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Clopidogrel

Pronunciation

Pronunciation: kloe-PID-oh-grel
Class: Aggregation inhibitor

Trade Names

Plavix
- Tablet 75 mg (as base)
- Tablet 300 mg (as base)

Pharmacology

Clopidogrel is a thienopyridine derivative, chemically related to ticlopidine, which inhibits platelet aggregation. It acts by irreversibly modifying the platelet adenosine diphosphate (ADP) receptor. Therefore, platelet aggregation is inhibited for both ADP-mediated and ADP-amplified (by other agonists) platelet activation. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.

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Pharmacokinetics

Absorption

Rapidly absorbed. T max is approximately 1 h. C max is approximately 3 mg/L.

Distribution

98% reversibly bound to plasma proteins; active metabolite is 94% reversibly bound to plasma proteins.

Metabolism

Extensively metabolized in the liver; undergoes rapid hydrolysis to carboxylic acid derivative (active).

Elimination

50% excreted in urine; 46% excreted in feces. The half-life of the active metabolite is 8 h.

Onset

2 h.

Peak

3 to 7 days.

Duration

Approximately 5 days.

Special Populations

Renal Function Impairment

After repeated doses of clopidogrel 75 mg/day, patients with severe (CrCl 5 to 15 mL/min) and moderate (CrCl 30 to 60 mL/min) renal impairment showed low (25%) inhibition of ADP-induced platelet aggregation.

Hepatic Function Impairment

After repeated dosages of clopidogrel 75 mg/day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy patients.

Elderly

Elderly patients 75 years of age and older and younger healthy patients had similar effects on platelet aggregation.

Gender

Less inhibition of ADP-induced platelet aggregation was observed in women.

Indications and Usage

Reduction of atherosclerotic events (eg, MI, stroke, vascular death) in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease; treatment of acute coronary syndrome (ACS) (unstable angina/non–ST-segment elevation MI), including patients managed with coronary revascularization; treatment of ACS in patients with ST-segment elevation acute MI.

Unlabeled Uses

As a loading dose regimen of clopidogrel with aspirin to prevent cardiac adverse reactions in patients undergoing coronary stent implantation.

Contraindications

Hypersensitivity to any component of the product; active pathological bleeding, such as peptic ulcer or intracranial hemorrhage.

Dosage and Administration

Acute Coronary Syndrome (ST-Segment Elevation Acute MI)
Adults

PO 75 mg once daily in combination with aspirin, with or without thrombolytic agents. Treatment may be initiated with or without a loading dose.

Acute Coronary Syndrome (Unstable Angina/Non–ST-Segment Elevation MI)
Adults

PO Start with a 300 mg loading dose, then continue at 75 mg once daily, initiating and continuing aspirin (75 to 325 mg/day) in combination with clopidogrel.

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

PO 75 mg once daily.

General Advice

Administer prescribed dose daily without regard to meals. Administer with food if GI upset occurs.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Aspirin

Clopidogrel and aspirin are coadministered in the treatment of ACS. The risk of life-threatening bleeding (eg, intracranial and GI hemorrhage) may be increased in high-risk patients with transient ischemic attack (TIA) or ischemic stroke. Avoid use of aspirin in high-risk patients with recent ischemic stroke or TIA who are receiving clopidogrel.

Bupropion

Plasma levels may be elevated by clopidogrel, increasing the risk of adverse reactions. Closely monitor patients. Adjust the bupropion dose as needed when clopidogrel is started or stopped.

CYP2C19 inhibitors (eg, cimetidine, esomeprazole, etravirine, felbamate, fluconazole, fluoxetine, fluvoxamine, ketoconazole, omeprazole, ticlopidine, voriconazole)

CYP2C19 inhibitors may decrease the pharmacologic effects of clopidogrel by decreasing metabolism to the active metabolite. Avoid coadministration of CYP2C19 inhibitors with clopidogrel.

Macrolide and related antibiotics (eg, erythromycin, telithromycin)

May inhibit the antiplatelet effects of clopidogrel. Monitor platelet function when starting or stopping macrolide and related antibiotics. Adjust the clopidogrel dose as needed. Because azithromycin does not inhibit CYP3A4, it may be a useful alternative.

