Apolets Adverse Reactions

Clopidogrel has been evaluated for safety in more than 44,000 patients, including over 12,000 patients treated for 1 year or more. The overall tolerability of clopidogrel 75 mg/day in CAPRIE was similar to that of aspirin (325 mg/day) 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 as follows.
Hemorrhagic: In CAPRIE patients receiving clopidogrel, 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 compared to 0.5% for aspirin.
In CURE, clopidogrel 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 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. (See Table 3.)

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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 + 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 + aspirin, and 6.3% for placebo + aspirin.
Neutropenia/Agranulocytosis: Ticlopidine, a drug chemically similar to clopidogrel, 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 and two on aspirin. Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received aspirin had neutrophil counts of zero. One of the four clopidogrel patients in CAPRIE was receiving cytostatic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with clopidogrel. In CURE, the numbers of patients with thrombocytopenia or neutropenia were similar in both clopidogrel + aspirin and placebo + aspirin groups. Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other sign of infection.
Gastrointestinal: Overall, the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) patients receiving clopidogrel 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 + 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 and 1.2% for aspirin. In the CURE trial the incidence of peptic, gastric or duodenal ulcers was 0.4% for clopidogrel + aspirin and 0.3% for placebo + aspirin.
Cases of diarrhea were reported in the CAPRIE trial in 4.5% of patients in the clopidogrel group compared to 3.4% in the aspirin group. However, these were rarely severe (clopidogrel = 0.2% and aspirin = 0.1%). In the CURE trial, the incidence of diarrhea for patients receiving clopidogrel + 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 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 + 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 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 + aspirin was 4.2% 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 and 0.8% for aspirin. In the CURE trials, the incidence of patients withdrawing because of skin and appendage disorders adverse reactions was 0.7% for clopidogrel + aspirin compared with 0.3% for placebo + aspirin.
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table as follows. Their frequency is defined using the following conventions: common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to 1/1,000); very rare (<1/10,000). Within each system organ class, adverse reactions are presented in order of decreasing seriousness. (See Table 4.)

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Other adverse experiences of potential importance occurring in 1% to 2.5% of patients receiving clopidogrel in the CAPRIE or CURE controlled clinical trials are listed as follows regardless of relationship to clopidogrel. 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: Atrial fibrillation. 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 as follows regardless of relationship to clopidogrel. 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.