AMIODARONE HUP

Amiodarone is a benzofuran derivative, anti-arrhythmic drug used commonly in a variety of settings.

Most known for its approved indication in life-threatening ventricular arrhythmias, it is also used off-label in the outpatient and inpatient setting for atrial fibrillation.

Because of its ability to cause serious toxicity and possibly death, amiodarone use should be reserved for its approved indications, according to prescribing information. 18, 19, 20.

FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT).

FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient.

Off-label indications include atrial fibrillation and supraventricular tachycardia. 7, 8, 9,

After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount.

Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. 2, 7, 18 When it is given Oral, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction.

Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival.

Amiodarone prolongs the QRS duration and

QT interval.

In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity.

Ectopic pacemaker automaticity is also inhibited.

Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function.

human cardiac K+ channel Inhibitor Beta adrenergic receptor Inhibitor Downregulator.

Cmax of amiodarone in the plasma is achieved about 3-7 hours after administration.

The general time to onset of action of amiodarone after one dose given by the intravenous route is between and 30 minutes, with therapeutic effects lasting from 1-3 hours.

Steady-state concentrations of amiodarone in the plasma ranges between 0.4-11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. 4, 5 Interestingly, its onset of action may sometimes begin after 2-3 days, but frequently takes 1-3 weeks, despite the administration of higher loading doses.

The bioavailability of amiodarone varies in clinical studies, averaging between and 65%.

Effect of food

In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times.

Food also enhances absorption, reducing the Tmax by about 37%.

In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients.

Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen.

One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone.

This drug is metabolized to the main metabolite desethylamiodarone (DEA) 4 by the CYP3A4 and CYP2C8 enzymes.

CYP3A4 enzyme is found in the liver and intestines.

A hydroxyl metabolite of

DEA has been identified in mammals, but its clinical significance is unknown.

Hover over products below to view reaction partners Amiodarone Desethylamiodarone 3'-hydroxylamiodarone.

Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion.

A small amount of desethylamiodarone (DEA) is found in the urine.

The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days.

The half-life duration varies according to different sources. 3, 7 According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15-142 days).

The terminal half-life range was between 14-75 days for the active metabolite, (DEA).

The plasma half-life of amiodarone after one dose ranges from 3.2-79.7 hours, according to one source.

The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220-440 ml/hr/kg in one clinically study.

Another study determined that the total body clearance of amiodarone varies from 0.10-0.77 L/min after one intravenous dose.

Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance.

Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone.

Severe left ventricular dysfunction prolongs the half-life of DEA.

A note on monitoring

No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities.

In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction.

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LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg.

An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia.

Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity.

In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents.

Temporary pacing may be required for heart block.

Ensure to monitor liver function regularly.

Amiodarone and its main metabolite, DEA, are not removable by dialysis.

Cardiogenic shock.

Sick sinus syndrome, second.

• or third-degree atrioventricular block, bradycardia leading to syncope without a functioning pacemaker.

Known hypersensitivity to the drug or to any of its components, including iodine.

Pacerone is contraindicated in patients with

• or third-degree AV block, bradycardia leading to syncope without a functioning pacemaker.

Known hypersensitivity to the drug or any of its components.

Dosage must be individualized based on severity of arrhythmia and response.

Use the lowest effective dose.

Obtain baseline chest x-ray, pulmonary function tests, thyroid function tests, and liver aminotransferases.

Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment.

Initiate treatment with a loading dose of to 1600 mg/day until initial therapeutic response occurs (usually to 3 weeks).

Once adequate arrhythmia control is achieved, or if side effects become prominent, reduce Pacerone tablets dose to to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day. Recommended Dosage: Initiate treatment with a loading dose of to 1600 mg/day until initial therapeutic response occurs (usually to 3 weeks).

Once adequate arrhythmia control is achieved, or if side effects become prominent, reduce Pacerone tablet dose to to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day. Administration: Administer Pacerone tablets consistently with regard to meals.

Administration of

Pacerone tablets in divided doses with meals is suggested for total daily doses of 1000 mg or higher, or when gastrointestinal intolerance occurs.

Pacerone ® (amiodarone hydrochloride tablets, USP) 100 mg are peach, round, flat-faced, uncoated tablets, debossed with "P" on one side, and "U-S" above "144" on the other side.

They are supplied as follows

Bottles of with child-resistant closure, NDC 0245-0144-30 Bottles of with child-resistant closure, NDC 0245-0144-11 Unit-dose cartons of 100 tablets, NDC 0245-0144-01 Pacerone ® (amiodarone hydrochloride tablets, USP) 200 mg, are pink, round, flat-faced, scored, uncoated tablets, debossed with "P 200 " on the unscored side, and "U-S" above and "0147" below the score on the reverse side.

Bottles of with child-resistant closure, NDC 0245-0147-60 Bottles of with child-resistant closure, NDC 0245-0147-90 Bottles of 500 tablets, NDC 0245-0147-15 Unit-dose cartons of 100 tablets, NDC 0245-0147-01 Pacerone ® (amiodarone hydrochloride tablets, USP) 400 mg, are white to off-white, round, uncoated, scored tablets, debossed with "U-S" above and "1645" below the score on one side and "P 400 " on the unscored side.

Bottles of with child-resistant closure, NDC 0245-1645-30 Unit-dose cartons of 100 tablets, NDC 0245-1645-01 Keep tightly closed.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from light.

Dispense in a tight, light-resistant container with a child-resistant closure.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from light.

Dispense in a tight, light-resistant container with a child-resistant closure.

Available data from post-marketing 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.

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.

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.

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.

Risk of arrhythmias may increase during labor and delivery.

Patients treated with

Pacerone should be monitored continuously during labor and delivery.

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 600 mg in a 60 kg patient (doses compared on a body surface area basis) ) had no adverse effects on the fetus.

In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose ) 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 ) 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 ).

The safety and effectiveness of

Pacerone in pediatric patients have not been established.

Normal subjects over 65 years of age show lower clearances and increased drug half-life than younger subjects.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.