NSAIDs

Risk of hemorrhage may be increased. Administer NSAIDs and clopidogrel with caution.

Proton pump inhibitors (eg, esomeprazole, omeprazole)

Controlled studies are needed to determine the magnitude of this interaction with each proton pump inhibitor and clopidogrel. The antiplatelet activity of clopidogrel may be decreased by proton pump inhibitors. Certain proton pump inhibitors (eg, omeprazole) may interfere with the metabolic (CYP2C19) conversion of clopidogrel to its active metabolite. If a proton pump inhibitor is clearly indicated in a patient receiving clopidogrel, use with caution. An antacid or H 2 receptor antagonist (eg, ranitidine) may be a safer alternative. Cimetidine inhibits CYP2C19 and is not recommended.

Rifamycins (eg, rifampin)

Antiplatelet effect of clopidogrel may be enhanced. Carefully monitor platelet function when starting, stopping, or changing the rifamycin dose. Adjust the clopidogrel dose as needed.

Warfarin

Because of the increased risk of bleeding, coadminister warfarin and clopidogrel with caution.

Adverse Reactions

The following adverse reactions were reported in combination with aspirin.

Cardiovascular

Hypotension, vasculitis (postmarketing).

CNS

Confusion, fatal intracranial bleeding, hallucinations (postmarketing).

Dermatologic

Angioedema, bullous dermatitis, eczema, erythema multiforme, lichen planus, maculopapular or erythematous rash, skin bleeding, Stevens-Johnson syndrome, TEN, urticaria (postmarketing).

EENT

Conjunctival, ocular, and retinal bleeding (postmarketing).

GI

Colitis (including ulcerative or lymphocytic), GI and retroperitoneal hemorrhage with fatal outcome, pancreatitis, stomatitis, taste disorders (postmarketing).

Genitourinary

Glomerulopathy, increased creatinine levels (postmarketing).

Hematologic

Minor bleeding (5%); major bleeding, any noncerebral bleeding, other non-major noncerebral bleeding (4%); life-threatening bleeding, other major bleeding (2%); life-threatening bleeding requiring transfusion (4 units or more) (1%); agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (postmarketing).

Hepatic

Abnormal LFTs, acute liver failure, hepatitis (postmarketing).

Musculoskeletal

Arthralgia, arthritis, musculoskeletal bleeding, myalgia (postmarketing).

Respiratory

Bronchospasm, interstitial pneumonitis, respiratory tract bleeding (postmarketing).

Miscellaneous

Anaphylactoid reactions, fever, hemorrhage of operative wound, hypersensitivity reactions, serum sickness (postmarketing).

Precautions

Warnings

The effectiveness of clopidogrel is dependent on its activation to an active metabolite, principally by CYP2C19. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with ACS or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher CV event rates than patients with normal CYP2C19 function.


Monitor

Bleeding

Monitor patient for bleeding or unusual bruising.


Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Experience is limited in patients with moderate and severe renal impairment.

Hepatic Function

No dosage adjustment is necessary in patients with hepatic impairment.

Bleeding risk

Use with caution in patients with increased bleeding from trauma, surgery, or other pathological conditions. If undergoing surgery and antiplatelet effect is not desired, discontinue clopidogrel 5 days prior.

Recent transient ischemic attack/stroke

The combination of clopidogrel and aspirin has been shown to increase major bleeding in these patients at high risk for recurrent ischemic reactions.

Thrombotic thrombocytopenic purpura

May occur, sometimes after short-term exposure (less than 2 wk).

Overdosage

Symptoms

Prolonged bleeding with subsequent bleeding complications.

Patient Information

  • Advise patient that each dose may be taken without regard to meals, but to take with food if stomach upset occurs.
  • Advise patient that if a dose is missed, to skip that dose and take the next dose at the regularly scheduled time.
  • Instruct patient not to change the dose or stop taking unless advised by health care provider.
  • Inform patient that it may take longer than usual to stop bleeding while taking clopidogrel and to report bleeding or unusual bruising to health care provider immediately.
  • Advise patient to inform health care providers about use of this drug before undergoing surgical or dental procedures, and before any new drug is taken.

Copyright © 2009 Wolters Kluwer Health.

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