Amiodarone

Amiodarone has been reported to produce negative inotropic and vasodilating effects in animals and humans. After long-term treatment with oral amiodarone in a dose range of 200 to 600 mg/day, patients with decreased left ventricular ejection fraction (LVEF) show no significant change in mean LVEF. Hypotension is uncommon (<1%) during chronic oral amiodarone therapy. In clinical studies of patients with refractory ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT), drug-related hypotension occurred in 15.6% of 1836 patients treated with intravenous amiodarone. No correlations have been seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during intravenous infusion of amiodarone.

Rapid onset of antiarrhythmic activity, well before significant blood levels of DEA (Desethylamiodarone) are present, has been shown in both a placebo-controlled study of intravenous amiodarone in patients with supraventricular arrhythmias and 2- to 3-consecutive beat ventricular arrhythmias, and in a pharmacokinetic/pharmacodynamic study evaluating rapid intravenous loading in patients with recurrent, refractory VT/VF. Approximately 1500 mg/day of intravenous amiodarone were administered using 2- and 3-stage infusion regimens. In the patients with complex ventricular arrhythmias, including sustained and nonsustained VT, amiodarone therapy reduced episodes of VT by 85%.

The acute effectiveness of intravenous amiodarone in suppressing recurrent VF or hemodynamically unstable VT has been supported by two randomized, parallel, dose-response studies of approximately 300 patients each. In these studies, patients with at least 2 episodes of VF or hemodynamically unstable VT in the preceding 24 hours were randomly assigned to receive doses of approximately 125 or 1000 mg over the first 24 hours, an 8-fold difference. In one study, a middle dose of approximately 500 mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional supplemental infusions of 150 mg were given for “breakthrough” VT/VF more frequently to the 125-mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the two studies.

The prospectively defined primary efficacy end point was the rate of VT/VF episodes per hour. For both studies, the median rate was 0.02 episodes per hour in patients receiving the high dose and 0.07 episodes per hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes per day (p=0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14 hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies.

At higher doses (>10 mg/kg) of intravenous amiodarone, prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and intravenous administration suggest that the initial acute effects of intravenous amiodarone may be predominantly focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to calcium channel blockade (Class IV activity) and β-adrenoreceptor antagonism (Class II activity).

During chronic treatment with oral amiodarone, close monitoring may be prudent for elderly patients and those with severe left ventricular dysfunction. However, during short-term intravenous use, age, sex, renal disease, and hepatic disease (cirrhosis) do not have clinically significant effects on the disposition of amiodarone and DEA. No dosage adjustment is necessary for patients in any of these populations.

There is no well-established relationship between drug concentration and therapeutic response for long-term oral or short-term intravenous use. Steady-state amiodarone concentrations of 1 to 2.5 mg/L, however, have been effective with minimal toxicity following chronic oral amiodarone.

Amiodarone can inhibit the metabolism mediated by cytochrome P450 enzymes, probably accounting for the significant effects of oral amiodarone (and presumably intravenous amiodarone) on the pharmacokinetics of various therapeutic agents including digoxin, quinidine, procainamide, warfarin, dextromethorphan, and cyclosporine. Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil. Conversely, agents producing a significant effect on amiodarone pharmacokinetics include phenytoin, cimetidine, and cholestyramine. The potential for drug interactions may persist long after discontinuation of amiodarone administration because of its long half-life. Few data are available on drug interactions with intravenous amiodarone.

Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone, since these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea and receiving concomitant diuretics.

Since amiodarone has weak beta-blocking activity, use with beta-blocking agents could increase risk of hypotension and bradycardia.

Amiodarone and its DEA metabolite are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.

The safety and efficacy of amiodarone in children have not been established; therefore, its use in children is not recommended. Experience with the use of oral or intravenous amiodarone has been reported in the medical literature but is limited.

Amiodarone Hydrochloride for Injection contains the preservative benzyl alcohol. There have been reports of fatal “gasping syndrome” in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Manifestations of the disease included: metabolic acidosis, respiratory distress, gasping respirations, central-nervous system dysfunction, convulsions, intracranial hemorrhages, hypoactivity, hypotonia, cardiovascular collapse and death.

Amiodarone Hydrochloride for Injection has been found to leach out plasticizers, such as DEHP (di-[2-ethylhexyl] phthalate) from intravenous tubing (including PVC tubing). The degree of leaching increases when infusing Amiodarone Hydrochloride for Injection at higher concentrations and at lower flow rates than provided in Dosage. DEHP is used in various plastic medical devices, generally to increase flexibility.

Based on data from animal studies, there was concern that exposure to DEHP may adversely affect male reproductive tract development during fetal, infant and toddler stages of development if the exposure in these immature stages is several fold higher than in adults, a situation that might be associated with intensive medical procedures such as those used in critically ill infants. Although a no-observable-adverse-effect level (NOAEL), by the oral route was identified for sexually mature rats (3.7-14 mg/kg per day), a NOAEL was not identified for rats in the postnatal stage. The maximum anticipated exposure to DEHP following Amiodarone IV administration under conditions of pediatric administration was calculated to be about 1.9 mg/kg per day for a 3 kg infant, which produces a safety margin of between twofold and sevenfold.

