Apo-Clopidogrel Adverse Reactions

Clinical Experience: Clopidogrel has been evaluated for safety in >42,000 patients, including >9000 patients treated for ≥1 year. 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 race. The clinically relevant adverse effects observed in the CAPRIE and CURE studies are discussed as follows:
Haemorrhagic Disorders: 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% and required hospitalisation in 0.7%. In patients that received ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The incidence of other bleeding 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/haematoma 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 the major, minor and other bleedings was significantly higher with clopidogrel + ASA: Nonlife-threatening major bleeds (1.6% clopidogrel + ASA vs 1% 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%; 100-200 mg: 2.3%; >200 mg: 4%).
The risk of bleeding (life-threatening, major, minor, others) decreased during the course of trial: 0-1 month [clopidogrel: 599/6259 (9.6%); placebo: 413/6303 (6.6%)], 1-3 months [clopidogrel: 276/6123 (4.5%); placebo: 144/6168 (2.3%)], 3-6 months [clopidogrel: 228/6037 (3.8%); placebo: 99/6048 (1.6%)], 6-9 months [clopidogrel: 162/5005 (3.2%); placebo: 74/4972 (1.5%)], 9-12 months [clopidogrel: 73/3841 (1.9%); placebo: 40/3844 (1%)].
There was no excess in major bleeds 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 + ASA, and 6.3% for placebo + ASA.
Haematological Disorders: 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 9599 patients who received clopidogrel and none of the 9586 patients who received ASA had neutrophil counts of zero. One case of aplastic anaemia occurred on clopidogrel treatment.
Other clinically relevant adverse drug reactions pooled from CAPRIE and CURE studies with an incidence >0.1% as well as all serious and relevant ADR are listed as follows according to the World Health Organisation classification. Their frequency is defined using the following conventions: common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Central and peripheral nervous system disorders: Uncommon: headache, dizziness and paraesthesia.
Rare: vertigo.
Gastrointestinal system disorders: Common: diarrhoea, abdominal pain, dyspepsia.
Uncommon: gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence.
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.
Post-Marketing Experience: Bleeding is the most common reaction reported in the post-marketing experience and was mostly reported during the first month of treatment.
Bleeding: Some cases were reported with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); serious cases of skin bleeding (purpurea), musculoskeletal 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 ASA or clopidogrel with ASA and heparin (see Precautions).
In addition to clinical studies experience, the following adverse reactions have been spontaneously reported. Within each system organ class (MedDRA classification), they are ranked under heading of frequency. "Very rare" corresponds to <1/10,000. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders: Very rare: thrombotic thrombocytopenic purpurea (TTP) (1/200,000 exposed patients), severe thrombocytopenia (platelet count <30x10⁹/l), agranulocytosis, granulocytopenia, aplastic anaemia/pancytopenia, anaemia.
Immune system disorders: Very rare: anaphylactoid reactions, serum sickness.
Psychiatric disorders: Very rare: confusion, hallucinations.
Nervous system disorders: Very rare: taste disturbances.
Vascular disorders: Very rare: vasculitis, hypotension.
Respiratory, thoracic and mediastinal disorders: Very rare: bronchospasm, interstitial pneumonitis.
Gastrointestinal disorders: Very rare: pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis.
Hepato-biliary disorders: Very rare: acute liver failure, hepatitis.
Skin and subcutaneous tissue disorder: Very rare: angioedema, bulluos dermatitis (erythema multiforme, Stevens Johnson Syndrome, toxic epidermal necrolysis), rash erythematous, urticaria, eczema and lichen planus.
Mucoskeletal, connective tissue and bone disorder: Very rare: arthralgia, arthritis, myalgia.
Renal and urinary disorders: Very rare: glomerulonephritis.
General disorders and administration site conditions: Very rare: fever.
Investigations: Very rare: abdominal liver function test, blood creatinine increase.