Drug Description
Each filmcoated tablet contains 75 mg of clopidogrel (as besilate).Excipients: each tablet contains 3.80 mg hydrogenated castor oil.
Presentation
Film coated tablet.White to offwhite, marbled, round and biconvex film coated tablets.
Indications
Clopidogrel is indicated in adults for the prevention of atherothrombotic events in: • Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
Adult Dosage
• Adults and elderlyClopidogrel should be given as a single daily dose of 75 mg with or without food.• Paediatric patientsThe safety and efficacy of clopidogrel in children and adolescents have not yet been established.• Renal impairmentTherapeutic experience is limited in patients with renal impairment• Hepatic impairmentTherapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses
Contra Indications
• Hypersensitivity to the active substance or to any of the excipients.• Severe liver impairment.• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
Special Precautions
Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment. As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or nonsteroidal antiinflammatory drugs including Cox2 inhibitors. 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. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings.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, and that they should report any unusual bleeding (site or duration) to their physician.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.In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients.Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.This product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.
Interactions
Oral anticoagulants : the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings.Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions that receive concomitant glycoprotein IIb/IIIa inhibitors.Acetylsalicylic acid (ASA): ASA did not modify the clopidogrelmediated inhibition of ADPinduced platelet aggregation, but clopidogrel potentiated the effect of ASA on collageninduced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or nonfibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are coadministered with ASA.NonSteroidal AntiInflammatory Drugs (NSAIDs): in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox2 inhibitors and clopidogrel should be coadministered with caution.Other concomitant therapy: a number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital, cimetidine, or oestrogen.The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased plasma levels of medicinal products such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely coadministered with clopidogrel.Apart from the specific medicinal products interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.
Adverse Reactions
Clopidogrel has been eva luated for safety for 1 year or more. The clinically relevant adverse reactions observed in the CAPRIE study are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. 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 postmarketing 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 1.4% for clopidogrel and 1.6% for ASA.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). Within each system organ class, adverse drug reactions are presented in order of decreasing seriousness.System Organ ClassCommonUncommonRareVery rareBlood and the lymphatic system disordersThrombocytopenia, leucopenia, eosinophiliaNeutropenia, including severe neutropeniaThrombotic thrombocytopenic purpura (TTP) (see section 4.4), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anaemiaImmune system disordersSerum sickness, anaphylactoid reactionsPsychiatric disordersHallucinations, confusionNervous system disordersIntracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizzinessTaste disturbancesEye disordersEye bleeding (conjunctival, ocular, retinal)Ear and labyrinth disordersVertigoVascular disordersHaematomaSerious haemorrhage, haemorrhage of operative wound, vasculitis, hypotensionRespiratory, thoracic and mediastinal disordersEpistaxisRespiratory tract bleeding (haemoptysis, pulmonary haemorrhage), bronchospasm, interstitial pneumonitisGastrointestinal disordersGastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsiaGastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulenceRetroperitoneal haemorrhageGastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitisHepatobiliary disordersAcute liver failure, hepatitis, abnormal liver function testSkin and subcutaneous tissue disordersBruisingRash, pruritus, skin bleeding (purpura)Bullous dermatitis (toxic epidermal necrolysis, Stevens Johnson Syndrome, erythema multiforme), angioedema, rash erythematous, urticaria, eczema, lichen planusMusculoskeletal, connective tissue and bone disordersMusculoskeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgiaRenal and urinary disordersHaematuriaGlomerulonephritis, blood creatinine increasedGeneral disorders and administration site conditionsBleeding at puncture siteFeverInvestigationsBleeding time prolonged, neutrophil count decreased, platelet count decreased
Manufacturer
Sandoz Limited
Drug Availability
POM – Prescription Only Medicine
Updated
05 March 2010