Patients with life-threatening arrhythmias may experience serious adverse events during their treatment and therefore should be properly monitored. Amiodarone hydrochloride should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and adverse events of treatment (see Indications).

Amiodarone has been shown to be embryotoxic in some animal species. In 3 different human case reports, both the parent drug and its DEA metabolite have been shown to pass through the placenta, quantitatively ranging between 10 and 50% of human maternal serum concentrations. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. Therefore, amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

It is not known whether the use of amiodarone during labour or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.

Amiodarone may have additive effects on atrioventricular conduction or myocardial contractility, increasing the risk of hypotension.

In addition to the interactions noted above, chronic (>2 weeks) oral amiodarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.

In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone therapy. However, patients receiving oral or intravenous amiodarone should be monitored carefully for evidence of progressive hepatic injury.

Elevations of blood hepatic enzyme values-alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT)-are seen commonly in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients with recent myocardial infarction, congestive heart failure, and in those who have received multiple electrical defibrillations.

Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline elevations in liver enzyme values, and 13% had clinically significant elevations. In 81% of patients with baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.

Two cases of fatal hepatocellular necrosis after treatment with intravenous amiodarone have been reported. The patients, one 28 years of age and the other 60 years of age, were treated for atrial arrhythmias with an initial infusion of 1500 mg over 5 hours, a rate much higher than recommended. Both patients developed hepatic and renal failure within 24 hours after the start of intravenous amiodarone treatment and died on day 14 and day 4, respectively. Because these episodes of hepatic necrosis may have been due to the rapid rate of infusion and hypotension is related to the rate of infusion, the initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.

Amiodarone may cause a worsening of the existing arrhythmias or precipitate a new arrhythmia. Amiodarone causes prolongation of the QT interval. Proarrhythmia, primarily torsades de pointes, has been associated with prolongation of the QTc interval to 500 ms or greater. Proarrhythmia has been reported (2 to 5%) with oral amiodarone, especially in the presence of concomitant antiarrhythmic therapy and has included new-onset VF, incessant VT, increased resistance to cardioversion, and paroxysmal polymorphic VT associated with QT prolongation (torsades de pointes). Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, torsades de pointes or new-onset VF occurred infrequently (less than 2% of all patients treated with intravenous amiodarone in controlled clinical trials). Patients should be monitored carefully for QTc prolongation during amiodarone therapy.

Hypotension is the most common adverse event seen with intravenous amiodarone therapy. In double-blind controlled clinical trials, hypotension was reported as an adverse event in 316 (39%) of 814 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating temporary discontinuation of intravenous amiodarone therapy was reported in 3% of the 814 patients, with permanent discontinuation required in an additional 2% of the 814 patients. Hypotension should be treated initially by slowing the infusion: additionally standard therapy may be needed including vasopressor drugs, positive inotropic agents and volume expansion. The initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.

Bradycardia was reported as an adverse drug reaction in 4.9% of patients receiving intravenous amiodarone for life-threatening VT/VF in clinical trials. AV block was reported as an adverse drug reaction in 1.4% of patients receiving intravenous amiodarone. There was no dose-related increase in bradycardia or AV block in these studies.

During intravenous amiodarone therapy, bradycardia should be treated by slowing the infusion rate or discontinuing therapy. In some patients inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 (<1%) patient during controlled clinical trials. Patients with a known predisposition to bradycardia or AV block should be treated with intravenous amiodarone in a setting where a temporary pacemaker is available.

One of the most serious complications resulting from oral amiodarone HCl therapy is pulmonary toxicity, characterized by pneumonitis. Clinical symptoms include cough, dyspnea, weight loss, and weakness.

On chest X-ray, there is a diffuse interstitial pattern of lung involvement frequently with patchy alveolar infiltrates, particularly in the upper lobe. Predicting which patient will develop pulmonary toxicity has been difficult (see Contraindications). Pulmonary toxicity can appear abruptly either early or late during therapy and it commonly mimics viral or bacterial infection or worsening congestive heart failure. The relationship of pulmonary toxicity to duration of therapy, maintenance dose, and total dose is unclear. Besides an immediate cessation of amiodarone administration, steroid therapy may be beneficial. The majority of patients have recovered with this management, although some fatalities have occurred. Chest X-rays and pulmonary function tests are recommended prior to, and periodically during, the chronic administration of oral amiodarone.

Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. The condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient had received oral amiodarone. Intravenous amiodarone therapy should be discontinued if a diagnosis of pulmonary fibrosis is made.

During clinical studies using intravenous amiodarone, 2% of patients were reported to have adult respiratory distress syndrome (ARDS). ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. It is not possible to determine what role, if any, intravenous amiodarone played in causing or exacerbating the pulmonary disorder in those patients.