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adverse reactions
ADVERSE REACTIONS Clopidogrel bisulfate has 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 clopidogrel bisulfate 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. The clinically important adverse events observed in CAPRIE and CURE are discussed below. Hemorrhagic: In CAPRIE patients receiving clopidogrel bisulfate, gastrointestinal hemorrhage occurred at a rate of 2%, 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 clopidogrel bisulfate compared to 0.5% for aspirin. In CURE, clopidogrel bisulfate use 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 receiving clopidogrel bisulfate plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidences 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 clopidogrel and aspirin in CURE, Table 3: CURE Incidence of bleeding complications (% patients) Event Clopidogrel bisulfate (+ aspirin) Other standard therapies were used as appropriate. Placebo (+ aspirin) P-value (n=6259) (n=6303) Major bleeding Life threatening and other major bleeding. 3.7 Major bleeding event rate for clopidogrel bisulfate + aspirin was dose-dependent on aspirin: <100 mg=2.6%; 100–200 mg= 3.5%; >200 mg=4.9% Major bleeding event rates for clopidogrel + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years 5.9% 2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg=2%; 100–200 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% 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 (≥4 units) 1.2 1 Other major bleeding 1.6 1 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 Led to interruption of study medication. 5.1 2.4 <0.001 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% clopidogrel bisulfate + 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 clopidogrel bisulfate + aspirin, and 6.3% for placebo + aspirin. Neutropenia/agranulocytosis: Ticlopidine, a drug chemically similar to clopidogrel bisulfate, is associated with a 0.8% rate of severe neutropenia (less than 450 neutrophils/µL). In CAPRIE severe neutropenia was observed in six patients, four on clopidogrel bisulfate and two on aspirin. Two of the 9599 patients who received clopidogrel bisulfate and none of the 9586 patients who received aspirin had neutrophil counts of zero. One of the four clopidogrel bisulfate patients in CAPRIE was receiving cytotoxic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with clopidogrel bisulfate. In CURE, the numbers of patients with thrombocytopenia (19 clopidogrel bisulfate + aspirin vs. 24 placebo + aspirin) or neutropenia (3 vs. 3) were similar. Although the risk of myelotoxicity with clopidogrel bisulfate thus appears to be quite low, this possibility should be considered when a patient receiving clopidogrel bisulfate demonstrates fever or other sign of infection. Gastrointestinal: Overall, the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving clopidogrel bisulfate was 27.1%, compared to 29.8% in those receiving aspirin in the CAPRIE trial. In the CURE trial the incidence of these gastrointestinal events for patients receiving clopidogrel bisulfate + aspirin was 11.7% compared to 12.5% for those receiving placebo + aspirin. In the CAPRIE trial, the incidence of peptic, gastric or duodenal ulcers was 0.7% for clopidogrel bisulfate and 1.2% for aspirin. In the CURE trial the incidence of peptic, gastric or duodenal ulcers was 0.4% for clopidogrel bisulfate + aspirin and 0.3% for placebo + aspirin. Cases of diarrhea were reported in the CAPRIE trial in 4.5% of patients in the clopidogrel bisulfate group compared to 3.4% in the aspirin group. However, these were rarely severe (clopidogrel bisulfate=0.2% and aspirin=0.1%). In the CURE trial, the incidence of diarrhea for patients receiving clopidogrel bisulfate + aspirin was 2.1% compared to 2.2% for those receiving placebo + aspirin. In the CAPRIE trial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 3.2% for clopidogrel bisulfate and 4% for aspirin. In the CURE trial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 0.9% for clopidogrel bisulfate + aspirin compared with 0.8% for placebo + aspirin. Rash and Other Skin Disorders: In the CAPRIE trial, the incidence