CoPlavix Adverse Reactions

Clopidogrel has been evaluated for safety in >44,000 patients who have participated in clinical studies, including over 30,000 patients treated with clopidogrel plus ASA and over 12,000 patients treated for ≥1 year. The clinically relevant adverse reactions observed in 4 major studies, the CAPRIE study (a study comparing clopidogrel alone to ASA) and the CURE, CLARITY and COMMIT studies (studies comparing clopidogrel plus ASA to ASA alone) are discussed as follows. Overall, clopidogrel 75 mg/day was similar to ASA 325 mg/day in CAPRIE regardless of age, gender and race. In addition to clinical studies experience, adverse reactions have been spontaneously reported.
Haemorrhagic Disorders: Bleeding is the most common reaction reported both in clinical studies as well as in the post-marketing experience where it was mostly reported during the 1st month of treatment.
In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was 1.4% and 1.6% in the clopidogrel and ASA groups, respectively.
In patients receiving clopidogrel, gastrointestinal bleeding occurred at a rate of 2% and required hospitalisation in 0.7%. In patients receiving ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%) compared to ASA (6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs 0.4%). The most frequent events reported were purpura/bruising and epistaxis. Other less frequently reported events were haematoma, haematuria and eye bleeding (mainly conjunctival).
The incidence of intracranial bleeding was 0.4% for clopidogrel compared to 0.5% for ASA.
In CURE, there was an increase in major and minor bleeding between the clopidogrel + ASA group compared with the placebo + ASA group (event rates 3.7% vs 2.7%, for major, respectively, and 5.1% vs 2.4% for minor). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites. The increase in life-threatening bleeding in the clopidogrel + ASA group compared to the placebo + ASA group was not statistically significant (2.2% vs 1.8%). There was no difference between the 2 groups in the rate of fatal bleeding (0.2% in both groups). The rate of non-life-threatening major bleeding was significantly higher in the clopidogrel + ASA group compared with the placebo + ASA group (1.6% vs 1%), and the incidence of intracranial bleeding was 0.1% in both groups.
The major bleeding event rate for clopidogrel + ASA was dose-dependent on ASA (<100 mg: 2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2%; 100-200 mg: 2.3%; >200 mg: 4%).
There was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy >5 days prior to surgery (4.4% clopidogrel + ASA vs 5.3% placebo + ASA). In patients who remained on therapy within 5 days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA.
In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group versus the group taking ASA alone. The incidence of major bleeding was similar between groups (1.3% vs 1.1% in the clopidogrel + ASA and in the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. The incidence of fatal bleeding (0.8% vs 0.6% in the clopidogrel + ASA and in the placebo + ASA groups, respectively) and intracranial hemorrhage (0.5% vs 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.
In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups.
In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% vs 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo + ASA group), mainly in the gastrointestinal tract (3.5% vs 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% vs 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding and hemorrhagic stroke (0.8% and 0.6%, respectively) between groups.
Haematological Disorders: In CAPRIE, severe neutropaenia (<0.45 g/L) was observed in 4 patients (0.04%) on clopidogrel and 2 patients (0.02%) on ASA.
Two (2) of the 9,599 patients who received clopidogrel and none of the 9,586 patients who received ASA had neutrophils counts of zero. 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.
One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopaenia (<80 g/L) was 0.2% on clopidogrel and 0.1% on ASA; very rare cases of platelet count ≤30 g/L have been reported.
In CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups.
Other clinically relevant adverse drug reactions pooled from CAPRIE and CURE, CLARITY and COMMIT studies with an incidence <0.1% as well as all serious and relevant adverse drug reaction with an incidence <0.1% are presented as follows.
Adverse reactions that occurred with clopidogrel alone, with ASA alone or with clopidogrel in combination with ASA either during clinical studies or that were spontaneously reported are presented 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 <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.
Central and Peripheral Nervous System Disorders: Uncommon: Headache, dizziness, paraesthesia. Rare: Vertigo.
