Drug Class Description
Platelet aggregation inhibitors excl. Heparin

Generic Name
Clopidogrel

Drug Description
Plavix 75mg tablets: Each filmcoated tablet contains 75 mg of clopidogrel (as hydrogen sulphate).Excipients: each tablet contains 3 mg lactose and 3.3 mg hydrogenated castor oil.Plavix 300mg tablets: Each filmcoated tablet contains 300 mg of clopidogrel (as hydrogen sulphate).Excipients: each tablet contains 12 mg lactose and 13.2 mg hydrogenated castor oil

Presentation
Filmcoated tablets.Plavix 75mg tablets: Pink, round, biconvex, engraved with «75» on one side and «1171» on the other side.Plavix 300mg tablets: Pink, oblong, engraved with «300» on one side and «1332» on the other side.

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.• Patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

Adult Dosage
• Adults and elderlyClopidogrel should be given as a single daily dose of 75 mg with or without food.The 300 mg tablet of clopidogrel is intended for use as a loading dose 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 300mg 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. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months.- ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300mg 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. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting.• 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.

Child Dosage
There is no experience in children.

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 anti-inflammatory drugs including Cox-2 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 (alone or in combination with ASA), 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.Plavix contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.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 clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced 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. However, clopidogrel and ASA have been administered together for up to one year.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. Co-administration 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 non-fibrin 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 co-administered with ASANonSteroidal Anti-Inflammatory 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 Cox-2 inhibitors and clopidogrel should be co-administered 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 co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital, cimetidine, or oestrogen.The pharmacokinetics of digoxin or theophylline were not modified by the co-administration 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 co-administered with clopidogrel.Apart from the specific medicinal product 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 in more than 42,000 patients who have participated in clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies 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.In CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA (<100mg: 2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo+ASA (<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%). The risk of bleeding (life-threatening, major, minor, other) decreased during the course of the trial: 01 months (clopidogrel: 9.6%; placebo: 6.6%), 13 months (clopidogrel: 4.5%; placebo: 2.3%), 36 months (clopidogrel: 3.8%; placebo: 1.6%), 69 months (clopidogrel: 3.2%; placebo: 1.5%), 912 months (clopidogrel: 1.9%; placebo: 1.0%). 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 (4.4% clopidogrel+ASA vs. 5.3% placebo+ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel+ASA, and 6.3% for placebo+ASA.In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs. the placebo + ASA group (12.9%).The incidence of major bleeding was similar between groups (1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). 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 (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups, respectively).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 Class;"> CommonUncommonRareVery 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), stomatitisHepato-biliary 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
Sanofi-Aventis/BMS

Drug Availability
(POM)

Updated
29 June 2009