Clopidogrel Taw Pharma (Previously Clopidogrel Mylan)

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.

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 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. 3%). 5% vs. 8%). 8%, respectively). 6%, respectively) between groups. 0001). 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 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 System Organ Class Common Uncommon Rare Very rare, not known* 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 Reproductive system and breast disorders Gynaecomastia Musculoskeletal, connective tissue and bone disorders Musculoskeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia Renal and urinary disorders Haematuria Glomerulonephritis, blood creatinine increased General disorders and administration site conditions Bleeding at puncture […]

8). 5). 8). 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 (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. The use of clopidogrel 600 mg loading dose is not recommended in patients with non-ST segment elevation acute coronary syndrome and ≥75 years of age due to increased bleeding risk in this population.

Due to the limited clinical data in patients ≥75 years old with STEMI PCI, and increased risk of bleeding, the use of clopidogrel 600 mg loading dose should be considered only after an individual assessment of the bleeding risk of the patient by the 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 • Initiation of therapy o In acute minor IS or moderate to high-risk TIA patients, dual antiplatelet therapy (clopidogrel and ASA) should be started no later than 24 hours after the event onset.

o There is no data regarding the benefit-risk of short term dual antiplatelet therapy in acute minor IS or moderate to high-risk TIA patients, with a history of (non-traumatic) intracranial haemorrhage. o In non-minor IS patients, clopidogrel monotherapy should be started only after the first 7 days of the event.

1). • Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated or planned There is no data to support the use of dual antiplatelet therapy in patients for whom treatment with carotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned for thrombolysis or anticoagulant therapy.

Dual antiplatelet therapy is not recommended in these situations.

Cytochrome P450 2C19 (CYP2C19) Pharmacogenetics:

In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel.

The clinical relevance of this interaction is uncertain. 2). Use of medicinal products that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk.

5). 5). 8). Thienopyridines may cause mild to severe allergic […]

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