Gastrointestinal System Disorders: Common: Dyspepsia, abdominal pain, diarrhoea, gastrointestinal haemorrhage. Uncommon: Nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer. Rare: Retroperitoneal haemorrhage. Very Rare, Not Known: Gastrointestinal and retroperitoneal haemorrhage with fatal outcome.
Platelet, Bleeding and Clotting Disorders: Uncommon: Increased bleeding time, decreased neutrophil count and platelets.
Skin and Appendages Disorders: Common: Bruising. Uncommon: Rash, skin bleeding (purpura), pruritus.
White Cell and RES Disorders: Uncommon: Leucopenia, decreased neutrophils, thrombocytopenia, eosinophilia. Rare: Neutropenia, including severe neutropenia. Very Rare, Not Known: Severe thrombocytopenia, granulocytopenia, anaemia.
Post-Marketing Experience: Clopidogrel: Frequencies for the following adverse reactions are not known (cannot be estimated from available data).
Blood and the Lymphatic System Disorders: Serious cases of bleeding, mainly skin, musculoskeletal, eye (conjunctival, ocular, retinal) and respiratory tract bleeding, epistaxis, haematuria and haemorrhage of operative wound; cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage), agranulocytosis, aplastic anaemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP) (see Precautions), acquired haemophilia A.
Immune System Disorders: Anaphylactoid reactions, serum sickness; cross-reactive drug hypersensitivity among thienopyridines (eg, ticlopidine, prasugrel) (see Precautions).
Psychiatric Disorders: Confusion, hallucinations.
Nervous System Disorders: Taste disturbances.
Vascular Disorders: Vasculitis, hypotension, serious haemorrhage, haemorrhage of operative wound, haematoma.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), epistaxis, eosinophilic pneumonia.
Gastrointestinal Disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.
Hepatobiliary Disorders: Hepatitis, acute liver failure.
Skin and Subcutaneous Tissue Disorders: Maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, lichen planus.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, arthritis, myalgia, musculoskeletal bleeding (haemarthrosis).
Renal and Urinary Disorders: Glomerulopathy, increased blood creatinine, haematuria.
General Disorders and Administration Site Conditions: Fever, bleeding at the puncture site.
Investigations: Abnormal liver function test, increased blood creatinine.
Acetylsalicylic Acid: Blood and the Lymphatic System Disorders: Thrombocytopaenia, haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, pancytopenia, bicytopenia, aplastic anemia, bone marrow failure, agranulocytosis, neutropenia, leukopenia (see Precautions).
Immune System Disorders: Anaphylactic shock, aggravation of allergic symptoms of food allergy.
Nervous System Disorders: Intracranial haemorrhage may be fatal, especially in the elderly.
Metabolism and Nutrition Disorders: Hypoglycaemia, gout (see Precautions).
Ear and Labyrinth Disorders: Hearing loss or tinnitus, vertigo.
Respiratory, Thoracic and Mediastinal Disorders: Noncardiogenic pulmonary edema with chronic use and in the context of a hypersensitivity reaction due to acetylsalicylic acid.
Gastrointestinal Disorders: Oesophagitis, oesophageal ulceration, perforation. Erosive gastritis, erosive duodenitis, gastroduodenal ulcer/perforations, upper gastrointestinal symptom eg, gastralgia. (See Precautions.)
Small (jejunum and ileum) and large (colon and rectum) intestinal ulcers, colistis and intestinal perforation. These reactions may or may not be associated with haemorrhage, and may occur at any dose of acetylsalicylic acid and in patients with or without warning symptoms or a previous history of serious gastrointestinal events.
Hepatobiliary Disorders: Elevation of hepatic enzymes liver injury, mainly hepatocellular, chronic hepatitis.
Renal and Urinary Disorders: Acute renal impairment (especially in patients with existing renal impairment, heart decompensation, nephritic syndrome or concomitant treatment with diuretics), renal failure.
Skin and Subcutaneous Tissue Disorders: Fixed eruption.