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amiodarone hcl 200 mg tablet

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Uses

Amiodarone appears to be effective in the management of a wide variety of ventricular as well as supraventricular arrhythmias. Because of amiodarone's potentially life-threatening adverse effects and the management difficulties associated with its use, the drug previously was not considered a first-line antiarrhythmic but generally was reserved for use in life-threatening ventricular arrhythmias. The drug also was used infrequently for the suppression or prevention of any type of arrhythmia and only when conventional antiarrhythmic therapy was considered ineffective or was not tolerated. However, amiodarone generally appears to exhibit greater efficacy and a lower incidence of proarrhythmic effects than class I or other class III antiarrhythmic drugs and therefore has become a mainstay in the management of various tachyarrhythmias, including expert recommendations for advanced cardiovascular life support (ACLS), despite labeling that continues to recommend more limited use. In addition, although no antiarrhythmic agent given routinely during cardiac arrest has been shown to increase survival to hospital discharge, amiodarone has been shown to increase short-term survival to hospital admission relative to lidocaine or placebo. Amiodarone should be used only by clinicians who are familiar with and have access to, either directly or through referral, the use of all currently available modalities for the management of recurrent life-threatening ventricular arrhythmias and who have access to appropriate evaluative and monitoring procedures, including continuous ECG monitoring and electrophysiologic techniques for evaluating the patient in both ambulatory and hospital settings.

Ventricular Arrhythmias

Amiodarone is used orally or IV to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (recurrent ventricular fibrillation and recurrent, hemodynamically unstable ventricular tachycardia) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents are not tolerated. Amiodarone is designated an orphan drug by the FDA for use in this condition. Amiodarone may be used IV to treat patients with ventricular tachycardia or fibrillation in whom oral amiodarone therapy is indicated, but who are unable to take oral medication.

It is difficult to assess the overall efficacy of amiodarone since response to the drug depends on many factors, including the specific cardiac arrhythmia being treated, the criteria used to evaluate efficacy, the presence of underlying cardiac disease in the patient, the number of antiarrhythmic agents used prior to amiodarone, the duration of follow-up, and the concomitant use of other antiarrhythmic agents. In addition, overall arrhythmia recurrence rates (fatal and nonfatal) appear to be highly variable and depend on many factors, including response to programmed electrical stimulation (PES) or other measures, and whether patients who do not appear to respond initially are included. When considering only those patients who responded well enough to amiodarone to be placed on long-term treatment, ventricular arrhythmia recurrence rates have ranged from 20-40% in most studies having an average follow-up period of 1 year or longer.

Life-Threatening Ventricular Arrhythmias and Advanced Cardiovascular Life Support

There is relatively limited experience from controlled studies with the use of amiodarone for suppression and prevention of recurrent life-threatening ventricular arrhythmias. Although comparative data are lacking, the efficacy of amiodarone in the management of severe refractory arrhythmias generally is considered to be at least comparable to and probably better than that of other antiarrhythmic agents (e.g., quinidine, procainamide). Data from most clinical studies indicate that the drug is effective in approximately 50-80% of patients with life-threatening ventricular arrhythmias, including those refractory to other antiarrhythmic agents. Previously, the potential severity of the drug's adverse effects generally had precluded amiodarone from being considered a first-line agent in the management of life-threatening ventricular arrhythmias, and use of the drug generally was reserved for patients in whom other antiarrhythmic agents were ineffective or not tolerated. Currently, however, amiodarone is considered a preferred or alternative agent for the management of various life-threatening ventricular arrhythmias, in part because of comparable or better efficacy and its apparent reduced risk of proarrhythmic activity.

Shock-Resistant Ventricular Fibrillation or Pulseless Ventricular Tachycardia

Amiodarone is used as adjunctive therapy for the treatment of ventricular fibrillation or pulseless ventricular tachycardia resistant to cardiopulmonary resuscitation (CPR), defibrillation, and a vasopressor (e.g., epinephrine).

Antiarrhythmic drugs are used during cardiac arrest to facilitate the restoration and maintenance of a spontaneous perfusing rhythm in patients with refractory (i.e., persisting or recurring after at least one shock) ventricular fibrillation or pulseless ventricular tachycardia; however, there is no evidence that these drugs increase survival to hospital discharge when given routinely during cardiac arrest. High-quality CPR and defibrillation are integral components of ACLS and the only proven interventions to increase survival to hospital discharge. Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation. The principal goal of pharmacologic therapy during cardiac arrest is to facilitate return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use. If an antiarrhythmic agent is needed for the treatment of refractory ventricular fibrillation or pulseless ventricular tachycardia during adult cardiac arrest, the American Heart Association (AHA) recommends amiodarone as the first-line drug of choice because of its proven benefits in improving rates of ROSC and hospital admission; lidocaine may be used as an alternative. Results of several studies suggest that amiodarone is more effective than lidocaine in improving rates of ROSC and hospital admission in patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. In pediatric advanced life support (PALS), current evidence supports the use of either amiodarone or lidocaine for these arrhythmias.

Results of a randomized, double-blind, placebo-controlled study in patients with out-of-hospital cardiac arrest due to defibrillation-refractory ventricular arrhythmias (i.e., ventricular fibrillation, pulseless ventricular tachycardia) who received a single 300-mg dose of IV amiodarone hydrochloride (after at least 3 precordial electrical shocks were administered) indicate that the drug improved the rate of survival to hospital admission by 29%. In a randomized, double-blind, comparative study with lidocaine, approximately 23% of patients with out-of-hospital cardiac arrest due to defibrillation-refractory ventricular arrhythmias who received IV amiodarone hydrochloride (5 mg/kg) or its matching placebo survived to hospital admission compared with 12% of those who received IV lidocaine (1.5 mg/kg) or its matching placebo following at least 3 precordial electrical shocks, IV epinephrine, and an additional precordial electrical shock. Among patients for whom the time from dispatch of the ambulance to the administration of the drug was equal to or less than the median time (24 minutes), approximately 28% of those given amiodarone and 15% of those given lidocaine survived to hospital admission. Despite these results, only about 5% of patients receiving IV amiodarone who survived to hospital admission lived to be discharged from the hospital compared with about 3% of those receiving IV lidocaine. Evidence supporting the use of amiodarone and lidocaine in pediatric cardiac arrest is more limited and principally based on extrapolation of data from the adult population. In a retrospective cohort study that included data from 889 pediatric patients with in-hospital cardiac arrest, improved ROSC was observed with lidocaine compared with amiodarone. Neither drug was associated with improved survival to hospital discharge.

IV amiodarone also may be used for the treatment of regular wide-complex tachycardias during the periarrest period and is included as a recommended antiarrhythmic agent in current ACLS guidelines for both adult and pediatric tachycardia.

Monomorphic and Polymorphic Ventricular Tachycardia

Some experts recommend that sustained monomorphic ventricular tachycardia not associated with angina, pulmonary edema, or hypotension (blood pressure less than 90 mm Hg) be treated with amiodarone or synchronized electrical cardioversion. Other experts recommend amiodarone for control of hemodynamically stable monomorphic ventricular tachycardia. Drug regimens including amiodarone or procainamide may be used initially for the treatment of patients with episodes of sustained ventricular tachycardia that are associated with myocardial infarction and somewhat better tolerated hemodynamically. If IV antiarrhythmic therapy is used for ventricular fibrillation or tachycardia, it probably should be discontinued (at least temporarily) after 6-24 hours so that the patient's ongoing need for antiarrhythmic drugs can be reassessed.

