Clinically Significant Amiodarone Drug Interactions
(Updated September 2008)
- Amiodarone is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP2C8.1 It is also a potent inhibitor of CYP1A2, 2C9, 2D6, and 3A4.1-3 In addition, amiodarone may interact with drugs via the inhibition of the P-glycoprotein membrane transporter system.1,2
- This list should not be considered all inclusive. There are other potential drug interactions with amiodarone.
- Abbreviations: INR= International Normalized Ratio, TdP= Torsade de Pointes, AV=Atrial Ventricular
| Interacting Drug | Findings and Mechanism of Interaction1-7,11 | Recommendation/Comments |
| 5-HT3 Antagonists Dolasetron (Anzemet) Granisetron (Kytril) Ondansetron (Zofran) Palonosetron (Aloxi) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. (Use amiodarone and palonosetron together with caution). Monitor cardiac function closely if concurrent use cannot be avoided. |
| Antidepressants Amitriptyline (Elavil, etc) Desipramine (Norpramin) Doxepin (Sinequan) Fluoxetine (Prozac) Imipramine (Tofranil) Sertraline (Zoloft) Trazodone (Desyrel) Venlafaxine (Effexor) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. Monitor cardiac function closely if concurrent use cannot be avoided. |
| Antipsychotics Chlorpromazine (Thorazine) Mesoridazine (Serentil) Quetiapine (Seroquel) Thioridazine (Mellaril) Haloperidol (Haldol) Pimozide (Orap) Risperidone (Risperdal) Ziprasidone (Geodon) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. Monitor cardiac function closely if concurrent use cannot be avoided. |
| Azole Antifungals Fluconazole (Diflucan) Itraconazole (Sporanox) Ketoconazole (Nizoral) Voriconazole (Vfend) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. Increased amiodarone effect due to decreased metabolism. | Avoid concurrent use. Monitor cardiac function closely if concurrent use cannot be avoided. |
| Beta-Blockers (Atenolol, Metoprolol, Propranolol, etc). | Significant bradycardia or AV block. Possible additive beta-blocking effect. | Monitor cardiac function, especially heart rate. |
| Calcium Channel Blockers (Diltiazem, Verapamil, etc). | Significant bradycardia or AV block. Possible additive calcium channel blocking. Interaction more likely with diltiazem and verapamil due to competition for metabolism. | Monitor cardiac function, especially heart rate. |
| Cholestyramine (Questran) | Decreased amiodarone effect due to increased enterohepatic elimination of amiodarone. | Monitor amiodarone effect and adjust dose accordingly. |
| Cimetidine (Tagamet) | Increased amiodarone effect due to decreased metabolism. | Monitor amiodarone effect and adjust dose accordingly. Use another H2 antagonist if possible. |
| Cisapride (Propulsid) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. |
| Clopidogrel (Plavix) | Decreased inhibition of platelet aggregation by clopidogrel. | Be aware of this potential interaction. |
| Cyclosporine (Neoral, etc) | Increased cyclosporine levels due to decreased metabolism and decreased gastric emptying. | Monitor cyclosporine levels and adjust dose accordingly. More than 50% decrease in cyclosporine clearance has been reported. |
| Digoxin (Lanoxin) | Increased digoxin levels due to inhibition of P-glycoprotein. | Monitor digoxin levels and decrease digoxin dose by 50%. Increase of digoxin levels up to 100% within the first two days of co-administration has been observed. |
| Disopyramide (Norpace) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. Increased disopyramide effect due to decreased metabolism. | Avoid concurrent use if possible. Monitor cardiac effect and adjust disopyramide dose as needed if concurrent use cannot be avoided. |
| Dofetilide (Tikosyn) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. |
| Fentanyl (Sublimaze, etc) | Increased risk for hypotension, bradycardia, and decreased cardiac output due to decreased fentanyl metabolism. | Monitor cardiac effects. Discontinue one or both of the drugs if needed. |
| Flecainide (Tambocor) | Increased risk for cardiac arrhythmia due to decreased flecainide metabolism. | Monitor flecainide levels and watch for cardiac arrhythmias. Flecainide dose may need to be decreased by 50%. |
| Fluoroquinolones Gemifloxacin (Factive) Levofloxacin (Levaquin) Lomefloxacin (Maxaquin) Moxifloxacin (Avelox) Norfloxacin (Noroxin) Ofloxacin (Floxin) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. Ciprofloxacin is unlikely to cause QT prolongation, but it is a 3A4 inhibitor and can potentially increase amiodarone levels. Norfloxacin is also a 3A4 inhibitor. |
