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
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.
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.
- 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.
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
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
LD, Wienkers L, Kunze K, et. al. The mechanism of the interaction
between amiodarone and warfarin in humans. Clin Pharmacol Ther
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.
NZ, Blevins RD, Goldman L, et. al. The incidence, magnitude, and time
course of the amiodarone-warfarin interaction. Arch Intern Med
- Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction. Chest. 2002;121(1):19-23.
- Hamer A, Peter T, Mandel WJ, et. al. The potentiation of warfarin anticoagulation by amiodarone. Circulation. 1982;65(5):1025-1029.