Amiodarone also may be used for the treatment of polymorphic (irregular) ventricular tachycardia associated with myocardial ischemia in the absence of QT interval prolongation. Although rare, episodes of drug-refractory sustained polymorphic ventricular tachycardia (electrical storm) have been reported in cases of acute myocardial infarction. Some experts state that these episodes should be managed by aggressive attempts at reducing myocardial ischemia, including therapies such as an IV β-adrenergic blocking agent, IV amiodarone, left stellate ganglion blockade, intra-aortic balloon counterpulsation (IABP), or emergency revascularization (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft [CABG] surgery); IV magnesium also may be used. Polymorphic ventricular tachycardia associated with QT interval prolongation usually is treated with IV magnesium sulfate.

Prevention of Ventricular Arrhythmias and Death Associated with Cardiac Arrest

Primary Prevention

Oral amiodarone has been used for primary prevention of sustained ventricular tachycardia (i.e., ventricular tachycardia lasting greater than 30 seconds and/or associated with hemodynamic compromise), ventricular fibrillation, or sudden cardiac death in patients with nonsustained ventricular arrhythmia following myocardial infarction. Such use of the drug was once thought to prevent sudden cardiac death because ventricular premature complexes (VPCs) were believed to be harbingers of more serious ventricular arrhythmias (e.g. ventricular fibrillation or tachycardia). However, conflicting results have been reported in studies evaluating the efficacy of antiarrhythmic agents on the risk of sudden death from cardiac causes in post-myocardial infarction patients.

Results of 2 multicenter, randomized, placebo-controlled studies in patients with frequent or repetitive ventricular premature complexes (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [CAMIAT]) or with left ventricular dysfunction (European Myocardial Infarct Amiodarone Trial [EMIAT]) indicate that therapy with oral amiodarone in patients who had survived a recent myocardial infarction appeared to reduce resuscitated cardiac arrest or ventricular fibrillation or arrhythmic death but was not associated with reduction of total mortality after 1-2 years of follow-up. These data are consistent with results of pooled analysis of small controlled trials in patients with structural heart disease, including post-myocardial infarction patients. However, in a smaller study (Basel Antiarrhythmic Study of Infarct Survival [BASIS]) comparing amiodarone with usual care in patients with persisting asymptomatic complex arrhythmias (multiform or repetitive ventricular arrhythmias [Lown class 3 or 4b]) after acute myocardial infarction, long-term therapy with amiodarone was associated with a reduction in mortality at 1 year compared with no antiarrhythmic therapy, possibly as a result of a decreased incidence of sudden death from ventricular tachycardia and fibrillation. In addition, analysis of pooled data from several other randomized studies in patients at risk of sudden cardiac death (e.g., those with congestive heart failure or left ventricular dysfunction, recent myocardial infarction, prior cardiac arrest) suggested that amiodarone therapy may reduce total mortality by 10-19%, and such risk reduction associated with the drug may be similar in the mentioned patient populations.

Findings from the National Heart, Lung, and Blood Institute (NHLBI)'s Cardiac Arrhythmia Suppression Trial (CAST) study indicated a substantially increased rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild to moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent VPC) who received encainide or flecainide (class I antiarrhythmic drugs) compared with placebo after an average of 10 months of follow-up, which resulted in considerably modified clinicians' use of not only class IC antiarrhythmics, but also class I antiarrhythmic agents in general, in post-myocardial infarction patients. Although it has been suggested that the applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or to predominantly class III antiarrhythmic agents such as amiodarone (a drug that has some characteristics of class IA and IC antiarrhythmic agents) is uncertain, the American College of Cardiology (ACC) and AHA state that β-adrenergic blocking agents are preferred over amiodarone for general prophylaxis. In addition, results of prospective, randomized clinical studies indicate improved survival following use of implantable cardioverter defibrillator (ICD) therapy compared with conventional drug therapy, including amiodarone, in patients with nonsustained ventricular tachycardia, reduced ejection fraction (less than 40%), and/or a history of myocardial infarction. However, preliminary reports suggest that only a small proportion of patients with a previous myocardial infarction would benefit from ICD therapy and it remains unclear whether routinely screening patients with impaired left ventricular function for prophylactic ICD therapy is clinically feasible and cost-effective.

Secondary Prevention

Amiodarone hydrochloride is used orally or IV to suppress or prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., recurrent ventricular fibrillation and recurrent, hemodynamically unstable ventricular tachycardia) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents cannot be tolerated. The effectiveness of IV amiodarone in suppressing recurrent ventricular fibrillation or hemodynamically unstable (destabilizing) ventricular tachycardia is supported by 2 randomized, parallel, dose-response studies of approximately 300 patients each. In patients with recurrent ventricular fibrillation or destabilizing ventricular tachycardia that was refractory to first-line (e.g., lidocaine) therapy, amiodarone produced a dose-dependent decrease in arrhythmia recurrence, although not in mortality. Patients with at least 2 episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia within the preceding 24 hours were randomly assigned to receive IV amiodarone hydrochloride doses of 125 mg or 1 g over 24 hours; one study also evaluated a dose of 500 mg. After 48 hours, patients were eligible to receive open access to any treatment deemed necessary (including IV amiodarone) to control their arrhythmias. Amiodarone was administered in a 3-phase sequence, with an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and a subsequent 18-hour maintenance infusion. Maintenance infusion was continued up through hour 48. Additional supplemental 10-minute infusions of 150 mg were administered for breakthrough arrhythmias; these occurred more frequently in patients receiving the 125-mg dosage regimen. Fewer patients receiving the 1-g IV amiodarone hydrochloride regimen required supplemental infusions. During treatment with IV amiodarone, median episodes of ventricular tachycardia or ventricular fibrillation were 0.02/hour in the group receiving the 1-g dosage regimen and 0.07/hour in the group receiving the 125-mg dosage regimen, or approximately 0.5 versus 1.7 episodes daily in patients receiving the 1-g versus 125-mg dosage regimen, respectively. In one study, the time to first episode of ventricular tachycardia or ventricular fibrillation was approximately 10 or 14 hours in patients receiving the 125- or 1000-mg amiodarone hydrochloride dosage regimens, respectively. Mortality rate was not affected by treatment in either of these studies.

Because there has been no evidence of improved survival with use of antiarrhythmic agents, including amiodarone and β-adrenergic blocking agents, whereas such evidence does exist for ICD therapy, ICDs have increasingly been used in the secondary prevention of life-threatening ventricular arrhythmias. In comparative studies, ICD therapy has been shown to be superior to antiarrhythmic drugs, principally amiodarone, for increasing overall survival of patients who had been resuscitated from near-fatal ventricular fibrillation or sustained ventricular tachycardia. Analysis of pooled data indicates that ICD therapy prolongs life by 2.1 or 4.4 months compared with amiodarone after a follow-up period of 3 or 6 years, respectively. Subgroup analysis of patients enrolled in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study indicates that patients with an isolated episode of ventricular fibrillation in the absence of cerebrovascular disease or history of prior arrhythmia who have undergone revascularization or who have moderately preserved left ventricular function (i.e., left ventricular ejection fraction greater than 27%) are not likely to benefit from ICD therapy compared with amiodarone therapy. However, results of this analysis must be considered speculative because the specific criteria used in defining the subgroups were not planned prior to collection of data, and additional studies are needed to verify these findings.

