Prevention of atherosclerotic events in patients with history of symptomatic atherosclerotic diseases (ischemic stroke, myocardial infarction or acute coronary syndrome)
Clopidogrel is a prodrug. It inhibits platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. Dose-dependent inhibition of platelet aggregation can be seen at 2 hours after single oral doses. Repeated doses of 75 mg per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7.
Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibiting the generation of thromboxane A2 a powerful inducer of platelet aggregation and vasoconstriction.
Pharmacokinetics: After repeated 75-mg oral doses of Clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.00025 mg/L) beyond 2 hours after dosing. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma. Following an oral dose of 14C-labeled Clopidogrel in humans, approximately 50% is excreted in the urine and approximately 46% in the faeces in the 5 days after dosing. The elimination half-life of the main circulating metabolite is 8 hours after single and repeated administration. Administration of Clopidogrel with meals did not significantly modify the bioavailability of Clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.
Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated doses
of 75 mg Clopidogrel (base), with peak plasma levels (3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of Clopidogrel.
Absorption is at least 50% based on urinary excretion of Clopidogrel-related metabolites. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 g/mL.
Metabolism and Elimination: In vitro and in vivo, Clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.
Study of specific drug interactions yielded the following results:
Aspirin: Aspirin does not modify the Clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Clopidogrel potentiates the effect of aspirin on collagen-induced platelet aggregation.
Heparin: Clopidogrel does not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin has no effect on inhibition of platelet aggregation induced by Clopidogrel.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Concomitant administration of Clopidogrel is associated with increased occult gastrointestinal blood loss. NSAIDs and Clopidogrel should be co-administered with caution.
Warfarin: The safety of the co-administration of Clopidogrel with warfarin has not been established. Consequently, concomitant administration of these two agents should be undertaken with caution.
Hypersensitivity to any of the components or NSAIDs. Active pathological bleeding such as peptic ulcer or intracranial hemorrhage or bleeding disorders like hemophilia. Recent history of gastrointestinal bleeding.
Abdominal pain, nausea, vomiting, neuralgia, paraesthesia, rash, pruritis.
The combination drug should be avoided during the last three months of pregnancy. It is not recommended for use during breast feeding because of the possible risk of developing Reye’s syndrome.
Clopidogrel overdose may lead to bleeding complications. Based on biological plausibility, platelet transfusion may restore clotting ability. In moderate aspirin intoxication dizziness, headache, tinnitus, confusion, and gastrointestinal symptoms may occur which can be treated by inducing vomiting followed by gastric lavage if needed. In severe Aspirin intoxication respiratory alkalosis respiratory acidosis, metabolic acidosis, hyperthermia, perspiration, dehydration can occur. It can be treated with haemodialysis and other symptomatic treatment.
Keep in a cool & dry place (below 30ºC), protected from light & moisture. Keep out of the reach of children.
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