PLAVIX

Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. 3, 9 Clopidogrel is indicated to reduce the risk of myocardial infarction for patients with non-ST elevated acute coronary syndrome (ACS), patients with ST-elevated myocardial infarction, and in recent MI, stroke, or established peripheral arterial disease, 9 It has been shown to be superior to aspirin in reducing cardiovascular outcomes in patients with cardiovascular disease and provides additional benefit to patients with acute coronary syndromes already taking aspirin.

Clopidogrel was granted

FDA approval on 17 November 1997.

Clopidogrel is indicated to reduce the risk of myocardial infarction for patients with non-ST elevated acute coronary syndrome (ACS), patients with ST-elevated myocardial infarction, and in recent MI, stroke, or established peripheral arterial disease,

Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. 3, 9 It has a long duration of action as it is taken once daily and a large therapeutic window as it is given in doses of 75-300 mg daily.

A 75 mg oral dose of clopidogrel is 50% absorbed from the intestine.

Clopidogrel can be taken with or without food.

A meal decreases the

AUC of the active metabolite by 57%.

The active metabolite of clopidogrel reaches a maximum concentration after 30-60 minutes.

Clopidogrel reached a

C max of 2.04±2.0ng/mL in 1.40±1.07h.

AUC for a 300 mg oral dose of clopidogrel was 45.1±16.2ngh/mL for poor metabolizers, 65.6±19.1ngh/mL for intermediate metabolizers, and 104.3±57.3ng*h/mL for extensive metabolizers.

C max was 31.3±13ng/mL for poor metabolizers, 43.9±14ng/mL for intermediate metabolizers, and 60.8±34.3ng/mL for extensive metabolizers.

The apparent volume of distribution of clopidogrel is 39,240±33,520 L.

85-90% of an oral dose undergoes first pass metabolism by carboxylesterase in the liver to an inactive carboxylic acid metabolite. 4 about 2% of clopidogrel is oxidized to 2-oxoclopidogrel.

This conversion is 35.8% by CYP1A2, 19.4% by CYP2B6, and 44.9% by CYP2C19 4 though other studies suggest CYP3A4, CYP3A5, and CYP2C9 also contribute. 3 2-oxoclopidogrel is further metabolized to the active metabolite. 3, 4 This conversion is 32.9% by CYP2B6, 6.79% by CYP2C9, 20.6% by CYP2C19, and 39.8% by CYP3A4. 3, 4 Hover over products below to view reaction partners Clopidogrel 2-Oxoclopidogrel Active Metabolite of Clopidogrel Clopidogrel carboxylic acid derivative.

An oral dose of radiolabelled clopidogrel is excreted 50% in the urine and 46% in the feces over 5 days.

The remainder of clopidogrel is irreversibly bound to platelets for their lifetime, or approximately 8-11 days.

That half life of clopidogrel is approximately 6 hours following a 75 mg oral dose while the half life of the active metabolite is approximately 30 minutes.

The clearance of a 75 mg oral dose was 18,960±15,890 L/h and for a 300 mg oral dose was 16,980±10,410 L/h.

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A single dose of clopidogrel at 1500-2000 mg/kg was lethal to mice and rats while 3000 mg/kg was lethal to baboons.

Symptoms of overdose include vomiting, breathing difficulty, gastrointestinal hemorrhage, and prostration.

Clopidogrel is irreversibly bound to platelets for their lifetime, which is approximately 11 days.

Overdoses of clopidogrel can be treated with platelet transfusions to restore clotting ability.

Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage Hypersensitivity to clopidogrel or any component of the product 4.1 Active Bleeding Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.

Acute coronary syndrome – Initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. – Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days.

MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose. 2.1 Acute Coronary Syndrome In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily.

Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days. 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 75 mg once daily orally without a loading dose.

USP, 75 mg are pink colored, round, biconvex, beveled edge, film-coated tablets debossed with ‘E’ on one side and ‘34’ on the other side.

Bottles of 30 NDC 65862-357-30 Bottles of 90 NDC 65862-357-90 Bottles of 100 NDC 65862-357-01 Bottles of 500 NDC 65862-357-05 Bottles of 1,000 NDC 65862-357-99 10 x 10 Unit-dose Tablets NDC 65862-357-10 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from moisture.

Preserve in well-closed containers.

Available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage.

There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke.

No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to and 78 times the recommended daily human dose.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Myocardial infarction and stroke are medical emergencies.

Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus.

Labor or delivery

Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage.

Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma.

When possible, discontinue clopidogrel to 7 days prior to labor, delivery, or neuraxial blockade.

Data Human data

The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes.

Animal data

Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to and 300 mg/kg/day, respectively, administered during organogenesis.

These doses, corresponding to and 78 times the recommended daily human dose, respectively, on a mg/m 2 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel.

Safety and effectiveness in pediatric populations have not been established.

A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt.

Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin, and the late initiation of therapy following shunt palliation.

It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older.

In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.

The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table and Table for the CURE and COMMIT trials, respectively.

No dosage adjustment is necessary in elderly patients.