Clopidogrel - Drug Monograph

Introduction

Clopidogrel is an oral antiplatelet medication belonging to the thienopyridine class. It is widely prescribed for the prevention of thrombotic events in patients with cardiovascular disease. As a prodrug, clopidogrel requires hepatic activation to exert its pharmacological effects. Since its approval in 1997, it has become a cornerstone therapy in cardiovascular medicine, particularly following acute coronary syndromes and percutaneous coronary interventions.

Mechanism of Action

Clopidogrel exerts its antiplatelet effects through irreversible inhibition of the P2Y12 adenosine diphosphate (ADP) receptor on platelet surfaces. After oral administration, clopidogrel undergoes hepatic biotransformation via cytochrome P450 enzymes (primarily CYP2C19) to form an active thiol metabolite. This active metabolite forms a disulfide bond with the P2Y12 receptor, permanently inhibiting ADP-mediated activation of the glycoprotein IIb/IIIa complex. This inhibition prevents ADP-induced platelet aggregation, reducing the formation of arterial thrombi.

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
• Prevention of thrombotic events following percutaneous coronary intervention with stent placement
• Reduction of atherosclerotic events in patients with atherosclerosis documented by recent stroke, recent MI, or established peripheral arterial disease

Dosage and Administration

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: Use with caution in patients with severe hepatic disease
• Geriatric patients: No dosage adjustment required
• 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 who may require urgent coronary artery bypass graft surgery

Warnings and Precautions

• Bleeding risk: Increased risk of bleeding including fatal bleeding events
• Thrombotic thrombocytopenic purpura (TTP): Rare cases reported, occurring within first two weeks of therapy
• Genotypic variations: CYP2C19 poor metabolizers have reduced antiplatelet response
• Discontinuation: Premature discontinuation increases risk of cardiovascular events
• Surgery: Consider discontinuing 5-7 days prior to elective surgery
• GI bleeding: Use with caution in patients with history of GI ulceration or bleeding

Drug Interactions

• NSAIDs: Increased risk of GI bleeding
• Warfarin: Increased risk of bleeding (avoid combination)
• Proton pump inhibitors: Omeprazole and esomeprazole may reduce antiplatelet effect through CYP2C19 inhibition
• Other antiplatelets: Increased bleeding risk with concomitant use
• CYP2C19 inhibitors: Fluconazole, fluoxetine, fluvoxamine, ticlopidine may reduce efficacy
• Opioids: May decrease absorption and antiplatelet effect

Adverse Effects

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

• Severe bleeding (GI, intracranial, retroperitoneal)
• Thrombotic thrombocytopenic purpura
• Neutropenia/agranulocytosis
• Aplastic anemia
• 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 effectiveness (reduction in thrombotic events)
• CYP2C19 genotype testing when available (for poor metabolizers)

Patient Education

• Take medication exactly as prescribed at the same time each day
• Do not discontinue without consulting healthcare provider
• Report any signs of bleeding (unusual bruising, blood in urine/stool, prolonged bleeding from cuts)
• Inform all healthcare providers about clopidogrel use before any procedures
• Use soft-bristle toothbrush and electric razor to minimize bleeding risk
• Avoid NSAIDs unless specifically advised by physician
• Report any fever, weakness, or pallor which may indicate blood disorders
• Carry medical identification indicating antiplatelet therapy

References

1. 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. 2. Yusuf S, Zhao F, Mehta SR, et al. 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. 3. Plavix® (clopidogrel) prescribing information. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. 4. Mega JL, Simon T, Collet JP, 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. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease. Circulation. 2016;134(10):e123-e155.