| Grapefruit/Grapefruit Juice | Increased amiodarone effect due to decreased metabolism. | Avoid concurrent use. |
| HMG-CoA Reductase Inhibitors Atorvastatin (Lipitor) Lovastatin (Mevacor) Simvastatin (Zocor) | Increased risk for myopathy/rhabdomyolysis due to decreased metabolism of these statins. | Avoid doses of simvastatin > 20 mg daily or doses of lovastatin > 40 mg daily or use pravastatin (Pravachol).12 Rosuvastatin (Crestor) unlikely to interact. Fluvastatin (Lescol) is primarily metabolized by CYP2C9. Amiodarone can also potentially decrease its metabolism. |
| Histamine H1 Antagonists Loratadine (Alavert, Claritin) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. |
| Ibutilide (Corvert) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. Do not give amiodarone within four hours of ibutilide infusion. |
| Lidocaine (Xylocaine) | Increased lidocaine levels due to decreased metabolism. | Monitor lidocaine levels and watch for cardiac/CNS toxicity. Adjust lidocaine dose as needed. |
| Macrolides Azithromycin (Zithromax) Clarithromycin (Biaxin) Erythromycin | Increased risk for QT prolongation and TdP due to additive effects of both drugs. Clarithromycin and erythromycin are also CYP3A4 inhibitors and can increase amiodarone effect due to decreased metabolism. | Avoid concurrent use. |
| Mexiletine (Mexitil) | Increased mexiletine levels due to decreased metabolism. | Avoid concurrent use. |
| Nevirapine (Viramune) | Decreased amiodarone effect due to increased metabolism. | Monitor amiodarone response and adjust amiodarone dose accordingly. |
| Phenytoin /Fosphenytoin (Dilantin/Cerebyx) | Increased phenytoin levels due to decreased phenytoin metabolism. Decreased amiodarone effect due to increased amiodarone metabolism. Fosphenytoin is a prodrug of phenytoin. | Monitor phenytoin levels and amiodarone effect. Adjust doses accordingly. |
| Procainamide (Procan) | Increased procainamide effect due to decreased clearance. | Monitor procainamide levels and cardiac function. Procainamide dose may need to be decreased by one-third. |
| Propafenone (Rythmol) | Increased propafenone effect due to decreased metabolism. | Monitor for propafenone toxicity and adjust dose if needed. |
| Protease Inhibitors Amprenavir (Agenerase) Atazanavir (Reyataz) Fosamprenavir (Lexiva) Indinavir (Crixivan) Lopinavir/Ritonavir (Kaletra) Nelfinavir (Viracept) Ritonavir (Norvir) Saquinavir (Invirase) Tipranavir (Aptivus) | Increased amiodarone effect due to decreased metabolism. | Avoid concurrent use. Monitor amiodarone levels and cardiac effect. Adjust amiodarone dose accordingly if concurrent use cannot be avoided. |
| Quinidine (Quinidex, etc) | Increased risk for prolonged QT interval and TdP due to decreased metabolism. 33% increase in quinidine serum concentration has been observed after two days of concurrent use. | Monitor quinidine levels and watch for cardiac arrhythmias. Quinidine dose may need to be decreased by 30% to 50%. |
| Rifampin (Rifadin) | Decreased amiodarone effect due to increased metabolism. | Avoid concurrent use. If concurrent use can't be avoided, monitor cardiac effect and increase amiodarone dose accordingly. |
| St. John's wort | Decreased amiodarone effect due to increased metabolism. | Monitor amiodarone effect and adjust dose accordingly. |
| Sotalol (Betapace) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. | Avoid concurrent use. |
| Telithromycin (Ketek) | Increased risk for QT prolongation and TdP due to additive effects of both drugs. Telithromycin is also a CYP3A4 inhibitor and can increase amiodarone effect due to decreased metabolism. | Avoid concurrent use. |
| Warfarin (Coumadin) | Increased bleeding risk due to decreased metabolism of warfarin. | Monitor INR closely and adjust warfarin dose accordingly. Warfarin dose may need to be decreased by 25% to 50%. Interactions may be seen as early as three to four days of concurrent use and may last up to one to two months after amiodarone discontinuation. |
Amiodarone Drug Interactions
Background
Amiodarone (Cordarone, etc) is a Class III antiarrhythmic drug that is commonly used to treat atrial fibrillation, ventricular fibrillation, and ventricular tachycardia. Amiodarone has an extensive side effect profile. Some of the side effects are potentially fatal. These include pulmonary toxicity, liver toxicity, and exacerbation of arrhythmias.
