Clopistad

Clopidogrel.

One film-coated tablet contains clopidogrel 75 mg.

Pharmacology: Pharmacodynamics: Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.
Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.
Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Pharmacokinetics: Clopidogrel is rapidly but incompletely absorbed after oral administration, absorption appears to be at least 50%. It is a prodrug and is extensively metabolised in the liver, mainly to the inactive carboxylic acid derivative. The oxidative step is regulated primarily by Cytochrome P450 isoenzymes 2B6, 3A4, 1A1, 1A2 and 2C19. The active metabolite appears to be a thiol derivative but has not been identified in plasma. Clopidogrel and the carboxylic acid derivative are highly plasma protein bound. Clopidogrel and its metabolites are excreted in urine and in faeces, after oral administration, about 50% of a dose is recovered from the urine and about 46% from the faeces.

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; ST segment elevation acute myocardial infarction, in medically treated patients eligible for thrombolytic therapy.

Clopistad is administered orally with or without food.
Adults and elderly: A single daily dose: 75 mg.
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).
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.

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species.
Treatment: Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of clopidogrel if quick reversal is required.

Known hypersensitivity to clopidogrel or any ingredient in the formulation.
Severe liver impairment.
Presence of active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).

Clopidogrel prolongs bleeding time.
Use with caution in patients at increased risk of bleeding from trauma, surgery, ulcers, or other pathology, particularly gastrointestinal or intramuscular conditions. If bleeding or hematologic disorders are suspected, promptly consider determining blood cell counts or other appropriate monitoring. Discontinue clopidogrel 5-7 days prior to elective surgery or coronary artery bypass graft (CABG), if antiplatelet effect is undesirable. Drugs (e.g., aspirin, other nonsteroidal anti-inflammatory drugs) that might induce such lesions should be used with caution in patients receiving clopidogrel.
Use with caution because of possibility of bleeding diatheses in patients with severe hepatic disease.
Experience is limited in patients with severe renal impairment (creatinine clearance of 5 - 15 mL/minute); use with caution.
Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19 function (intermediate or poor metabolisers) have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function.
Effects on ability to drive and use machines: Clopidogrel has no or negligible influence on the ability to drive and use machine.

Pregnancy: There are no adequate and well-controlled studies in pregnant women, clopidogrel should be used during pregnancy only if clearly needed.
Lactation: Not known whether the drug is distributed into milk in humans. Discontinue nursing or the drug because of potential for severe adverse effects in infants.

The incidence of adverse effects, particularly blood dyscrasias, is lower with clopidogrel, although fatalities have been reported.
Common: Haematoma, epistaxis, gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia, bruising, bleeding at puncture site.
Uncommon: Thrombocytopenia, leucopenia, eosinophilia, intracranial bleeding, headache, paraesthesia, dizziness, eye bleeding, gastric ulcer and duodenal ulcer, gastritis, vomiting, nausea, constipation, flatulence, rash, pruritus, skin bleeding (purpura), haematuria.
Rare: Neutropenia including severe neutropenia, vertigo, retroperitoneal haemorrhage.
Very rare: Thrombotic thrombocytopenic purpura (TTP), aplastic anaemia, pancytopenia, agranulocytosis, severe thrombocytopenia, granulocytopenia, anaemia, serum sickness, anaphylactoid reactions, hallucinations, confusion, taste disturbances, serious haemorrhage, haemorrhage of operative wound, vasculitis, hypotension, respiratory tract bleeding, bronchospasm, interstitial pneumonitis, gastrointestinal and retroperitoneal haemorrhage with fatal outcome, pancreatitis, colitis, stomatitis, acute liver failure, hepatitis, abnormal liver function test, bullous dermatitis, angioedema, rash erythematous, urticaria, eczema, lichen planus, musculo-skeletal bleeding, arthritis, arthralgia, myalgia, glomerulonephritis, blood creatinine increased, fever.

Since clopidogrel is metabolised to its active metabolite by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 (e.g. proton pump inhibitors) should be discouraged.
Aspirin: There is an increased risk of bleeding if clopidogrel is given with aspirin, but the use of low-dose aspirin and clopidogrel can be beneficial.
Heparin: No alteration of heparin dosage or coagulation effect and no effect on clopidogrel-induced inhibition of platelet aggregation with concomitant therapy. 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 ASA.
Other nonsteroidal anti-inflammatory agents: Clopidogrel warn about possible gastrointestinal bleeding if it is used with naproxen or other nonsteroidal anti-inflammatory drugs.
Warfarin: Potential pharmacodynamic interaction (increased risk of bleeding).

Do not store above 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

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