Clinical Studies Experience:
Clopidogrel has been evaluated for safety in more than 44,000 patients, including over 12,000 patients treated for 1 year or more. The clinically relevant adverse effects observed in the CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A studies are discussed below. Clopidogrel 75 mg/day was well tolerated compared to ASA 325 mg/day in CAPRIE. The overall tolerability of clopidogrel in this study was similar to ASA, regardless of age, gender and ethnicity.
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% for clopidogrel and 1.6% for ASA. In patients that received clopidogrel, gastrointestinal bleeding occurred at a rate of 2.0%, and required hospitalisation in 0.7%. In patients that received ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall incidence of other bleedings was higher in patients that received clopidogrel compared to ASA (7.3% vs 6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs 0.4%). The most frequently reported events in both treatment groups 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% in patients that received clopidogrel and 0.5% for patients that received ASA.
In CURE, the administration of clopidogrel + ASA as compared to placebo + ASA was not associated with a statistically significant increase in life-threatening bleeds (event rates 2.2% vs 1.8%) or fatal bleeds (0.2% vs 0.2%), but the risk of major, minor and other bleedings was significantly higher with clopidogrel + ASA: major bleeds (3.7% clopidogrel + ASA vs 2.7% placebo + ASA), non-life-threatening major bleeds (1.6% clopidogrel + ASA vs 1.0% placebo + ASA), primarily gastrointestinal and at puncture sites, and minor bleeds (5.1% clopidogrel + ASA vs 2.4% placebo + ASA). 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: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).
The risk of bleeding (life-threatening, major, minor, other) decreased during the course of the trial: 0-1 months [clopidogrel: 599/6,259 (9.6%); placebo: 413/6,303 (6.6%)], 1-3 months [clopidogrel: 276/6,123 (4.5%); placebo: 144/6,168 (2.3%)], 3-6 months [clopidogrel: 228/6,037 (3.8%); placebo: 99/6,048 (1.6%)], 6-9 months [clopidogrel: 162/5,005 (3.2%); placebo: 74/4,972 (1.5%)], 9-12 months [clopidogrel: 73/3,841 (1.9%); placebo: 40/3,844 (1.0%)].
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel + ASA vs 5.3% placebo + ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel + ASA, and 6.3% for placebo + ASA.
In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs the placebo + ASA group (12.9%). The incidence of major bleeding was similar between groups (1.3% vs 1.1% for the clopidogrel + ASA and 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 the placebo + ASA groups, respectively) and intracranial hemorrhage (0.5% vs 0.7% in the clopidogrel + ASA and the placebo + ASA groups, respectively) was low and similar in both groups.
In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleedings was low and similar in both groups (0.6% vs 0.5% in the clopidogrel + ASA and the placebo + ASA groups, respectively).
In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 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.
In CAPRIE, severe neutropenia (<0.45 x 109/L) was observed in 4 patients (0.04%) that received clopidogrel and 2 patients (0.02%) that received ASA.
Two of the 9,599 patients who received clopidogrel and none of the 9,586 patients who received ASA had neutrophil counts of zero.
One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopenia (<80 x 109/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 numbers of patients with thrombocytopenia or neutropenia was similar in both groups.
Other clinically relevant adverse drug reactions pooled from CAPRIE, CURE, CLARITY, COMMIT, and ACTIVE-A studies with an incidence >0.1% as well as all serious and relevant ADR are listed as follows.
The following CIOMS frequency rating is used, when applicable: Very common >10%; Common >1 and <10%; Uncommon >0.1 and <1%; Rare >0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).
Central and Peripheral Nervous System Disorders:
Uncommon: Headache, dizziness and paraesthesia. Rare: Vertigo.
Gastrointestinal System Disorders:
Common: Dyspepsia, abdominal pain, diarrhoea. Uncommon: Nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer and duodenal ulcer.
Platelet, Bleeding and Clotting Disorders:
Uncommon: Bleeding time increased and platelets decreased.
Skin and Appendages Disorders:
Uncommon: Rash and pruritus.
White Cell and RES Disorders:
Uncommon: Leucopenia, neutrophils decreased and eosinophilia.
Bleeding is the most common reaction reported in the post-marketing experience and was mostly reported during the first month of treatment.
Some cases were reported with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); serious cases of skin bleeding (purpura), musculo-skeletal bleeding (haemarthrosis, haematoma), eye bleeding (conjunctival, ocular, retinal), epistaxis, respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), haematuria and haemorrhage of operative wound have been reported; cases of serious haemorrhage have been reported in patients taking clopidogrel concomitantly with acetylsalicylic acid or clopidogrel with acetylsalicylic acid and heparin (see Precautions).
Frequencies for the following adverse reactions are not known (cannot be estimated form available data).
Blood and the Lymphatic System Disorders:
Serious cases of bleeding, mainly skin, musculo-skeletal, 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), acquired haemophilia A.
Immune System Disorders:
Anaphylactoid reactions, serum sickness. Cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see Precautions).
Nervous System Disorders:
Respiratory, Thoracic and Mediastinal Disorders:
Bronchospasm, Interstitial Pneumonitis, eosinophilic pneumonia.
Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.
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.
Renal and Urinary Disorders:
General Disorders and Administration Site Conditions:
Abnormal liver function test, blood creatinine increase.