Amiodarone HCl (Page 3 of 6)

7 DRUG INTERACTIONS

Because of amiodarone’s long half-life, expect drug interactions to persist for weeks to months after discontinuation of amiodarone.

Drug interactions with amiodarone are described in Table 1 below.

Table 1: Amiodarone Drug Interactions

Concomitant Drug Class/Name	Examples	Clinical Comment
Pharmacodynamic Interactions
QT Prolonging Drugs	class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents	Increased risk of Torsade de Pointes. Avoid concomitant use.
Negative Chronotropes	digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradine	Potentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate.
Pharmacokinetic Interactions
CYP450 Inhibitors	grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain	Increased exposure of amiodarone. Avoid concomitant use.
	protease inhibitors
CYP450 Inducers	St. John’s Wort	Reduced amiodarone serum levels.
Cyclosporine		Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use.
Cholestyramine		Reduced amiodarone serum levels.
Antiarrhythmics	quinidine, procainamide, flecainide	Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic.
Digoxin		Increased digoxin concentration. Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity.
HMG-CoA Reductase Inhibitors	simvastatin, lovastatin, atorvastatin	Increased plasma concentration of HMG-CoA reductase inhibitor. Limit the dose of lovastatin to 40 mg. Limit the coadministered dose of simvastatin to 20 mg. Lower starting dose of other CYP3A4 substrates may be required.
Warfarin		Potentiates anticoagulant response and can result in serious or fatal bleeding. Coadministration increases prothrombin time by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one- half and monitor prothrombin times.
Phenytoin		Increased steady-state levels of phenytoin. Monitor phenytoin levels.
Hepatitis C Direct Acting Antiviral	sofosbuvir	Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with sofosbuvir.
CYP3A Substrate	lidocaine	Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine given for local anesthesia. Monitor heart rate. A lower starting dose of lidocaine may be required.
CYP3A Substrate	fentanyl	Fentanyl in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from postmarketing reports and published case series indicate that amiodarone use in pregnant women may increase the risk for fetal adverse effects including neonatal hypo- and hyperthyroidism, neonatal bradycardia, neurodevelopmental abnormalities, preterm birth and fetal growth restriction. Amiodarone and its metabolite, desethylamiodarone (DEA), cross the placenta. Untreated underlying arrhythmias, including ventricular arrhythmias, during pregnancy pose a risk to the mother and fetus (see Clinical Considerations). In animal studies, administration of amiodarone to rabbits, rats, and mice during organogenesis resulted in embryo-fetal toxicity at doses less than the maximum recommended human maintenance dose (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and or embryo/fetal Risk

The incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may therefore, increase during pregnancy due to the increased propensity to ectopic activity. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Fetal/Neonatal adverse reactions

Amiodarone and its metabolite have been shown to cross the placenta. Adverse fetal effects associated with maternal amiodarone use during pregnancy may include neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles, neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure, neonatal hyperthyroxinemia, neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia, jerk nystagmus with synchronous head titubation, fetal growth restriction, and premature birth. Monitor the newborn for signs and symptoms of thyroid disorder and cardiac arrhythmias.

Labor and Delivery

Risk of arrhythmias may increase during labor and delivery. Patients treated with amiodarone hydrochloride should be monitored continuously during labor and delivery [see Warnings and Precautions ( 5.4)].

Data

Animal Data

In pregnant rats and rabbits during the period of organogenesis, amiodarone hydrochloride in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose ¹) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose ¹) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose ¹) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose ¹).

¹ 600 mg in a 60 kg patient (doses compared on a body surface area basis)