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Cardiac products (Clopivas)
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Cardiac products (Clopivas)
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Clopivas
Clopidogrel Bisulphate Tablets
COMPOSITION
Each film-coated tablet contains:
Clopidogrel (as bisulfate) …… 75 mg
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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
Absorption
Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (is approximately equal to3 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.
Distribution
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 μg/mL.
Metabolism
Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it too has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma.
Elimination
Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.
INDICATIONS
Clopidogrel is indicated for the reduction of thrombotic events in patients with recent MI, recent stroke or established peripheral arterial disease and in acute coronary syndrome .
DOSAGE AND ADMINISTRATION
• Recent MI, recent stroke or established PAD: The recommended dose is 75 mg once daily.
• Acute Coronary Syndrome : Clopidogrel should be initiated with a single 300 mg loading dose and then continued at 75 mg once daily. Aspirin (75-325 mg) once daily should be initiated and continued in combination with clopidogrel.
CONTRAINDICATIONS
• Hypersensitivity to the drug
• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage
WARNINGS AND PRECAUTIONS
Drug Interactions
Aspirin: Clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. Clopidogrel and aspirin have been used together up to one year.
Heparin: In a study in healthy volunteers, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by clopidogrel.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In healthy volunteers receiving naproxen, concomitant administration of clopidogrel was associated with increased occult gastrointestinal blood loss. NSAIDs and clopidogrel should be coadministered with caution.
Warfarin: Because of the increased risk of bleeding , the concomitant administration of warfarin and clopidogrel should be undertaken with caution
Phenytoin, tamoxifen, tolbutamide, torsemide, fluvastatin and many NSAIDs : At high concentrations in vitro, clopidogrel inhibits P450 (2C9). Accordingly, clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, torsemide and fluvastatin, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with clopidogrel.
Thrombotic thrombocytopenic purpura (TTP)
TTP has been reported rarely following use of clopidogrel, sometimes after a short exposure (<2weeks). TTP is a serious condition requiring prompt treatment. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological findings, renal dysfunction, and fever. TTP has been reported at a rate of about four cases per million patients exposed, or about 11 cases per million patient-years.
GI Bleeding
Clopidogrel prolongs the bleeding time. Clopidogrel should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions (such as aspirin and other nonsteroidal anti-inflammatory drugs [NSAIDs]) should be used with caution in patients taking clopidogrel.
General
As with other anti-platelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 days prior to surgery.
Hepatic Impairment
Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Clopidogrel should be used with caution in this population.
Renal Impairment
Experience is limited in patients with severe renal impairment. Clopidogrel should be used with caution in this population.
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Clopidogrel should be used during pregnancy only if clearly needed.
Lactation
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.
Paediatric Use
Safety and effectiveness in the paediatric population have not been established.
UNDESIRABLE EFFECTS
The drug is generally well tolerated. Side effects that have been reported include abdominal pain, dyspepsia, gastritis, diarrhoea, constipation, gastrointestinal haemorrhage, neutropenia, rash, palpitation, syncope, asthenia, neuralgia, paresthesia and vertigo.
PACKAGING INFORMATION
Strip of 10 tablets
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