Prediction of the efficacy of any antiarrhythmic agent in the long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial. Many authorities currently recommend the use of ambulatory ECG monitoring, programmed electrical stimulation (PES), or a combination of both to assess patient response to amiodarone. There is no consensus on many aspects of how best to assess patient response to the drug; however, there is reasonable agreement on some aspects. If a patient with a prior history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during ECG monitoring prior to treatment, some provocative approach such as exercise or PES is required to assess the efficacy of amiodarone. The need for provocation in patients who do manifest life-threatening arrhythmias spontaneously remains to be established, although there are reasons to consider PES or other means of provocation in such patients. In patients whose PES-induced arrhythmia is made noninducible by amiodarone, the prognosis is almost uniformly excellent, with very low rates of arrhythmia recurrence or sudden death. The meaning of continued inducibility during therapy with the drug is controversial. Although not clearly established, increased difficulty of arrhythmia induction by PES and/or the ability to tolerate the induced ventricular tachycardia without severe symptoms may be useful criteria for identifying patients who may benefit from amiodarone therapy despite continued inducibility of the arrhythmia during therapy with the drug. Generally, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of the need to revise treatment. Other criteria for predicting the efficacy of amiodarone therapy, including complete suppression of nonsustained ventricular tachycardia determined by ambulatory ECG monitoring and the documentation of very low rates of VPCs, also have been suggested. These issues remain unsettled for amiodarone as well as for other antiarrhythmic agents. Specialized references should be consulted for additional information.

Combination Antiarrhythmic Regimens

Amiodarone has been used in combination with numerous other antiarrhythmic agents for the management of severe refractory ventricular arrhythmias; however, such combination therapy has not been evaluated in well-controlled studies and is associated with an increased risk of adverse cardiovascular effects.(See Drug Interactions: Antiarrhythmic Agents.)

Other Ventricular Arrhythmias

Amiodarone has been used with good results in a limited number of patients experiencing life-threatening ventricular arrhythmias associated with post-infarction aneurysm or with chronic myocarditis induced by Chagas' disease. IV amiodarone has been used with some success in a limited number of patients for the management of ventricular tachycardia and ventricular fibrillation associated with cardiac glycoside intoxication.

Supraventricular Tachyarrhythmias

Amiodarone appears to be effective in the suppression and prevention of various supraventricular tachycardias (SVTs); because of a higher risk of toxicity and proarrhythmic effects, antiarrhythmic agents generally should be reserved for patients who do not respond to or cannot be treated with AV nodal blocking agents (β-adrenergic blocking agents and nondihydropyridine calcium-channel blocking agents). Some experts state that amiodarone may be useful in situations where ventricular rate control is needed but AV nodal blocking agents are contraindicated, such as in patients with preexcited atrial arrhythmias associated with an accessory pathway. However, IV amiodarone is potentially harmful when used for the acute treatment of patients with preexcited atrial fibrillation since it has the potential to accelerate the ventricular response and precipitate fatal arrhythmias.

Atrial Fibrillation and Flutter

Amiodarone has been used orally and IV in the management of atrial fibrillation or flutter.

Amiodarone is one of several antiarrhythmic agents that may be used to maintain sinus rhythm in patients with atrial fibrillation or flutter. Long-term therapy with oral amiodarone alone or in combination with other antiarrhythmic agents has been effective for suppression and prevention of refractory atrial fibrillation. Limited data indicate that long-term amiodarone therapy may be effective in about 70% (range: 35-95%) of patients with atrial fibrillation, including those whose arrhythmia is refractory to conventional therapy. Although not clearly established, the efficacy of amiodarone in the suppression of atrial fibrillation may result from the drug's ability to maintain normal sinus rhythm (probably by increasing atrial refractoriness), suppress atrial premature complexes (which may precipitate atrial fibrillation), and control ventricular rate. There is some evidence that amiodarone may be substantially more effective than sotalol or propafenone for long-term prevention of recurrent atrial fibrillation. Whether maintaining sinus rhythm in patients with recurrent atrial fibrillation will result in improved survival or a reduction in the risk of thromboembolic complications remains to be established.

Oral or IV amiodarone may be effective for conversion of atrial fibrillation to normal sinus rhythm (i.e., rhythm control). In current expert guidelines, amiodarone is considered a reasonable option for pharmacological conversion of atrial fibrillation; however, other antiarrhythmic agents (e.g., flecainide, dofetilide, propafenone, ibutilide) are preferred. IV amiodarone may be harmful, and therefore should not be used, in patients with Wolff-Parkinson-White (WPW) syndrome who have preexcited atrial fibrillation because the drug can accelerate ventricular rate and potentially cause life-threatening ventricular arrhythmias. Conversion of atrial fibrillation to normal sinus rhythm may be associated with embolism, particularly when atrial fibrillation has been present for more than 48 hours, unless the patient is adequately anticoagulated.

Further studies are needed to evaluate the comparative efficacy and safety of oral amiodarone, other antiarrhythmic agents, and cardioversion (direct-current countershock). Although cardioversion has been used safely and effectively following oral or IV amiodarone administration, decreased efficacy of cardioversion in patients receiving the drug has also been reported. Further studies are needed to evaluate the effect of amiodarone therapy on the efficacy of cardioversion.

Paroxysmal Supraventricular Tachycardia

Limited data suggest that IV amiodarone is effective in terminating paroxysmal supraventricular tachycardia (PSVT), including atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) (e.g., WPW syndrome). Some experts state that IV amiodarone may be considered for the acute treatment of hemodynamically stable patients with AVNRT when other therapies are ineffective or contraindicated. However, IV use of amiodarone can be potentially harmful in patients with preexcited atrial fibrillation because the drug may accelerate ventricular rate and cause life-threatening ventricular arrhythmias.

Long-term oral amiodarone therapy appears to be particularly effective in the suppression and prevention of paroxysmal reentrant supraventricular tachycardias (AVNRT and AVRT [e.g., WPW syndrome]) including those refractory to other antiarrhythmic agents. Some experts state that oral amiodarone may be reasonable for ongoing management of AVNRT or AVRT in patients who are not candidates for, or prefer not to undergo, catheter ablation and in whom first-line drugs (e.g., β-adrenergic blocking agents, diltiazem, verapamil) are not effective or contraindicated. Oral amiodarone also has been effective in some patients for the suppression and prevention of atrial fibrillation or flutter associated with WPW syndrome. Although amiodarone also has been used IV in such patients, IV use of the drug has resulted in acceleration of ventricular rate.(See Cautions: Arrhythmogenic Effects.)

Atrial Tachycardia

IV amiodarone may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia (i.e., regular SVT arising from a localized atrial site), and oral amiodarone may be reasonable for the ongoing management of such patients.

