Amiodarone Drug Interactions

Amiodarone Drug Interactions

ANTOINE T. JENKINS, PharmD
Methodist University Hospital

CARRIE OLIPHANT, PharmD, BCPS and TIMOTHY H. SELF, PharmD—Series Editor
University of Tennessee, Memphis

Volume 46 - Issue 14 - December 2006

Amiodarone, a class III antiarrhythmic, has become the drug of choice for the management of supraventricular and ventricular arrhythmias.1,2 Although not an FDA- approved indication, the use of amiodarone to treat atrial fibrillation is supported by practice guidelines from the American College of Cardiology/ American Heart Association (AHA) and the European Society of Cardiology.3 The AHA 2005 Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care suggest that amiodarone may be considered--before other antiarrhythmic therapy is given--for treatment of recurrent ventricular fibrillation and pulseless ventricular tachycardia that is resistant to CPR, precordial shocks, and vasopressors.4

A HIGH-RISK AGENT

Although amiodarone is widely used, it must be considered a high-risk agent. The drug has an extensive adverse-effect profile, including thyroid, hepatic, and pulmonary toxicities.5,6 Before therapy is initiated, baseline thyroid, liver, and pulmonary function tests are recommended. In addition, a baseline chest radiograph and eye examination should be performed. Because of the extremely long half-life of amiodarone, its effects can persist long after it has been discontinued.

Furthermore, amiodarone is associated with significant drug interactions, which require prudent monitoring and dosage adjustments. Our emphasis here is on the clinically relevant interactions; in Tables 1 through 5, we provide strategies to minimize risk.

     
 Table 1 — Amiodarone and CV agents: examples of clinically significant interactions* 
     
 Drug Comment/management 
 
 
 Warfarin2,7 
  • Significant increase in INR. Onset may be seen within 1 to 2 weeks. Peak effect is at 7 weeks.
 
   
   
  • Decrease warfarin dose by 20% to 30%. Higher maintenance doses of amiodarone may require even greater reductions in warfarin dose. Closely monitor INR.
 
 
 
 Simvastatin, lovastatin, atorvastatin8-10 
  • Increases risk of myopathy and rhabdomyolysis. Onset may be seen within 2 weeks.
 
   
   
  • Simvastatin dosage should not exceed 20 mg/d. Lovastatin dosage should not exceed 40 mg/d. No specific recommended dosage of atorvastatin.
 
   
   
  • Ask patients about muscle pain and weakness.
 
 
 
 Digoxin1,11 
  • Serum digoxin concentrations can increase by up to 104%. Onset can be as early as 2 days.
 
   
   
  • Monitor for GI, neurologic, and cardiac toxicities. Reduce digoxin dose by 50%. Monitor digoxin levels.
 
 
 
 Calcium channel blockers,2,12,13 ß-blockers2,14 
  • Additive effect, which can cause significant bradycardia and AV block.
 
   
  • Use combination with caution, especially in patients with underlying sinus node dysfunction or partial AV block.
 
  
 

MECHANISMS OF INTERACTION
Cytochrome P-450 enzyme system. Amiodarone is metabolized hepatically and serves as a substrate primarily for cytochrome P-450 (CYP) 3A4. In addition, it is a potent inhibitor of CYP 3A4, 2C9, 2D6, and 1A2.2

As a result, concurrent use of CYP 3A4 inhibitors can cause levels of amiodarone to increase and the use of CYP 3A4 inducers can result in decreased concentrations of amiodarone. Numerous amiodarone drug interactions are associated with the inhibition of CYP 3A4 and other CYP isoenzymes by amiodarone, resulting in increased serum concentrations of the other medications (see Tables 1 through 5 for examples).

Transporter proteins. P-glycoproteins act as energy-dependent transmembrane efflux pumps that play a role in the distribution of medications such as digoxin, cyclosporine, and protease inhibitors.2 These proteins are widely distributed in the intestines, but they are also located among the endothelial cells of the blood-brain barrier, kidneys, liver, and other organs. Amiodarone can inhibit P-glycoprotein expression, which results in supratherapeutic levels of agents absorbed via this pathway.

Pharmacodynamic interaction. This interaction occurs when the pharmacologic response to a given agent is changed by the actions of another drug.2 An example of this type of interaction would be 2 drugs that produce additive effects.

     
 Table 1 —Amiodarone and CV agents: examples of clinically significant interactions* (continued) 
     
 Drug Comment/management 
 
 
 Dofetilide, ibutilide, torsades quinidine, sotalol2,15-17 
  • Additive effect, which increases risk of QT prolongation and de pointes. Effects can be rapid.
 