Due to its extensive side-effect profile, the requirement for a Medication Guide to be dispensed with each amiodarone prescription was mandated by the FDA in December of 2004.8,9 Aside from its extensive side-effect profile, amiodarone is also associated with numerous drug interactions.
Mechanisms of Interactions
Drug interactions with amiodarone can be divided into two major categories: pharmacodynamic and pharmacokinetic interactions.2,3
A pharmacodynamic interaction occurs when the clinical response to a given drug is either enhanced or inhibited without a change in pharmacokinetic parameters.2,3 This can occur when a patient take two agents that produce similar pharmacological effects. For example, when patients take two medications that prolong the QT interval, the risk of torsade de pointes is increased.
Pharmacokinetic interactions can result when one drug interferes with the absorption, distribution, metabolism, and/or elimination of another drug.2,3 Amiodarone is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP2C8.1 It is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4.1-3 In addition, amiodarone may interact with drugs via the inhibition of the P-glycoprotein membrane transporter system.1,2 P-glycoproteins are transmembrane proteins that act as efflux transporters.10 They play a key role in absorption, distribution, and elimination of many cancer chemotherapy agents and other drugs such as cyclosporine and digoxin.10 They are located in the intestine, the gonads, kidneys, biliary system, brain, and other organs.10
Conclusion
In general, the concurrent use of amiodarone with a drug that has been reported to significantly alter the pharmacokinetics and/or pharmacodynamics of amiodarone and vice versa is not recommended due to the potential for serious adverse consequences.2 If the concurrent use of amiodarone and the interacting drug cannot be avoided, caution should be exercised and the patient should be closely monitored to avoid or minimize the risk for adverse events. In some cases, the dosage of amiodarone or the interacting drug may need to be altered.
In some cases, the onset of the drug interaction may be delayed due to amiodarone's long and variable half-life (average 50 days).1,2 In addition, due to amiodarone's long and variable half-life, the potential for drug interactions exists not only with concomitant use but also with drugs administered after discontinuation of amiodarone.1,2
Clinicians should also be aware that drugs which cause electrolyte abnormalities, especially hypokalemia or hypomagnesemia (e.g., diuretics, amphotericin B, cisplatin), can cause patients to become more prone to the proarrhythmic effects of amiodarone.2 Patients taking amiodarone and diuretics concurrently should be monitored closely to ensure proper electrolyte balance.
Finally, due to amiodarone's extensive and potentially serious side effect profile, patients on long-term amiodarone therapy should be monitored closely.1,4 It is recommended to check liver function tests and thyroid function tests at baseline and every six months.4 Physical exam with chest x-ray should be checked every three to six months.1,11 ECG should be checked at baseline then annually. Serum creatinine and electrolytes should be checked at baseline and as needed.4 Pulmonary function tests and ophthalmology evaluations should also be done at baseline and as needed.4
Project Leaders in preparation of this Detail-Document: Wan-Chih Tom, Pharm.D. (original 2005); Stacy A. Hester, R.Ph., BCPS, Assistant Editor (Update September 2008)
References
- Product information for Cordarone. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. April 2008.
- Yamreudeewong W, DeBisschop M, Martin LG, Lower DL. Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Safety 2003;26:421-38.
- Trujillo TC, Nolan PE. Antiarrhythmic agents. Drug interactions of clinical significance. Drug Safety 2000;23:509-32.
- Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Arch Intern Med 2000;160:1741-8.
- Drugs that prolong QT interval and/or torsade de pointes. Pharmacist's Letter/Prescriber's Letter 2004;20(11):201111.
- Cytochrome P-450 drug interactions. Pharmacist's Letter/Prescriber's Letter 2006;22(2):220233.
- Roten L, Schoenenberger RA, Krahenbuhl S, et al. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004;38:978-81.
- Medication Guide for Cordarone Tablets. Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. September 2005.
- Medication Guide Required for Cordarone (Amiodarone). Pharmacist's Letter/Prescriber's Letter 2005;21(2):210207.
- Fatal interaction between clarithromycin and colchicines. Pharmacists' Letter/Prescriber's Letter 2005;21(10):211004.
- Product monograph for Cordarone. Wyeth. St. Laurent, QC H4R 1J6. September 2007.
- Becquemont L, Neuvonen M, Verstuyft C, et al. Amiodarone interacts with simvastatin but not with pravastatin disposition kinetics. Clin Pharmacol Ther 2007;81:679-84.
Cite this Detail-Document as follows: Clinically significant amiodarone drug interactions. Pharmacist's Letter/Prescriber's Letter 2005;21(12):211209.