While evidence is more limited, amiodarone also has been used in patients with multifocal atrial tachycardia (i.e., rapid, irregular rhythm with at least 3 distinct P-wave morphologies). However, such arrhythmia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic therapy. Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of chronic obstructive pulmonary disease or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity).

Junctional Tachycardia

Amiodarone may be used for the treatment of junctional tachycardia (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia; however, efficacy data is available only for pediatric patients. β-Adrenergic blocking agents generally are considered the drugs of choice for terminating and/or reducing the incidence of junctional tachycardia.

Bradycardia-Tachycardia Syndrome

Amiodarone has been effective in the prevention of supraventricular arrhythmias associated with bradycardia-tachycardia syndrome in a limited number of patients; however, the drug should be used with caution in such patients, since it may depress sinoatrial node function, possibly resulting in marked bradycardia. Some clinicians recommend insertion of a temporary or permanent artificial pacemaker prior to initiation of amiodarone therapy in patients with bradycardia-tachycardia syndrome.

Angina

Amiodarone has been used in a limited number of patients for the management of chronic stable angina pectoris. Limited data suggest that amiodarone is as effective as diltiazem and more effective than sublingual nitroglycerin in increasing exercise tolerance and decreasing ST-segment depression in patients with chronic stable angina pectoris. Amiodarone also has been used with good results in some patients with Prinzmetal variant angina. Because of the potential toxicity associated with amiodarone, the drug generally is not considered a first-line agent for the management of chronic stable angina pectoris or Prinzmetal variant angina but may have a beneficial antianginal effect in patients receiving the drug for the management of arrhythmias.

Hypertrophic Cardiomyopathy

Amiodarone has been used with good results in some patients for the management of ventricular and supraventricular arrhythmias associated with hypertrophic cardiomyopathy. In addition to its antiarrhythmic effects, the drug may also relieve symptoms and increase exercise capacity in some patients, including those whose arrhythmias are refractory to conventional treatment. Pending further accumulation of data, some clinicians recommend that treatment with amiodarone be considered only in patients with refractory hypertrophic cardiomyopathy.

Dosage and Administration

Reconstitution and Administration

Amiodarone hydrochloride is administered orally or by IV infusion. Amiodarone also has been administered by intraosseous (IO) injection in the setting of advanced cardiovascular life support (ACLS); however, there is limited experience with the drug given by this route.

Oral Administration

For the management of life-threatening ventricular arrhythmias, oral amiodarone hydrochloride usually is administered once daily. When dosages of 1 g or more daily are administered (e.g., during the loading-dose phase of therapy) or when intolerable adverse GI effects occur with once-daily dosing, it is recommended that the drug be given in divided doses (e.g., twice daily) with meals. Because food can increase the rate and extent of absorption of amiodarone, the drug should be administered in a consistent manner relative to food intake.

Patients should be advised not to stop taking amiodarone without their clinician's knowledge, even if they feel better, as their condition may worsen. If a patient misses an oral dose of amiodarone, a double dose should not be taken to make up for the missed dose; instead, the next dose should be taken at the regularly scheduled time. If additional oral doses of amiodarone are ingested, patients should seek medical attention urgently by contacting their clinician or immediately proceeding to the nearest hospital emergency department.

IV Infusion

Commercially available amiodarone hydrochloride concentrate for injection containing 50 mg of the drug per mL must be diluted prior to administration. To produce the solution required for the first rapid loading infusion or for supplemental amiodarone infusions, 3 mL of amiodarone hydrochloride concentrate should be added to 100 mL of 5% dextrose, resulting in a final concentration of 1.5 mg/mL. To produce the solution for slow infusion and the maintenance infusion, 18 mL of amiodarone hydrochloride concentrate should be added to 500 mL of 5% dextrose, resulting in a final amiodarone concentration of 1.8 mg/mL. For subsequent maintenance infusions, solutions containing a final amiodarone hydrochloride concentration of 1-6 mg/mL may be used. Parenteral amiodarone hydrochloride solutions should be inspected visually for particulate matter whenever solution and container permit.

For IV infusion, the recommended dose of the diluted amiodarone hydrochloride solution is administered in a 3-phase sequence: a rapid loading phase, a slow loading phase, and a maintenance infusion phase. Parenteral amiodarone therapy should be used for acute antiarrhythmic therapy until the patient's cardiac rhythm is stabilized and oral therapy can be initiated. The manufacturer states that most patients will require IV therapy for 48-96 hours, but that parenteral therapy may be administered safely for longer periods of time.

Solutions containing an amiodarone hydrochloride concentration of 2 mg/mL or more should be administered via a central venous catheter, although the manufacturer states that parenteral amiodarone solutions should be administered via a central venous catheter dedicated to administration of the drug whenever possible. An in-line filter also should be used for administration of IV amiodarone hydrochloride solutions. Amiodarone hydrochloride infusions that will exceed 2 hours must be administered in glass or polyolefin bottles.(See Chemistry and Stability: Stability.) Although amiodarone hydrochloride adsorbs to polyvinyl chloride (PVC), the drug dosages used in clinical trials were designed to take this factor into account; therefore, the manufacturer recommends that solutions containing amiodarone hydrochloride injection be administered through PVC tubing. Polysorbate (Tween) 80, a component of IV amiodarone, can cause leaching of diethylhexylphthalate (DEHP) from IV tubing, including PVC tubing. Leaching of DEHP increases at lower than recommended flow rates and at higher than recommended infusion concentrations. Therefore, the manufacturer's dosage recommendations should be followed closely.

The surface properties of solutions containing amiodarone hydrochloride injection are altered such that the drop size may be reduced. This reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used. Therefore, the manufacturer states that solutions containing amiodarone hydrochloride injection must be administered by a volumetric infusion pump.

Dosage

A uniform and optimal dosage schedule for amiodarone hydrochloride has not been established.Amiodarone is a highly toxic drug, and the lowest effective dosage should be used to minimize the risk and occurrence of adverse effects. Dosage of amiodarone hydrochloride must be carefully adjusted according to individual requirements and response, patient tolerance, and the general condition and cardiovascular status of the patient. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring) and/or programmed electrical stimulation (PES), as appropriate, is recommended during therapy with the drug. When dosage adjustment is necessary, the patient should be monitored closely for an extended period of time because of the long and variable elimination half-life of amiodarone and the difficulty in predicting the length of time required to attain a new steady-state plasma concentration of the drug. When feasible, monitoring of plasma amiodarone concentrations may be helpful in evaluating patients who are not responding to the drug or who experience unexpectedly severe toxicity. Monitoring of plasma amiodarone concentrations may also be useful in identifying patients whose concentrations are unusually low and who might benefit from an increase in dosage or those whose concentrations are unusually high in whom dosage reduction might minimize the risk of adverse effects.

Patients should be advised not to double the next dose if a dose is missed.