   
   
  • Withhold amiodarone for at least 3 half-lives before administering dofetilide or sotalol.
 
   
   
  • Withhold amiodarone for 5 half-lives before and 4 hours after administering ibutilide.
 
   
   
  • Quinidine concentrations can increase by 33% with concurrent amiodarone use; decrease quinidine dose by 30% to 50%.
 
 
 
 Lidocaine, procainamide, flecainide, propafenone15,18-21 
  • Amiodarone increases serum levels of each agent.
 
   
   
  • Monitor for lidocaine-induced CNS toxicity and adjust lidocaine dose.
 
   
   
  • Monitor for procainamide-induced hypotension and arrhythmias; procainamide dose may need to be reduced by one third.
 
   
  • Monitor for flecainide-induced proarrhythmias; reduce flecainide dose by 50%.
 
   
  • Monitor for propafenone-induced GI and CNS effects; reduce propafenone dose as needed.
 
 
 CV, cardiovascular; INR, international normalized ratio; AV, atrioventricular.
*These are examples only. See current texts and reviews for further information
 
     
 Table 2 — Amiodarone and antimicrobial agents: examples of clinically significant interactions* 
     
 Drug Comment/management 
 
 
 Quinolones,2,15,22,23 macrolides,2,15,24 ketolides25 
  • Additive effect, which increases risk of QT prolongation and torsades de pointes. Delayed onset.
 
   
   
  • Consider another antibacterial agent.
 
 
 
 Rifampin15 
  • Decreased amiodarone levels.
 
   
   
  • Monitor amiodarone efficacy; increase dose as needed.
 
   
 
 
 Protease inhibitors2,15,26 
  • Elevated amiodarone levels. Delayed onset.
 
   
   
  • Concomitant administration with ritonavir and nelfinaviris contraindicated.

     

 
   
   
  • Monitor for amiodarone toxicity, and reduce dose as needed.
 
 
 *These are examples only. See current texts and reviews for further information.
 
     
 Table 3 —Amiodarone and GI agents: examples of clinically significant interactions* 
     
 Drug Comment/management 
 
 
 Cholestyramine15 
  • Decreased amiodarone levels
 
   
   
  • Monitor amiodarone efficacy; increase dose as needed.
 
 
 
 Prokinetic agents,27 5-HT3 antagonists2,28 
  • Additive effect, which increases risk of QT prolongation and torsades de pointes.
 
   
   
  • Increased cisapride levels. Avoid concomitant use. Use metoclopramide as an alternative.

     

 
   
   
   
  • Monitor cardiac function if concurrent use of 5-HT3 antagonists and amiodarone cannot be avoided.
 
 
 
 Cimetidine29 
  • Can increase amiodarone levels by about 40%.
 
   
   
  • Avoid concomitant use. Use another H2-blocker.
 
 
 *These are examples only. See current texts and reviews for further information.
 
     
 Table 4 — Amiodarone and neurologic agents: examples of clinically significant interactions* 
     
 Drug Comment/management 
 
 
 Antipsychotics30 torsades 
  • Additive effect, which increases risk of QT prolongation and de pointes.
 
   
   
  • Avoid concomitant use. Monitor closely if use cannot be avoided.
 
   
   
  • Other antipsychotics and antidepressants could cause QT prolongation, but not all interactions are supported by primary literature.
 
 
 
 Phenytoin, fosphenytoin2,31,32 
  • Increases serum phenytoin concentrations or decreases amiodarone concentrations. Delayed onset.
 
   
   
  • Monitor for CNS toxicity and amiodarone clinical efficacy. Adjust doses accordingly.
 
 
 *These are examples only. See current texts and reviews for further information.
 
     
 Table 5 —Amiodarone and miscellaneous agents: examples of clinically significant interactions* 
     
 Drug Comment/management 
 
 
 Cyclosporine33,34 
  • Elevated cyclosporine levels; levels can increase 2- to 3-fold.
 
   
   
  • Supratherapeutic cyclosporine levels affect every organ system. Delayed onset. Monitor levels and adjust dose accordingly.
 
 
 
 Grapefruit/grapefruit juice15,35 
  • Increased amiodarone levels. Can occur with 200 - 300 mL of juice or with whole fruit segments.
 
   
   
  • Avoid concomitant use.
 
 
 
 Anesthetic agents15,36 
  • Additive effect, which increases risk of hypotension and bradycardia.
 
   
  • Close monitoring is necessary.
 
 
 *These are examples only. See current texts and reviews for further information.
 
