indication

Intravenously, for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. Orally, for the treatment of life-threatening recurrent ventricular arrhythmias such as recurrent ventricular fibrillation and recurrent hemodynamically unstable ventricular tachycardia.

pharmacology

Amiodarone belongs to a class of drugs called Vaughan-Williams Class III antiarrhythmic agents. It is used in the treatment of a wide range of cardiac tachyarhthmias, including both ventricular and supraventricular (atrial) arrhythmias. After intravenous administration in man, amiodarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. Amiodarone prolongs phase 3 of the cardiac action potential. It has numerous other effects however, including actions that are similar to those of antiarrhythmic classes Ia, II, and IV. Amiodarone shows beta blocker-like and calcium channel blocker-like actions on the SA and AV nodes, increases the refractory period via sodium- and potassium-channel effects, and slows intra-cardiac conduction of the cardiac action potential, via sodium-channel effects.

mechanism of action

The antiarrhythmic effect of amiodarone may be due to at least two major actions. It prolongs the myocardial cell-action potential (phase 3) duration and refractory period and acts as a noncompetitive a- and b-adrenergic inhibitor.

toxicity

Intravenous, mouse: LD₅₀ = 178 mg/kg. Some side effects have a significant mortality rate: specifically, hepatitis, exacerbation of asthma and congestive failure, and pneumonitis.

biotransformation

Amiodarone is extensively metabolized in the liver via CYP2C8 (under 1% unchanged in urine), and can effect the metabolism of numerous other drugs. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone.

absorption

Slow and variable (about 20 to 55% of an oral dose is absorbed).

half life

58 days (range 15-142 days)

route of elimination

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine.

drug interactions

Acenocoumarol: Amiodarone may increase the anticoagulant effect of acenocoumarol.

Amprenavir: The protease inhibitor, amprenavir, may increase the effect and toxicity of amiodarone.

Anisindione: Amiodarone may increase the anticoagulant effect of anisindione.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atazanavir: Increased risk of cardiotoxicity and arrhythmias.

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clarithromycin: Increased risk of cardiotoxicity and arrhythmias

Colesevelam: Bile Acid Sequestrants may decrease the bioavailability of Amiodarone. Consider alternative antilipemic agent. The risk of subtherapeutic amiodarone serum concentrations when such is being used for the treatment of malignant arrhythmias can be very large. The effect (ie, reduced risk) of separating doses of these agents is unknown. Amiodarone should be administered at least 1 hour before or 4 hours after colesevelam.1 Similar dosing with other agents seems warranted.

Cyclosporine: Amiodarone may increase the therapeutic and adverse effects of cyclosporine.

Dabigatran etexilate: Amiodarone may increase the serum concentration of dabigatran etexilate, resulting in increased risk of bleeding. Consider modifying therapy.

Dicumarol: Amiodarone may increase the anticoagulant effect of dicumarol.

Digoxin: Amiodarone may increase the effect of digoxin.

Dihydroquinidine barbiturate: Increases the effect of quinidine

Diltiazem: Increased risk of cardiotoxicity and arrhythmias

Erythromycin: Increased risk of cardiotoxicity and arrhythmias

Ethotoin: Increases the effect of hydantoin

Fentanyl: Possible bradycardia, hypotension

Flecainide: Amiodarone may increase the effect and toxicity of flecainide

Fosamprenavir: The protease inhibitor, fosamprenavir, may increase the effect and toxicity of amiodarone.

Fosphenytoin: Amiodarone may increase the effect of fosphenytoin.

Gatifloxacin: Increased risk of cardiotoxicity and arrhythmias

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Indinavir: Indinavir increases the effect and toxicity of amiodarone

Iohexol: Increased risk of cardiotoxicity and arrhythmias

Levofloxacin: Increased risk of cardiotoxicity and arrhythmias

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephenytoin: Increases the effect of hydantoin

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Moxifloxacin: Increased risk of cardiotoxicity and arrhythmias

Nelfinavir: Nelfinavir may increase the effect and toxicity of amiodarone.

Phenytoin: Amiodarone may increase the therapeutic and adverse effects of phenytoin.

Procainamide: Amiodarone may increase serum levels and toxicity of procainamide.

Quinidine: Amiodarone may increase the effect of quinidine.

Quinidine barbiturate: Increases the effect of qiunidine

Ranolazine: Possible additive effect on QT prolongation

Rifampin: Rifampin decreases the effect of amiodarone

Ritonavir: Ritonavir increases the effect and toxicity of amiodarone

Saquinavir: The protease inhibitor, saquinavir, may increase the effect and toxicity of amiodarone.

Simvastatin: Increased risk of rhabdomyolysis

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Tamoxifen: Amiodarone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Amiodarone, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Amiodarone is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Amiodarone. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Amiodarone if Telithromycin is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Amiodarone. Concomitant therapy is contraindicated.

Tizanidine: Amiodarone may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Tolterodine: Amiodarone may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The p-glycoprotein inhibitor, Amiodarone, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Amiodarone may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Amiodarone may decrease the effect of Tramadol by decreasing active metabolite production.

Trazodone: The CYP3A4 inhibitor, Amiodarone, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Amiodarone is initiated, discontinued or dose changed.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Vardenafil: Increased risk of cardiotoxicity and arrhythmias

Verapamil: Additive bradycardic effects may occur. One case report of sinus arrest has been reported. Monitor for changes in the therapeutic effect and signs of Verapamil toxicity if Amiodarone is initiated, discontinued or dose changed.

Voriconazole: Additive QTc prolongation may occur. Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of amiodarone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of amiodarone if voriconazole is initiated, discontinued or dose changed.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Warfarin: Amiodarone may increase the anticoagulant effect of warfarin. Monitor for changes in prothrombin time and therapeutic effects of warfarin if amiodarone is initiated, discontinued or dose changed.

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).