Major
amiodarone × warfarin
Class III antiarrhythmics (Vaughan Williams)×Vitamin K antagonist anticoagulants
Mechanism
Amiodarone potently inhibits CYP2C9 (the main enzyme metabolizing S-warfarin) and, to a lesser extent, CYP3A4 (R-warfarin metabolism). Warfarin concentration rises, with INR doubling or tripling. The effect develops gradually over 1–7 weeks and persists for weeks after amiodarone discontinuation due to its long half-life.
Management
When starting amiodarone in a patient on warfarin, empirically reduce the warfarin dose by 30–50 %. Monitor INR weekly for the first 6–8 weeks, then every 2 weeks until stable. After amiodarone discontinuation, expect warfarin requirements to rise for several more months.
Sources
- Pharmaceutical Press: Stockley's Drug Interactions, 12th edition (2024)— Preston CL (ed.). Stockley's Drug Interactions. 12th ed. London: Pharmaceutical Press; 2024
- Lexicomp: Lexicomp Drug Interactions (2024)— Wolters Kluwer Clinical Drug Information, Inc. Lexi-Interact Online, 2024
- FDA: FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers (2024)— FDA Center for Drug Evaluation and Research, last updated 2024
- Lexicomp: Drug Interactions: Warfarin and Amiodarone (2024)