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adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling: Bleeding [see Warnings and Precautions (5.2) ] Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.5) ] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below. Bleeding CURE In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise. The overall incidence of bleeding is described in Table 1. Table 1: CURE Incidence of Bleeding Complications (% patients) Event Clopidogrel Bisulfate (+ aspirin)* (n=6259) Placebo (+ aspirin)* (n=6303) * Other standard therapies were used as appropriate. † Life-threatening and other major bleeding. ‡ Major bleeding event rate for clopidogrel bisulfate + aspirin was dose-dependent on aspirin: <100 mg = 2.6%; 100 to 200 mg = 3.5%; >200 mg = 4.9%. Major bleeding event rates for clopidogrel bisulfate + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years = 5.9%. § Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg = 2%; 100 to 200 mg = 2.3%; >200 mg = 4%. Major bleeding event rates for placebo + aspirin by age were: <65 years = 2.1%, ≥65 to <75 years = 3.1%, ≥75 years = 3.6%. ¶ Led to interruption of study medication. Major bleeding † 3.7 ‡ 2.7 § Life-threatening bleeding 2.2 1.8 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 (≥4 units) 1.2 1 Other major bleeding 1.6 1 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2 to 3 units of blood 1.3 0.9 Minor bleeding ¶ 5.1 2.4 Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin (see Table 2). Table 2: Incidence of Bleeding Events in COMMIT (% patients) Type of bleeding Clopidogrel Bisulfate (+ aspirin) (n=22961) Placebo (+ aspirin) (n=22891) p-value * Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. ** The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for clopidogrel bisulfate + aspirin by age were: <60 years = 0.3%, ≥60 to <70 years = 0.7%, ≥70 years = 0.8%. Event rates for placebo + aspirin by age were: <60 years = 0.4%, ≥60 to <70 years = 0.6%, ≥70 years = 0.7%. Major* noncerebral or cerebral bleeding** 0.6 0.5 0.59 Major noncerebral 0.4 0.3 0.48 Fatal 0.2 0.2 0.9 Hemorrhagic stroke 0.2 0.2 0.91 Fatal 0.2 0.2 0.81 Other noncerebral bleeding (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Clopidogrel Bisulfate vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo. In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clopidogrel bisulfate. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A Eye disorders : Eye (conjunctival, ocular, retinal) bleeding Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea General disorders and administration site condition: Fever, hemorrhage of operative wound Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache Psychiatric disorders: Confusion, hallucinations Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia Renal and urinary disorders: Increased creatinine levels Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus Vascular disorders: Vasculitis, hypotension