Plavix - Drug Monograph

Introduction

Plavix (clopidogrel bisulfate) is an oral antiplatelet medication belonging to the thienopyridine class. It is widely prescribed for the prevention of thrombotic events in patients with cardiovascular diseases. As a prodrug, clopidogrel requires hepatic activation to exert its therapeutic effects through irreversible inhibition of platelet aggregation.

Mechanism of Action

Clopidogrel is a prodrug that requires hepatic biotransformation via cytochrome P450 enzymes (primarily CYP2C19) to form an active metabolite. This active metabolite selectively and irreversibly inhibits the P2Y12 component of adenosine diphosphate (ADP) receptors on platelet surfaces. By blocking ADP-induced activation of the glycoprotein GPIIb/IIIa complex, clopidogrel prevents platelet aggregation and subsequent thrombus formation. The antiplatelet effect persists for the lifespan of platelets (approximately 7-10 days).

Indications

• Acute coronary syndrome (unstable angina, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction)
• Recent myocardial infarction, recent stroke, or established peripheral arterial disease
• Post-percutaneous coronary intervention (PCI) with stent placement to prevent stent thrombosis
• Reduction of atherosclerotic events in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease

Dosage and Administration

• Loading dose: 300-600 mg initially (higher loading doses provide more rapid antiplatelet effect)
• Maintenance dose: 75 mg daily

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: Use with caution in patients with severe hepatic disease
• Geriatric patients: No dosage adjustment necessary
• Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Hypersensitivity to clopidogrel or any component of the formulation
• Active pathological bleeding such as peptic ulcer or intracranial hemorrhage
• Severe hepatic impairment
• Use with caution in patients with genetic variants associated with poor CYP2C19 metabolism

Warnings and Precautions

• Bleeding risk: Increased risk of bleeding events including fatal bleeding. Discontinue 5-7 days prior to elective surgery.
• Thrombotic thrombocytopenic purpura (TTP): Rare cases reported, usually within first two weeks of therapy
• Genetic variability: CYP2C19 poor metabolizers have reduced antiplatelet effect and higher cardiovascular event rates
• Impaired CYP2C19 function: Proton pump inhibitors (especially omeprazole) may reduce antiplatelet effect
• Recent GI bleeding or peptic ulcer disease: Increased risk of GI bleeding

Drug Interactions

• NSAIDs: Increased risk of GI bleeding
• Warfarin: Increased risk of bleeding (avoid combination)
• Proton pump inhibitors: Omeprazole and esomeprazole significantly reduce antiplatelet effect (avoid or use alternative PPIs)
• Other antiplatelet agents: Increased bleeding risk
• CYP2C19 inhibitors: Fluconazole, fluvoxamine, fluoxetine, etc. may reduce efficacy
• Opioids: Delayed and reduced absorption of clopidogrel

Adverse Effects

• Bleeding (various types)
• Purpura
• Diarrhea
• Rash
• Pruritus

• Major bleeding (GI, intracranial)
• Thrombotic thrombocytopenic purpura
• Severe neutropenia/agranulocytosis
• Hepatitis
• Anaphylaxis

Monitoring Parameters

• Signs and symptoms of bleeding
• Complete blood count (particularly during first weeks of therapy)
• Liver function tests
• Stool occult blood testing
• Clinical efficacy (reduction in thrombotic events)
• Consider platelet function testing or genetic testing in high-risk patients

Patient Education

• Take medication exactly as prescribed at the same time each day
• Do not discontinue without consulting your physician
• Report any unusual bleeding or bruising immediately
• Inform all healthcare providers about clopidogrel use before any procedures
• Use caution with activities that may cause injury
• Avoid NSAIDs unless specifically approved by your physician
• Be aware that genetic factors may affect medication effectiveness
• Carry medical identification indicating antiplatelet therapy

References

1. FDA Prescribing Information: Plavix (clopidogrel bisulfate) 2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329-1339. 3. CURE Study Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502. 4. Mega JL, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821-1830. 5. Current guidelines from ACC/AHA and ESC for antiplatelet therapy 6. Product monograph: Sanofi-Aventis Canada Inc