References

1. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Arch Intern Med. 2000;160: 1741-1748.
2. Yamreudeewong W, DeBisschop M, Martin LG, Lower DL. Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf. 2003;26: 421-438.
3. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2001;38: 1231-1266.
4. American Heart Association. AHA 2005 Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care. Part 7.2: Management of cardiac arrest. Circulation. 2005;112(suppl 24):IV-58-IV-66.
5. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects: a review with special reference to torsade de pointes tachycardia. Ann Intern Med. 1994;121:529-535.
6. Siddowat LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician. 2003;68:2189-2196.
7. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest. 2002;121:19-23.
8. Zocor [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2005.
9. Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother. 2004;38: 978-981.
10. Mevacor [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2006.
11. 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: 111-116.
12. Lubic SP, Nguyen KPV, Dave B, Giacomini JC. Antiarrhythmic agent amiodarone possesses calcium channel blocker properties. J Cardiovasc Pharmacol. 1994;24:707-714.
13. Marcus FI. Drug interactions with amiodarone. Am Heart J. 1983;106:924-928.
14. Werner D, Wuttke H, Fromm MF, et al. Effect of amiodarone on the plasma levels of metoprolol. Am J Cardiol. 2004;94:1319-1321.
15. Cordarone [package insert]. Madison, NJ: Wyeth Pharmaceuticals; 2005.
16. Tikosyn [package insert]. New York: Pfizer, Inc; 2004.
17. Tartini R, Kappenberger L, Steinbrunn W, Meyer UA. Dangerous interaction between amiodarone and quinidine. Lancet. 1982;1:1327-1329.
18. Saal AK, Werner JA, Greene HL, et al. Effect of amiodarone on serum quini-dine and procainamide levels. Am J Cardiol. 1984;53:1264-1267.
19. Ha HR, Candinas R, Stieger B, et al. Interaction between amiodarone and lidocaine. J Cardiovasc Pharmacol. 1996;28:533-539.
20. Windle J, Prystowsky EN, Miles WM, Heger JJ. Pharmacokinetic and elec-trophysiologic interactions with amiodarone and procainamide. Clin Pharmacol Ther. 1987;41:603-610.
21. Leclercq JF, Denjoy I, Mentre F, Coumel P. Flecainide acetate dose-concentration relationship in cardiac arrhythmias: influence of heart failure and amiodarone. Cardiovasc Drugs Ther. 1990;4:1161-1165.
22. Kahn JB. Quinolone-induced QT prolongation: a not-so-unexpected class effect. J Antimicrob Chemother. 2000;46:847-848.
23.Culley CM, Lacy MK, Klutman N, Edwards B. Moxifloxacin: clinical efficacy and safety. Am J Health Syst Pharm. 2001;58:379-388.
24. Samarendra P, Kumari S, Evans SJ, et al. QT prolongation associated with azithromycin/amiodarone combination. Pacing Clin Electrophysiol. 2001;24: 1572-1574.
25. File TM. Telithromycin new product overview. J Allergy Clin Immunol. 2005;115:S1-S13.
26. Lohman JJ, Reichert LJ, Degen LP. Antiretroviral therapy increases serum concentrations of amiodarone. Ann Pharmacother. 1999;33:645-646.
27. Michalets EL, Williams CR. Drug interactions with cisapride: clinical implications. Clin Pharmacokinet. 2000;39:49-75.
28. Anzemet [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2005.
29. Hogan C, Landau S, Tepper D, et al. Cimetidine-amiodarone interaction. J Clin Pharmacol. 1988;28:909.
30. O'Brien JM, Rockwood RP, Suh KI. Haloperidol-induced torsade de pointes. Ann Pharmacother. 1999;33:1046-1050.
31. Nolan PE Jr, Marcus FI, Karol MD, et al. Effect of phenytoin on the clinical pharmacokinetics of amiodarone. J Clin Pharmacol. 1990;30:1112-1119.
32. McGovern B, Geer VR, LaRaia PJ, et al. Possible interaction between amiodarone and phenytoin. Ann Intern Med. 1984;101:650-651.
33. Chitwood KK, Abdul-Haqq AJ, Heim-Duthoy KL. Cyclosporine-amiodarone interaction. Ann Pharmacother. 1993;27:569-571.
34. Mamprin F, Mullins P, Graham T, et al. Amiodarone-cyclosporine interaction in cardiac transplantation. Am Heart J .1992;123:1725-1726.
35. Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs. 2004;4:281-297.
36. Liberman BA, Teasdale SJ. Anaesthesia and amiodarone. Can Anaesth Soc J. 1985;32:629-638.