Skin and appendage disorders: Bullous eruption, rash erythematous, rash maculopapular, urticaria. Urinary system disorders : Abnormal renal function, acute renal failure. White cell and reticuloendothelial system disorders: Agranulocytosis, granulocytopenia, leukemia, leukopenia, neutropenia. Postmarketing Experience The following events have been reported spontaneously from worldwide postmarketing experience: Body as a whole: - hypersensitivity reactions, anaphylactoid reactions, serum sickness Central and Peripheral Nervous System disorders: - confusion, hallucinations, taste disorders Hepato-biliary disorders: - abnormal liver function test, hepatitis (non-infectious), acute liver failure Platelet, Bleeding and Clotting disorders: - cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal hemorrhage) - thrombotic thrombocytopenic purpura (TTP) – some cases with fatal outcome – (see WARNINGS ) - agranulocytosis, aplastic anemia/pancytopenia - conjunctival, ocular and retinal bleeding Respiratory, thoracic and mediastinal disorders: - bronchospasm, interstitial pneumonitis Skin and subcutaneous tissue disorders: - angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichen planus Renal and urinary disorders: - glomerulopathy, increased creatinine levels Vascular disorders: - vasculitis, hypotension Gastrointestinal disorders: - colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis Musculoskeletal, connective tissue and bone disorders: - myalgia