Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Clopidogrel has been evaluated for safety in more than 44,000 patients, who have participated in clinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first 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 similar for clopidogrel and ASA.

In CURE, there was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five 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 vs. the placebo plus ASA group. The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

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% 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 from 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% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo + ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups.

In TARDIS, patients with recent ischemic stroke receiving intensive antiplatelet therapy with three medicinal products (ASA + clopidogrel + dipyridamole) had more bleeding and bleeding of greater severity when compared with either clopidogrel alone or combined ASA and dipyridamole (adjusted common OR 2.54, 95% CI 2.05-3.16, P<0.00001).


Tabulated list of adverse reactions
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

System
Organ             Common             Uncommon                       Rare                    Very rare, not known* Class
Blood and the                         Thrombocytopenia,          Neutropenia,      Thrombotic thrombocytopenic purpura (TTP) (see lymphatic                             leucopenia,                including         section 4.4), aplastic anaemia, pancytopenia, system                                eosinophilia               severe            agranulocytosis, severe thrombocytopenia, disorders                                                        neutropenia       acquired haemophilia A, granulocytopenia, anaemia
Cardiac                                                                            Kounis syndrome (vasospastic allergic angina / disorders                                                                          allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel*
Immune system                                                                      Serum sickness, anaphylactoid reactions, disorders                                                                          cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel)
(see section 4.4)*, insulin autoimmune syndrome,
which can lead to severe hypoglycemia,
particularly in patients with HLA DRA4 subtype
(more frequent in the Japanese population)*
Psychiatric                                                                        Hallucinations, Disorders                                                                          confusion Nervous                               Intracranial                                 Taste disturbances, ageusia system                                bleeding (some disorders                             cases were reported with fatal outcome),
headache,
paraesthesia,
dizziness
Eye                                   Eye bleeding disorders                             (conjunctival,
ocular, retinal)
Ear and                                                          Vertigo labyrinth disorders
Vascular           Haematoma                                                       Serious haemorrhage, haemorrhage of disorders                                                                          operative wound, vasculitis, hypotension Respiratory,       Epistaxis                                                       Respiratory tract bleeding (haemoptysis, thoracic and                                                                       pulmonary haemorrhage), bronchospasm, mediastinal                                                                        interstitial pneumonitis, eosinophilic pneumonia disorders
Gastrointestinal   Gastrointestinal   Gastric ulcer and          Retroperitoneal   Gastrointestinal and retroperitoneal disorders          haemorrhage,       duodenal ulcer,            haemorrhage       haemorrhage with fatal outcome, pancreatitis, diarrhoea,         gastritis, vomiting,                         colitis (including ulcerative or lymphocytic colitis), abdominal          nausea,                                      stomatitis pain, dyspepsia    constipation,
flatulence
Hepato-biliary                                                                     Acute liver failure, hepatitis, abnormal liver function disorders                                                                          test Skin and           Bruising           Rash, pruritus, skin                         Bullous dermatitis (toxic epidermal necrolysis, subcutaneous                          bleeding (purpura)                           Stevens Johnson Syndrome, erythema multiforme, tissue                                                                             acute generalised exanthematous pustulosis disorders                                                                          (AGEP)), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms
(DRESS), rash erythematous or exfoliative,
urticaria, eczema, lichen planus
Reproductive                                                     Gynaecomastia systems and breast disorders
Musculoskeletal,                                                                   Musculo-skeletal bleeding (haemarthrosis), connective                                                                         arthritis, arthralgia, myalgia tissue and bone disorders

System
Organ             Common               Uncommon                 Rare             Very rare, not known* Class
Renal and                              Haematuria                         Glomerulonephritis, urinary                                                                   blood creatinine increased disorders
General           Bleeding at                                             Fever disorders         puncture site and administration site conditions
Investigations                           Bleeding time prolonged,
neutrophil count decreased, platelet count decreased
* Information related to clopidogrel with frequency "not known".

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il