of skin and appendage disorders in patients receiving clopidogrel bisulfate was 15.8% (0.7% serious); the corresponding rate in aspirin patients was 13.1% (0.5% serious). In the CURE trial the incidence of rash or other skin disorders in patients receiving clopidogrel bisulfate + aspirin was 4% compared to 3.5% for those receiving placebo + aspirin. In the CAPRIE trial, the overall incidence of patients withdrawing from treatment because of skin and appendage disorders adverse reactions was 1.5% for clopidogrel bisulfate and 0.8% for aspirin. In the CURE trial, the incidence of patients withdrawing because of skin and appendage disorders adverse reactions was 0.7% for clopidogrel bisulfate + aspirin compared with 0.3% for placebo + aspirin. Adverse events occurring in ≥2.5% of patients on clopidogrel bisulfate in the CAPRIE controlled clinical trial are shown below regardless of relationship to clopidogrel bisulfate. The median duration of therapy was 20 months, with a maximum of 3 years. Table 4: Adverse Events Occurring in ≥2.5% of Clopidogrel Bisulfate Patients in CAPRIE % Incidence (% Discontinuation) Body System Clopidogrel bisulfate Aspirin Event [n=9599] [n=9586] Body as a Whole general disorders Chest Pain 8.3 (0.2) 8.3 (0.3) Accidental/Inflicted injury 7.9 (0.1) 7.3 (0.1) Influenza-like symptoms 7.5 (<0.1) 7.0 (<0.1) Pain 6.4 (0.1) 6.3 (0.1) Fatigue 3.3 (0.1) 3.4 (0.1) Cardiovascular disorders, general Edema 4.1 (<0.1) 4.5 (<0.1) Hypertension 4.3 (<0.1) 5.1 (<0.1) Central & peripheral nervous system disorders Headache 7.6 (0.3) 7.2 (0.2) Dizziness 6.2 (0.2) 6.7 (0.3) Gastrointestinal system disorders Abdominal pain 5.6 (0.7) 7.1 (1.0) Dyspepsia 5.2 (0.6) 6.1 (0.7) Diarrhea 4.5 (0.4) 3.4 (0.3) Nausea 3.4 (0.5) 3.8 (0.4) Metabolic & nutritional disorders Hypercholesterolemia 4.0 (0) 4.4 (<0.1) Musculo-skeletal system disorders Arthralgia 6.3 (0.1) 6.2 (0.1) Back Pain 5.8 (0.1) 5.3 (<0.1) Platelet, bleeding, & clotting disorders Purpura/Bruise 5.3 (0.3) 3.7 (0.1) Epistaxis 2.9 (0.2) 2.5 (0.1) Psychiatric disorders Depression 3.6 (0.1) 3.9 (0.2) Respiratory system disorders Upper resp tract infection 8.7 (<0.1) 8.3 (<0.1) Dyspnea 4.5 (0.1) 4.7 (0.1) Rhinitis 4.2 (0.1) 4.2 (<0.1) Bronchitis 3.7 (0.1) 3.7 (0) Coughing 3.1 (<0.1) 2.7(<0.1) Skin & appendage disorders Rash 4.2 (0.5) 3.5 (0.2) Pruritus 3.3 (0.3) 1.6 (0.1) Urinary system disorders Urinary tract infection 3.1 (0) 3.5 (0.1) Incidence of discontinuation, regardless of relationship to therapy, is shown in parentheses. Adverse events occurring in ≥2.0% of patients on clopidogrel bisulfate in the CURE controlled clinical trial are shown below regardless of relationship to clopidogrel bisulfate. Table 5: Adverse Events Occurring in ≥2.0% of Clopidogrel Bisulfate Patients in CURE % Incidence (% Discontinuation) Body System Clopidogrel bisulfate (+ aspirin) Other standard therapies were used as appropriate. Placebo (+ aspirin) Event [n=6259] [n=6303] Body as a Whole– general disorders Chest Pain 2.7 (<0.1) 2.8 (0.0) Central & peripheral nervous system disorders Headache 3.1 (0.1) 3.2 (0.1) Dizziness 2.4 (0.1) 2 (<0.1) Gastrointestinal system disorders Abdominal pain 2.3 (0.3) 2.8 (0.3) Dyspepsia 2 (0.1) 1.9 (<0.1) Diarrhea 2.1 (0.1) 2.2 (0.1) Other adverse experiences of potential importance occurring in 1% to 2.5% of patients receiving clopidogrel bisulfate in the CAPRIE or CURE controlled clinical trials are listed below regardless of relationship to clopidogrel bisulfate. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in CURE). 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 & 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 (<1%) in patients who received clopidogrel bisulfate in the CAPRIE or CURE controlled clinical trials are listed below regardless of relationship to clopidogrel bisulfate. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in CURE). Body as a whole: Allergic reaction, necrosis ischemic. Cardiovascular disorders: Edema generalized. Gastrointestinal system disorders: 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, neutrophils decreased. 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 system 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