Although amiodarone dosage requirements generally appear to be similar in geriatric and younger adults, relatively high dosages should be used with caution in geriatric patients since they may be more susceptible to bradycardia and conduction disturbances induced by the drug. In addition, some manufacturers state that dosage in general for geriatric patients should be selected carefully, usually starting at the low end of the dosage range, because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Life-threatening Ventricular Arrhythmias in Adults

Oral Dosage

For the management of life-threatening ventricular arrhythmias, loading doses of amiodarone hydrochloride are required to ensure an antiarrhythmic effect without waiting several months. The loading-dose phase of therapy should be performed in a hospital setting. Close monitoring of patients is necessary, especially until the risk of recurrent ventricular tachycardia or fibrillation has abated. Upon initiating amiodarone therapy in patients receiving other antiarrhythmic agents, an attempt should be made to gradually discontinue the other antiarrhythmic agents.(See Drug Interactions: Antiarrhythmic Agents.)

In adults, oral amiodarone hydrochloride loading dosages of 800-1600 mg daily generally are required for 1-3 weeks (and occasionally for longer periods of time) until an initial therapeutic response occurs. Some clinicians have used oral loading dosages exceeding 1600 mg daily or IV loading-dose regimens. Clinicians should consult published protocols for specific information on oral loading-dose regimens using dosages greater than 1600 mg daily or on IV loading-dose regimens. If an IV loading-dose regimen is used, oral therapy should be initiated as soon as possible after an adequate response is obtained and IV amiodarone therapy gradually eliminated. If adverse effects become excessive during the loading-dose phase of therapy, a reduction in dosage is recommended. Elimination of recurrent ventricular tachycardia and recurrent ventricular fibrillation as well as reduction in VPCs and total ventricular ectopic beats usually occur within about 1-3 weeks.

When adequate control of ventricular arrhythmias is achieved or adverse effects become prominent, the dosage of amiodarone hydrochloride should be reduced to 600-800 mg daily for about 1 month and then reduced again to the lowest effective maintenance dosage, usually 400 mg daily. Further cautious reductions in maintenance dosage (e.g., to 200 mg daily) may be possible in some patients. Adequate maintenance dosages generally range from less than 400 mg daily up to 600 mg daily. Because absorption and elimination of amiodarone are variable, adjustment of maintenance dosage is difficult, and it is not unusual to require dosage reductions or temporary withdrawal or discontinuance of the drug.

Parenteral Dosage

For the management of life-threatening ventricular arrhythmias, the recommended starting dose of IV amiodarone hydrochloride over the first 24 hours is approximately 1000 mg. The amiodarone hydrochloride dose for the first rapid loading infusion is 150 mg administered at a rate of 15 mg/minute (i.e., over 10 minutes); the initial infusion rate should not exceed 30 mg/minute. The slow loading phase of the infusion is 360 mg of amiodarone hydrochloride administered at a rate of 1 mg/minute (i.e., over 6 hours). The first maintenance phase of the infusion is 540 mg of amiodarone hydrochloride administered at a rate of 0.5 mg/minute (i.e., over 18 hours). The first 24-hour dose of amiodarone hydrochloride may be individualized for each patient; however, in controlled clinical trials, mean daily dosages exceeding 2.1 g were associated with an increased risk of hypotension.

After the first 24 hours, the maintenance infusion rate of 0.5 mg/minute (i.e., 720 mg over 24 hours) should be continued; however, the rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression. In the event of breakthrough episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia, supplemental amiodarone hydrochloride infusions of 150 mg administered at a rate of 15 mg/minute (i.e., over 10 minutes) may be given. Based on experience from clinical trials of IV amiodarone hydrochloride, a maintenance infusion of up to 0.5 mg/minute can be administered with caution for 2-3 weeks, regardless of the patient's age, renal function, or left ventricular function. The manufacturer states that there is limited experience in patients receiving parenteral amiodarone hydrochloride for longer than 3 weeks.

For cardiac arrest secondary to pulseless ventricular tachycardia or ventricular fibrillation, experts recommend an initial adult loading dose of amiodarone hydrochloride of 300 mg, given by rapid IV or IO injection; an additional dose of 150 mg may be considered.

Supraventricular Arrhythmias in Adults

For acute treatment of supraventricular tachycardia (SVT) in adults, an IV amiodarone hydrochloride loading dose of 150 mg over 10 minutes is recommended. The drug should then be administered at a rate of 1 mg/minute for 6 hours, then 0.5 mg/minute for the remaining 18 hours or until oral dosing is initiated. For ongoing management of SVT, some experts recommend an oral amiodarone hydrochloride loading dosage of 400-600 mg daily (in divided doses) in adults for approximately 2-4 weeks, followed by a maintenance dosage of 100-200 mg daily. Clinicians should consult published protocols for specific information on oral loading-dose regimens using higher dosages.

When used for rate control of atrial fibrillation, some experts recommend an initial IV amiodarone hydrochloride dose of 300 mg over 1 hour, followed by 10-50 mg/hr over 24 hours; the usual oral maintenance dose is 100-200 mg daily.

For the long-term management of recurrent atrial fibrillation in adults, an oral dosage regimen that includes an initial amiodarone hydrochloride loading dose of 10 mg/kg daily for 14 days, followed by 300 mg daily for 4 weeks, and then by a maintenance dosage of 200 mg daily has been used effectively to prevent recurrences.

Pediatric Dosage

Oral Dosage

Pediatric dosage of oral amiodarone hydrochloride has not been established, and dosage may vary considerably. For the management of ventricular and supraventricular arrhythmias in children, some clinicians have recommended oral amiodarone hydrochloride loading dosages of 10-15 mg/kg daily or 600-800 mg/1.73 m daily for approximately 4-14 days and/or until adequate control of cardiac arrhythmias is achieved or adverse effects become prominent. Dosage of the drug is then reduced to 5 mg/kg daily or 200-400 mg/1.73 m for several weeks. If possible, dosage is then reduced gradually to the lowest effective level. Children younger than 1 year of age appear to require higher loading and maintenance dosages of amiodarone hydrochloride than older children when dosage of the drug is calculated on the basis of body weight, but not on the basis of body surface area.

Parenteral Dosage

The manufacturer states that pediatric dosage of IV amiodarone hydrochloride has not been established. For the management of refractory ventricular fibrillation or pulseless ventricular tachycardia during pediatric resuscitation, the recommended amiodarone hydrochloride IV or IO dose is 5 mg/kg as a rapid bolus injection. Some experts recommend that if adequate control of cardiac arrhythmia is not achieved, the dose may be repeated twice (maximum single dose of 300 mg) up to a total dosage of 15 mg/kg. If used for the management of wide-complex tachycardias or SVT in pediatric patients who are not in cardiac arrest, an IV amiodarone hydrochloride dose of 5 mg/kg is recommended (infused slowly over 20-60 minutes depending on the urgency). Alternative methods of dosing IV amiodarone hydrochloride (e.g., loading dose of 5 mg/kg given in 5 divided doses of 1 mg/kg, with each incremental dose infused over 5-10 minutes) may be considered in order to minimize pediatric exposure to the plasticizer DEHP.(See Cautions: Pediatric Precautions).

