Clopidogrel Ratiopharm GmbH

Posology • Adults and elderly Clopidogrel should be given as a single daily dose of 75 mg. In patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily).

Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. 1). 2Medicinal product no longer authorised - ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300 mg loading dose in combination with ASA and with or without thrombolytics.

For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. 1). If a dose is missed: - Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.

- For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose. 1). 4). 4). Method of administration For oral use It may be given with or without food.

Summary of the safety profile Clopidogrel has been evaluated for safety in more than 42,000 patients who have participated in clinical studies, including over 9,000 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 and COMMIT 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.

3%. The incidence of severe cases was similar for clopidogrel and ASA. In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery.

3% for placebo plus ASA. In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. 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. 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 the available data).

Within each system organ class, adverse reactions are presented in order of decreasing seriousness. 4)*, insulin autoimmune syndrome, which can lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population)* Psychiatric disorders Hallucinations, confusion Nervous system disorders Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness Taste disturbances, ageusia 8Medicinal product no longer authorised Eye disorders Eye bleeding (conjunctival, ocular, retinal) Ear and labyrinth disorders Vertigo Vascular disorders Haematoma Serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension Respiratory, thoracic and mediastinal disorders Epistaxis Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Gastrointestinal disorders Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia Gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence Retroperitoneal haemorrhage Gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis Hepato-biliary disorders Acute liver failure, hepatitis, abnormal liver function test Skin and subcutaneous tissue disorders Bruising Rash, pruritus, skin bleeding (purpura) Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme, acute generalised exanthematous pustulosis (AGEP)), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), rash erythematous, or exfoliative, urticaria, eczema, lichen planus 9Medicinal product no longer authorised Reproductive systems and breast disorders Gynaecomastia Musculoskeletal , connective tissue and bone disorders Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia Renal and urinary disorders Haematuria Glomerulonephritis, blood creatinine increased General disorders and administration site conditions Bleeding at puncture site Fever 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.

8). 5). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. 5). If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery.

Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel 3Medicinal product no longer authorised (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP) Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever.

TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. Acquired haemophilia Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered.

Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued. Recent ischaemic stroke In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

1. • Severe hepatic impairment. • Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.