Why is amiodarone discontinued in a patient with elevated International Normalized Ratio (INR) on Coumadin (warfarin)?

Amiodarone Discontinuation with Elevated INR on Warfarin

Amiodarone should be discontinued in a patient with an INR of 4.6 on warfarin 5mg due to its potent inhibition of warfarin metabolism through CYP2C9, which significantly increases bleeding risk. 1, 2

Mechanism of Interaction

Amiodarone and its active metabolite desethylamiodarone inhibit multiple CYP450 enzymes, particularly:

• CYP2C9 (primarily by desethylamiodarone) - the main enzyme that metabolizes warfarin 3
• P-glycoprotein - affects warfarin transport 2

This interaction results in:

• Reduced warfarin clearance
• Increased prothrombin time and INR
• Significantly elevated bleeding risk

Evidence of Interaction Severity

The interaction between amiodarone and warfarin is well-documented and clinically significant:

• Amiodarone increases mean INR from 2.6 to 3.1 in patients on stable warfarin therapy 4
• 37% of patients develop supratherapeutic INR >3.0 after amiodarone initiation 4
• 5.5% develop dangerously high INR >4.0 4
• The interaction peaks at approximately 7 weeks after initiation 5
• Requires an average 25% reduction in warfarin dose to maintain therapeutic INR 4

Management Algorithm

1. For INR 4.6 on warfarin 5mg with concurrent amiodarone:

   • Discontinue amiodarone due to dangerous elevation of INR 1
   • Hold warfarin doses until INR approaches therapeutic range
   • Consider vitamin K administration if bleeding risk is high 1

2. After amiodarone discontinuation:

   • Monitor INR at least weekly for 6-8 weeks 1
   • Gradually increase warfarin dose as amiodarone is eliminated
   • Be aware that amiodarone has an extremely long half-life (average 58 days) 6

3. Alternative antiarrhythmic considerations:

   • Consider alternative antiarrhythmics with less interaction potential
   • If amiodarone is absolutely necessary, reduce warfarin dose by 25-40% depending on amiodarone maintenance dose 5

Dose-Dependent Relationship

The magnitude of interaction depends on amiodarone dosage:

• 400mg/day amiodarone: reduce warfarin by ~40%
• 300mg/day amiodarone: reduce warfarin by ~35%
• 200mg/day amiodarone: reduce warfarin by ~30%
• 100mg/day amiodarone: reduce warfarin by ~25% 5

Monitoring Recommendations

When amiodarone and warfarin must be used concurrently:

• Monitor INR at least weekly during first 6 weeks of treatment 1
• Continue close monitoring throughout treatment
• Anticipate that the interaction may take weeks to fully manifest
• Be aware that the interaction persists for weeks to months after amiodarone discontinuation due to its long half-life 6

Clinical Implications

An INR of 4.6 represents a significant bleeding risk that requires immediate intervention. The FDA label specifically warns that amiodarone "can result in serious or fatal bleeding" when combined with warfarin 2. Given this patient's already elevated INR of 4.6 (well above the therapeutic range of 2-3), discontinuing amiodarone is necessary to reduce the risk of serious hemorrhagic complications.