Conversion from IV to Oral Dosage

Patients whose arrhythmias have been controlled successfully with IV amiodarone hydrochloride may be switched to oral therapy. The manufacturer states that since there are some differences in the safety and efficacy profiles of the oral and IV preparations of amiodarone, clinicians should review the prescribing information for oral amiodarone when switching from IV to oral therapy. The optimal dose of oral amiodarone hydrochloride will depend on the dose and duration of IV therapy, as well as the bioavailability of the oral drug. The manufacturer suggests that for patients receiving a daily dose of 720 mg of amiodarone hydrochloride IV (assuming an infusion rate of 0.5 mg/minute) for less than 1 week, 1-3 weeks, or longer than 3 weeks, the initial daily oral amiodarone hydrochloride dose should be 800-1600, 600-800, or 400 mg of the drug, respectively. These recommendations are made on the basis of a comparable total body amount of amiodarone hydrochloride delivered by IV and oral routes, taking into consideration the drug's oral bioavailability of 50%. When switching from IV to oral amiodarone hydrochloride therapy, clinical monitoring is recommended, particularly for geriatric patients.

Dosage in Renal and Hepatic Impairment

Routine reduction of amiodarone hydrochloride dosage in patients with renal impairment does not appear to be necessary, although the risk of excessive accumulation of iodine and possible resultant thyroid effects should be considered.

The effects of hepatic impairment on the elimination of amiodarone have not been evaluated. Because the drug is extensively metabolized, probably in the liver, some clinicians caution that dosage reduction is probably warranted in patients with substantial hepatic impairment. Dosage reduction or discontinuance of amiodarone may be necessary in patients who develop evidence of hepatotoxicity during therapy with the drug.(See Cautions: Precautions and Contraindications.)

Cautions

Amiodarone is a highly toxic drug and exhibits several potentially fatal toxicities, notably pulmonary toxicity. Adverse reactions to amiodarone are common in nearly all patients receiving the drug for the treatment of ventricular arrhythmias. With relatively large dosages of amiodarone hydrochloride (400 mg or more daily), adverse reactions occur in about 75% of patients and require discontinuance of the drug in about 5-20% of patients.

The most severe reactions to oral amiodarone are pulmonary toxicity, arrhythmogenic effects, and rare, but potentially serious, liver injury; however, numerous other adverse reactions to the drug also may be clinically important. Amiodarone-induced adverse effects are often reversible following dosage reduction and nearly always reversible following discontinuance of the drug, although adverse effects may persist for weeks or months after discontinuance of therapy because of the drug's prolonged elimination. The most common adverse reactions requiring discontinuance of oral amiodarone are pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevations of serum hepatic enzyme concentrations. The likelihood of most adverse reactions appears to increase after the first 6 months of therapy with the drug and then remains relatively constant beyond 1 year of therapy. The most common adverse effect observed with IV amiodarone therapy in clinical trials was hypotension, which resulted in discontinuation of therapy in less than 2% of patients. Additional experience with amiodarone is needed to more fully characterize the adverse effect profile of the drug, particularly in relation to duration of therapy and dosage.

Pulmonary Effects

Pulmonary toxicity, which is potentially fatal, is the most severe adverse effect associated with oral amiodarone therapy with or without initial IV therapy. Acute-onset (days to weeks) pulmonary toxicity has been reported during postmarketing experience; manifestations include radiographic evidence of pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, hypoxia, or adult respiratory distress syndrome (ARDS), sometimes leading to respiratory failure and/or death.

Amiodarone-induced pulmonary toxicity may result from pulmonary interstitial pneumonitis (or alveolitis) or from hypersensitivity pneumonitis (e.g., eosinophilic pneumonia). Clinically apparent interstitial pneumonitis (or alveolitis), hypersensitivity pneumonitis, and pulmonary fibrosis have occurred in up to 10-17% of patients with ventricular arrhythmias receiving amiodarone hydrochloride therapy at oral dosages of about 400 mg daily, and an abnormal diffusion capacity without symptoms occurs in a much higher percentage of patients. Only one patient in clinical trials of IV amiodarone therapy developed pulmonary fibrosis; in this patient, the condition was diagnosed 3 months after IV therapy, during which time the patient had begun treatment with oral amiodarone. Amiodarone-induced pulmonary toxicity has been fatal in about 10% of cases. Rarely, amiodarone has been associated with exacerbation of bronchial asthma, possibly because of its antiadrenergic effects. Hemoptysis has been reported during postmarketing experience.

Amiodarone pneumonitis is a clinical syndrome consisting of progressive dyspnea and cough accompanied by functional, radiographic, scintigraphic, and pathological data consistent with pulmonary toxicity. The clinical course of pulmonary toxicity appears to be quite variable. Although a slow, progressive course is often described, an abrupt onset of febrile illness resembling infectious illness (e.g., pneumonia) also may occur. Early symptoms may include dyspnea (particularly with exertion), cough (generally without sputum production), fever or chills, chest pain (generally pleuritic), malaise, weakness, fatigue, myalgia, myopathy, nausea, anorexia, and/or weight loss. Bronchiolitis obliterans organizing pneumonia (that may be fatal) and pleuritis have been reported during postmarketing experience.

The overall incidence of amiodarone-induced pulmonary toxicity has generally been reported to range from about 2-7%, but some studies indicate that pulmonary toxicity may occur in about 10-17% of patients receiving the drug orally. Adult respiratory distress syndrome (ARDS) and lung edema were reported in 2% and less than 2%, respectively, of patients receiving IV amiodarone therapy. Limited evidence suggests that the incidence may increase with duration of therapy, total daily dose, age of the patient, and cumulative dose. However, pulmonary toxicity has been reported during postmarketing experience in patients receiving low dosages. Although not clearly established, limited data suggest that patients with evidence of pulmonary disease prior to amiodarone therapy may have an increased risk of amiodarone-induced pulmonary toxicity, although there may be a bias toward detection in such patients. Some clinicians state, however, that preexisting pulmonary disease does not appear to increase the risk of amiodarone-induced pulmonary toxicity; however, these patients have a poorer prognosis than patients without preexisting pulmonary disease if toxicity develops. The syndrome is usually reversible following discontinuance of the drug (with or without corticosteroid therapy), but pulmonary toxicity may be fatal in some patients.

Hypersensitivity pneumonitis has been reported in about one-third of patients with amiodarone-induced pulmonary toxicity, and may occur earlier during amiodarone therapy than interstitial pneumonitis. Hypersensitivity pneumonitis does not appear to be dose related and may be characterized by acute onset of symptoms (e.g., fever). Alveolar infiltrates appear to be the most common radiographic findings in patients with amiodarone-induced hypersensitivity pneumonitis; increased suppressor/cytotoxic (CD8, T8) T cells and neutrophils often are found in the bronchoalveolar lavage of these patients. It is not known whether fatalities secondary to amiodarone-induced hypersensitivity pneumonitis occur more frequently than fatalities secondary to other pulmonary toxicity induced the drug. The precise mechanism of amiodarone-induced hypersensitivity pneumonitis, including the possible role of immunoglobulins, complement deposition, and cytokines in the development of pulmonary toxicity, remains to be more fully elucidated.

Physical findings in patients with amiodarone interstitial pneumonitis (alveolitis) may include rales, decreased breath sounds, and/or a pleuritic friction rub. Laboratory abnormalities may include hypoxemia, hypercarbia, leukocytosis, and elevated erythrocyte sedimentation rate. Diffuse interstitial infiltrates appear to be the most common radiographic finding in patients with amiodarone-induced pulmonary toxicity; however, airspace opacities (particularly patchy, peripheral alveolar infiltrates), well-localized infiltrates, and mixed interstitial and airspace disease patterns have also been reported.

