It is important to take the discussion further by looking at how much of an impact amiodarone has on digoxin concentrations, if it is clinically relevant and what clinicians should do with the dose of digoxin.    

A number of small studies and case reports have documented the increases in digoxin concentration when being administered with amiodarone.(1-5)  The most common dose of amiodarone used ranged from 400 - 1600 mg per day.  This resulted in reductions in systemic or total body clearances by 26-29%, nonrenal clearances by 32-33% and renal clearances by 20-22%.(1-5)  While these reductions in clearances may seem minor, because digoxin is a narrow therapeutic index drug it can result in nearly a doubling of the serum concentrations.(4)  One study done in both humans and animals showed that, when compared to baseline, amiodarone initiation resulted in an increase in digoxin concentrations from 1.0 +/- 0.4 ng/mL to 1.9 +/- 0.9 ng/ml (p<0.001) in humans and 0.6 +/- 0.2 ng/mL to 1.2 +/- 0.6 ng/mL in animals.4  As a result of these changes, most recommend at least a 50% reduction in the digoxin maintenance dose when initiating amiodarone.(2,3,6,7)

However, one factor may need to be considered when interpreting a serum digoxin concentration:  the timing of the blood draw used to assess the digoxin concentration in relation to the time of administration of amiodarone.(5)  Amiodarone appears to cause changes in serum digoxin concentrations because of an effect it has on tissue distribution.  A case report and animal studies have suggested that amiodarone decreases digoxin tissue distribution in a concentration dependent manner.5 At higher amiodarone concentrations, there appears to be a greater redistribution of digoxin from tissue to the serum.  As such, some have suggested waiting at least 8-10 hours after a patient has received a high dose of amiodarone before checking a digoxin concentration.(5)  This may not always be feasible, but may need to be taken into consideration when interpreting lab results.

Therefore, based on the above pharmacokinetic studies, digoxin's narrow therapeutic index profile and recognizing the lack of data demonstrating a mortality reduction, a standard reduction of 50% in the maintenance dose of digoxin when initiating amiodarone is appropriate.  In addition, consideration should be given to the time that the digoxin concentration is obtained and processed by the lab since changes in serum concentrations may fluctuate based on amiodarone concentrations.

• Drug Monograph: Amiodarone (Cordarone; Pacerone)
• Pharmacology: The Evidence & Mechanism - Amiodarone Induced Hyperthyroidism
• Pharmacology: Drug Interaction - Amiodarone and Warfarin
  
• Clinical Trials:  ARREST Trial - Amiodarone for Out-of-Hospital Pulseless Ventricular Tachycardia/Fibrillation

High-Yield Med Reviews publishes their Rapid Reviews by Dr. Anthony Busti occasionally that relate to EBM Consult topics:

• YouTube Lecture:  How Amiodarone Causes QT Prolongation by Dr. Anthony Busti

1. Moysey JO, Jaggarao NS, Grundy EN et al.  Amiodarone increases plasma digoxin concentrations.  Br Med J  1981;282:272.
2. Nademanee K, Kannan R, Hendrickson J et al.  Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications.  J Am Coll Cardiol  1984;4:111-6.
3. Fenster PE, White NE Jr, Hanson CD.  Pharmacokinetic evaluation of the digoxin-amiodarone interaction.  J Am Coll Cardiol  1985;5:108-12.
4. Oetgen WJ, Sobol SM, Tri TB et al.  Amiodarone-digoxin interaction.  Clinical and experimental observations.  Chest  1984;86:75-9.
5. DeVores KJ, Hobbs RA.  Plasma digoxin concentration fluctuations associated with timing of plasma sampling and amiodarone administration.  Pharmacotherapy  2007;27:472-475.
6. Winter M.  Chapter 3: Drug Monograph Digoxin.  In: Basic Clinical Pharmacokinetics. 4^th ed.  Winters M ed.  Lippincott Williams & Wilkins.  2003;184-221.
7. Siddoway LA.  Amiodarone: guidelines for use and monitoring.  Am Fam Physician  2003;68:2189-96.

Amiodarone, Dig, Digoxin, Amiodarone Digoxin Interaction, Digoxin Dosing Amiodarone