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adverse reactions
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. Table 6: CURE Incidence of bleeding complications (% patients) Event PLAVIX (+ aspirin) Other standard therapies were used as appropriate. (n=6259) Placebo (+ aspirin) (n=6303) P-value Major bleeding Life threatening and other major bleeding. 3.7 Major bleeding event rate for PLAVIX + aspirin was dose-dependent on aspirin: <100 mg=2.6%; 100–200 mg= 3.5%; >200 mg=4.9% Major bleeding event rates for PLAVIX + 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=2.0%; 100–200 mg= 2.3%; >200 mg=4.0% 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 1.0 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 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% 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 > 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. Table 7: Number (%) of Patients with Bleeding Events in COMMIT Type of bleeding PLAVIX (+ aspirin) (N=22961) Placebo (+ aspirin) (N=22891) P-value Major Major bleeds are cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleeding The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for PLAVIX + 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%. 134 (0.6%) 125 (0.5%) 0.59 Major noncerebral 82 (0.4%) 73 (0.3%) 0.48 Fatal 36 (0.2%) 37 (0.2%) 0.90 Hemorrhagic stroke 55 (0.2%) 56 (0.2%) 0.91 Fatal 39 (0.2%) 41 (0.2%) 0.81 Other noncerebral bleeding (non-major) 831 (3.6%) 721 (3.1%) 0.005 Any noncerebral bleeding 896 (3.9%) 777 (3.4%) 0.004 Adverse events occurring in ≥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. Table 8: Adverse Events Occurring in ≥2.5% of PLAVIX Patients in CAPRIE % Incidence (% Discontinuation) Body System Event PLAVIX [n=9599] Aspirin [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 Any event 27.1(3.2) 29.8 (4.0) 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 Any event 15.8 (1.5) 13.1 (0.8) 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) No additional clinically relevant events to those observed in CAPRIE with a frequency ≥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 & 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 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