Microscopic tissue changes in patients with amiodarone pneumonitis appear to be nonspecific but generally are consistent. Pathologic changes may include accumulation of foamy macrophages in alveolar spaces (the presence of lamellated cytoplasmic inclusions probably causes their foamy appearance), hyperplasia of type II pneumocytes, and thickening of the alveolar septal membrane by connective tissue. Although lamellated cytoplasmic inclusions appear to occur predominantly in macrophages, they may also occur in epithelial cells of respiratory bronchioles, type II pneumocytes, endothelial cells, and interstitial cells. Interstitial thickening secondary to an infiltrate of lymphocytes, histiocytes, and occasional plasma cells may also occur. Because foamy alveolar macrophages and lamellated cytoplasmic inclusions have been reported in approximately 50% of patients receiving amiodarone without clinical evidence of pulmonary toxicity, these pathologic changes alone should not be relied on in the diagnosis of amiodarone pneumonitis.

Pulmonary function tests most commonly reveal impairment of diffusion capacity, but reductions of total lung capacity (TLC) and forced vital capacity (FVC) may also occur. Limited data suggest that pulmonary function testing is neither sensitive nor specific enough to be the only method employed in monitoring for amiodarone-induced pulmonary toxicity.

Patients receiving amiodarone should be carefully monitored for the development of pulmonary toxicity.(See Cautions: Precautions and Contraindications.) If hypersensitivity pneumonitis occurs, corticosteroid therapy should be initiated and amiodarone discontinued. Rechallenge with the drug in patients with hypersensitivity pneumonitis results in more rapid and more severe adverse effects. If interstitial pneumonitis (alveolitis) occurs, dosage reduction and preferably discontinuance of the drug is necessary, especially in patients in whom other acceptable antiarrhythmic therapies are available. Following dosage reduction or discontinuance of amiodarone in patients with interstitial pneumonitis, clinical improvement usually is evident within the first week and is maximal after 2 or 3 weeks; radiographic abnormalities usually resolve within 2-4 months. In some patients with interstitial pneumonitis, rechallenge with a lower dosage of amiodarone has not resulted in recurrence of pulmonary toxicity; however, in some patients (e.g., those with severe alveolar damage), pulmonary lesions have been irreversible. Treatment of amiodarone pneumonitis is mainly supportive and may include mechanical ventilation, if necessary. Although data from uncontrolled studies suggest that corticosteroid therapy is of some benefit, controlled studies are needed to fully evaluate the safety and efficacy of corticosteroids in the management of amiodarone-induced pulmonary toxicity. Some patients have received prednisone dosages of 40-60 mg daily, which were tapered in small decrements during several weeks, depending on the patient's condition.

Adult respiratory distress syndrome (ARDS) has occurred occasionally following cardiothoracic or other surgery in patients with or without preexisting amiodarone-induced pulmonary toxicity. A causal relationship between ARDS and amiodarone has not been clearly established, and other factors (e.g., prolonged pump-oxygenator time, oxygen toxicity, anesthetic agents) may have contributed to the development of the syndrome. Although patients usually have responded to vigorous respiratory therapy, fatalities have occurred rarely. Some manufacturers state that forced inspiratory oxygen (FiO2) and determinants of tissue oxygenation (e.g., arterial oxygen saturation [SaO2], arterial oxygen pressure [PaO2]) should be monitored closely.

Hepatic Effects

Abnormalities of liver function test results have generally been reported in about 3-20% of patients receiving amiodarone, although the incidence has been as high as 40-55% in some studies. Nonspecific hepatic disorders have occurred in about 1-3% of patients.

Amiodarone-induced elevations in serum AST (SGOT), ALT (SGPT), γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), and alkaline phosphatase concentrations usually are minor, not accompanied by clinical symptoms, and generally return to normal following dosage reduction or discontinuance of the drug. Rarely, severe hepatic injury (i.e., clinical hepatitis, cholestatic hepatitis, hepatocellular necrosis, cirrhosis), which has been fatal in some patients (including at least one child), has occurred. Signs and symptoms of amiodarone-induced hepatotoxicity may include hepatomegaly, ascites, abdominal pain, nausea, vomiting, anorexia, and weight loss. Hypoalbuminemia, hyperbilirubinemia, and hyperammonemia have also been reported.

Liver biopsies performed in a limited number of patients with amiodarone-induced hepatic dysfunction have revealed histologic changes resembling alcoholic hepatitis or cirrhosis. Microscopic tissue changes may include Mallory bodies within hepatocytes, mixed inflammatory infiltrates, collagen deposits and/or fibrosis, steatosis, hepatocyte destruction, and/or cholangitis. Electron microscopic studies have revealed the presence of phospholipid-laden lysosomal inclusions within hepatocytes, bile duct epithelium, Kupffer cells, and endothelial cells, even in the absence of clinically apparent hepatic disease. Although the exact mechanism of amiodarone-induced hepatic injury has not been determined, limited evidence suggests that the drug may form amiodarone-phospholipid complexes within lysosomes, resulting in phospholipidosis. Acute centrolobular confluent hepatocellular necrosis, leading to hepatic coma, acute renal failure, and death, has been associated with administration of IV amiodarone at a much higher loading dose concentration and more rapid infusion rate than recommended.(See Precautions and Contraindications.)

Serum hepatic enzyme concentrations should be monitored in patients receiving amiodarone.(See Cautions: Precautions and Contraindications.) Persistent elevations in enzyme concentrations or the development of hepatomegaly may necessitate dosage reduction or discontinuance of the drug.

Arrhythmogenic Effects

Like other antiarrhythmic agents, amiodarone can worsen existing arrhythmias or cause new arrhythmias. Arrhythmogenic effects associated with amiodarone have occurred in approximately 2-5% of patients and have included progression of ventricular tachycardia to ventricular fibrillation, sustained ventricular tachycardia, increased resistance to cardioversion, atrial fibrillation, nodal arrhythmia, and atypical ventricular tachycardia (torsades de pointes). Transient exacerbation of preexisting cardiac arrhythmias with subsequent control during continued therapy has also been reported. Prolongation of the QT interval was reported in less than 2% of patients receiving IV amiodarone. Acceleration of ventricular rate was reported in a patient receiving IV amiodarone for the treatment of atrial fibrillation associated with Wolff-Parkinson-White syndrome. In most cases, amiodarone-induced arrhythmogenic effects should be manageable in the proper clinical setting.

Arrhythmogenic effects do not appear to occur more frequently with amiodarone than with other antiarrhythmic agents; however, such effects may be prolonged if they occur. Concomitant use of cardiac glycosides and/or other antiarrhythmic agents may increase the risk of arrhythmogenic effects during amiodarone therapy. Limited data suggest that hypokalemia may increase the risk of amiodarone-induced atypical ventricular tachycardia.

Chronic administration of antiarrhythmic drugs (e.g., amiodarone) in patients with an implanted cardiac device (e.g., defibrillator, pacemaker) may affect pacing and/or defibrillating thresholds. Therefore, the manufacturer recommends that pacing and defibrillation thresholds should be assessed at the inception of and during amiodarone therapy.

