Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.
Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established atherosclerotic cardiovascular disease as evidence by stroke or transient ischemic attacks, myocardial infarction, or need for bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.
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 as active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet activation by released ADP. Clopidogrel are affected for the remainder of their lifespan. Dose dependent inhibition of platelet aggregation can be seen 2 hours after oral single doses of Clopidogrel. Repeated doses of 75mg 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.
Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated doses 75mg Clopidogrel (base), with peak plasma levels (≡ 3mg/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 50mg to 150mg 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 protein (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100mcg/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.
Clopidogrel is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.
- The use of Clopidogrel is contraindicated in the following conditions:
- Hypersensitivity to the drug substance or any component of the product.
- Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
- Severe liver impairment.
- Pregnancy and Breast Feeding
DOSAGE AND ADMINISTRATION:
For prophylaxis of Thromboembolic events: The usual dose is Clopidogrel 75mg once daily.
For the management of acute coronary syndrome, including unstable angina and non-Q wave myocardial infarction: Clopidogrel is given as single 300mg loading dose, followed by 75mg once daily. Or as prescribed by physician. Drug is not approved for use in children.
No dosage adjustment is necessary for elderly patients or patients with renal disease.
Clopidogrel can be taken with or without the food. If you forget to take a dose of Clopidogrel take it as soon as you remember. If it is almost time for your next dose, skip the forgotten dose and continue with your regular schedule.
PRECAUTION AND WARNING:
Thrombotic Thrombocytopenic Purpura (TTP): TTP has been reported rarely following the use of Clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious condition requiring prompt treatment. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes (fragmented RBC) seen on peripheral smear), neurological findings, renal dysfunctions, and fever.
General: 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. If a patient is to undergo elective surgery and an antiplatelet effect is not desired. Clopidogrel should be discontinued 7 days prior to surgery.
Gastrointestinal Bleeding: Clopidogrel can prolong the bleeding time. In CAPRIE, Clopidogrel was associated with a rate of gastrointestinal bleeding of 2.0% vs 2.7% of aspirin. 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 non-steroidal anti-inflammatory (NSAIDs) should be used with caution in patients taking Clopidogrel.
Use in Hepatically Impaired Patients: Experience is limited in patients with severe hepatic disease, who may have bleeding diathesis. Clopidogrel should be used with caution in this population.
Information for Patients: Patients should be told that is may take them longer than usual to stop bleeding when they take Clopidogrel, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking Clopidogrel before any surgery is scheduled and before any new drug is taken.
Pregnancy: Clopidogrel should be used during pregnancy only if clearly needed.
Nursing Mothers: Studies in rats have shown that Clopidogrel and/or its metabolites are excreted in the milk. 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 or to discontinue the drug, taking into account the importance of the drug to the nursing woman.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established.]
The side effects from Clopidogrel are not common but in few cases any of the following symptoms may occur. Upset stomach, fatigue, muscle aches (flu-like symptoms), stomach pain, headaches, diarrhea, constipation, rash or purple areas on skin. If you experience any of the following symptoms, consult physician immediately: i.e. chest pain, unusual bleeding or bruising, bloody vomit, dark urine, bloody diarrhea, tarry stools, fever, constipation, rash or purple areas on skin.
Other side effects, reported rarely, include serum sickness, interstitial pneumonitis, erythema multiforme, Stevens-Johnson syndrome, lichen planus, and myalgia.
- Aspirin did not modify the Clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500mg of Aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by Clopidogrel. Clopidogrel potentiated the effect of Aspirin on collagen-induced platelet aggregation. The safety of chronic concomitant administration of Aspirin and Clopidogrel has not been established.
- In a study in healthy volunteers, 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 inhibition of platelet aggregation induced by Clopidogrel. The safety of this combination has not been established, however, concomitant use should be undertaken with caution.
- In healthy volunteers receiving Naproxen, concomitant administration of Clopidogrel was associated with increased occult gastrointestinal blood loss. Non-steroidal Anti-inflammatory Drugs (NSAIDs) and Clopidogrel should be coadministered with caution.
- The safety of the coadministration of Clopidogrel with Warfarin has not been established. Consequently concomitant administration of these two agents should be undertaken with caution.
- No clinically significant pharmacodynamic interactions were observed when Clopidogrel was coadministered with Atenolol, or both Atenolol and Nifedipine. The pharmacodynamic activity of Clopidogrel was also not significantly influenced by the coadministration of phenobarbital, Cimetidine or estrogen. The pharmacokinetics of Digoxin or Theophylline were not modified by the coadministration of Clopidogrel.
Store at a temperatures not exceeding 30oC.
Protect from light and moisture. Keep out of the reach of children.