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The Mechanism and Drug Interaction - Warfarin (Coumadin) and Amiodarone (Cordarone)

Summary:

  • Patients who have conditions that require warfarin therapy frequently experience arrhythmias that may require treatment with an antiarrhythmic such as amiodarone.
  • Amiodarone is a potent inhibitor of the enzymes responsible for warfarin metabolism.
  • Decreased metabolism of warfarin leads to higher plasma concentrations and an increased risk of bleeding complications.
  • When initiating amiodarone in a patient receiving warfarin, the dose of warfarin should be decreased and more frequent monitoring of the INR should occur.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
  Donald S. Nuzum, PharmD, BCACP, CDE
Last Reviewed: October 2015

Explanation

  • Warfarin (Coumadin, Jantoven) is an oral anticoagulant most commonly used for the prevention and treatment of thromboembolic events (blood clots) in patients with atrial fibrillation, prosthetic heart valves, venous thrombosis and/or pulmonary embolism.1  As a complication of their diagnosis, some patients taking warfarin will also develop supraventricular or ventricular arrhythmias which may require treatment with an antiarrhythmic medication.  Amiodarone (Cordarone, Pacerone) is considered one of the first-line antiarrhythmics for these conditions.2,3  Therefore, many patients will have an indication for concomitant warfarin and amiodarone therapy.

    The reason for considering a dosage reduction of warfarin when initiating amiodarone is the effect of amiodarone on warfarin metabolism.  Warfarin is a racemic (equal) mixture of two enantiomers, S-warfarin and R-warfarin.  While both enantiomers are pharmacologically active, S-warfarin is known to be responsible for the majority of the clinical effect and toxicity of warfarin as it is five times more potent than R-warfarin.  Both S-warfarin and R-warfarin are metabolized by cytochrome P450 (CYP) enzymes (a group of gastrointestinal and liver enzymes responsible for drug metabolism).  Amiodarone is a potent inhibitor of a number of cytochrome P450 enzymes.  This includes CYP2C9 and CYP(1A2 and 3A4) which are largely responsible for S-warfarin and R-warfarin metabolism, respectively.4,5   Inhibition of these enzymes by amiodarone will result in increased plasma concentrations and decreased clearance of both enantiomers, thereby increasing the patient's prothrombin time and international normalized ratio (INR).5  This places the patient at significant risk for bleeding complications.  Therefore, initiation of amiodarone in a patient receiving stable doses of warfarin will potentiate the action of warfarin and result in an increased risk of hemorrhagic complications.

    The effects of this interaction are typically seen in the first two weeks, usually within the first few days.6,7  However, in some patients the full manifestation of this effect may not be evident for several weeks.7  Because of the severity and consistency of this interaction, it is recommended that the dose of warfarin be reduced by one-third to one-half when initiating amiodarone therapy.6-8  Furthermore, given the long-half life of amiodarone, several dosage adjustments maybe needed before the patient's new warfarin dosage is finally determined and the INR has completely stabilized.  This would be especially true in patients whose amiodarone dose has been changed as well.

    References:

    1. Ansell J, Hirsh J, Hylek E, et. al.  Pharmacology and management of the vitamin K antagonists:  American College of Chest Physicians evidence-based clinical practice guidelines  Chest  2008;133(6 Suppl):160S-198S.
    2. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et. al.  ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary. a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology committee for practice guidelines.  J Am Coll Cardiol  2003;42(8):1493-1531.
    3. Zipes DP, Camm AJ, Borggrefe M, et. al.  ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines.  Circulation  2006;114(10):e385-484.
    4. Heimark LD, Wienkers L, Kunze K, et. al.  The mechanism of the interaction between amiodarone and warfarin in humans.  Clin Pharmacol Ther  1992;51:398-407.
    5. O'Reilly RA, Trager WF, Rettie AE, et. al.  Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans.  Clin Pharmacol Ther  1987;42(3):290-294.
    6. Kerin NZ, Blevins RD, Goldman L, et. al.  The incidence, magnitude, and time course of the amiodarone-warfarin interaction.  Arch Intern Med  1988;148(8):1779-1781.
    7. Sanoski CA, Bauman JL.  Clinical observations with the amiodarone/warfarin interaction.  Chest.  2002;121(1):19-23.
    8. Hamer A, Peter T, Mandel WJ, et. al.  The potentiation of warfarin anticoagulation by amiodarone.  Circulation.  1982;65(5):1025-1029.

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MESH Terms & Keywords

  • Warfarin, Coumadin, Jantoven, Amiodarone, Cordarone, Pacerone, Warfarin and Amiodarone Dug interaction