Nervous System Effects

Adverse nervous system effects occur in approximately 20-40% of patients receiving oral amiodarone. Amiodarone-induced nervous system effects may be alleviated by dosage reduction and rarely require discontinuance of the drug.

Malaise and fatigue, tremor and/or involuntary movements, lack of coordination, abnormal gait and/or ataxia, dizziness, and paresthesia occur in about 4-9% of patients. Other adverse nervous system effects occurring in about 1-3% of patients receiving the drug include abnormal smell, insomnia, sleep disturbances, headache, and decreased libido. Adverse nervous system effects occurring less frequently include difficulty in handwriting, postural instability, dyskinetic movements, decreased ability to concentrate, confusion, memory loss, and mood lability. Delirium, hallucination, confusional state, disorientation, and parkinsonian symptoms (e.g., akinesia, bradykinesia) have been reported during postmarketing experience.

Peripheral neuropathy, demyelinating polyneuropathy, and proximal myopathy have been reported rarely in patients receiving amiodarone. Although not fully established, these adverse effects may be dose related. Amiodarone-induced peripheral neuropathy, which occurs rarely during chronic oral administration of the drug, is usually symmetrical and involves all four limbs; the neurologic deficit is usually more marked in the lower limbs than in the upper limbs. Signs and symptoms may include distal sensory loss, sensory ataxia, loss of vibratory sensation, paresthesia, and/or decreased tendon reflexes. Proximal muscle weakness also may be present. Nerve biopsies in patients with amiodarone-induced peripheral neuropathy have demonstrated complete loss of large myelinated fibers, marked reduction of small myelinated and unmyelinated axons, and evidence of lysosomal inclusion bodies within Schwann cells. Nerve conduction studies have demonstrated normal or reduced nerve conduction velocities. Although the mechanism(s) of amiodarone-induced peripheral neuropathy has not been fully determined, the mechanism may involve formation of drug-phospholipid complexes within neurons. Peripheral neuropathy and proximal myopathy generally are slowly reversible following dosage reduction or discontinuance of the drug, although resolution of peripheral neuropathy has been incomplete.

Amiodarone-induced tremor generally presents as a fine hand tremor that is clinically indistinguishable from essential tremor; the tremor may be more prominent on one side of the body than the other. Amiodarone has also reportedly exacerbated preexisting tremor or parkinsonian tremor in some patients. Although limited data suggest that cautious use of propranolol may be of some benefit in the management of amiodarone-induced tremor, further study is needed.

Pseudotumor cerebri (with papilledema) has been reported rarely during postmarketing experience in patients receiving amiodarone. Although a causal relationship has not been established, chronic anxiety reactions have also occurred during therapy with the drug.

Thyroid Effects

Thyroid nodules or thyroid cancer, sometimes accompanied by hyperthyroidism, has been reported during postmarketing experience.

Amiodarone alters thyroid function test results in many patients and thyroid function in some patients. Because amiodarone appears to partially inhibit the peripheral conversion of thyroxine (T4) to triiodothyronine (T3), serum T4 and reverse triiodothyronine (reverse T3, rT3) concentrations may be increased and serum T3 concentrations may be decreased. Most patients remain clinically euthyroid despite these changes in serum thyroid hormone concentrations; however, clinical hypothyroidism or hyperthyroidism may occur, and thyroid function should therefore be monitored in patients receiving amiodarone.(See Cautions: Precautions and Contraindications.) Geriatric patients and/or patients with a history of thyroid dysfunction (e.g., goiter, hypothyroidism, hyperthyroidism, thyroid nodules) may be more likely to develop adverse thyroid effects while receiving the drug. Because of the slow elimination of amiodarone and its metabolites from the body, increased plasma iodide concentration, alterations in thyroid function, and/or abnormal thyroid function test results may persist for several weeks or months following discontinuance of the drug.

Amiodarone-induced increases in serum T4 and rT3 concentrations with normal or decreased serum T3 concentrations often occur in patients receiving amiodarone and generally are not accompanied by clinical evidence of thyroid dysfunction. Such changes may be referred to as ''euthyroid hyperthyroxinemia'' and generally do not require specific treatment. Periodic monitoring of thyroid function tests, including serum T3, T4, and thyrotropin (thyroid-stimulating hormone, TSH) concentrations, is recommended in these patients.

Amiodarone-induced hypothyroidism has been reported in about 2-4% of patients receiving oral drug therapy in most clinical studies, although this effect has occurred more frequently (8-10%) in some patient series. Although not clearly established, limited data suggest that hypothyroidism may be more likely to occur in females and in patients with a prior history of thyroid dysfunction. The clinical manifestations of hypothyroidism associated with amiodarone appear to be the same as those occurring in primary idiopathic hypothyroidism. Amiodarone-induced hypothyroidism is probably best detected by monitoring for the signs and symptoms of hypothyroidism and for an elevation in serum thyrotropin concentration, a decrease in serum T3 concentration, and/or a decrease or no change in free serum T4 concentration compared with baseline values.

Hypothyroidism induced by amiodarone may be managed by reduction in amiodarone dosage and/or careful supplementation with thyroid agents (e.g., levothyroxine sodium) if necessary. Some clinicians have recommended cautious titration of levothyroxine sodium until serum T4 concentrations, but not serum thyrotropin concentrations, are within the normal range. Thyroid agents must be administered with extreme caution, however, in patients with angina pectoris or cardiovascular disease; if chest pain or aggravation of cardiovascular disease occurs, dosage of the thyroid agent should be reduced or the thyroid agent discontinued. Amiodarone-induced hypothyroidism may require discontinuance of the drug in some patients and appears to regress slowly once the drug is discontinued, usually over a period of 2-3 months.

Amiodarone-induced hyperthyroidism occurs in approximately 2% of patients receiving the drug orally and may require dosage reduction or discontinuance of amiodarone therapy. Hyperthyroidism may occur more frequently in geographic areas where iodine intake is relatively low. Hyperthyroidism may occur 3 or more months following discontinuance of amiodarone therapy. Hyperthyroidism associated with amiodarone therapy generally is more difficult to diagnose and manage and more poorly tolerated than hypothyroidism. Amiodarone-associated hyperthyroidism can be fatal. The clinical manifestations of amiodarone-induced hyperthyroidism may include weight loss, anxiety, tremor, heat intolerance, thyrotoxicosis, and breakthrough arrhythmias or exacerbation of cardiac arrhythmias. Patients receiving the drug should contact their physician if exacerbation of angina or recurrence of cardiac arrhythmias occurs after an initial apparent response to therapy, even several months after discontinuing the drug, since these signs may suggest the presence of amiodarone-induced hyperthyroidism. Hyperthyroidism is probably best detected by monitoring for signs and symptoms associated with hyperthyroidism and by monitoring for elevations in serum T3 concentrations, elevations in serum T4 concentrations, or subnormal serum thyrotropin concentrations. A thyrotropin-releasing hormone (protirelin) stimulation test may be performed in patients with suspected hyperthyroidism to confirm diagnosis in equivocal cases, although the availability of sensitive assays for serum thyrotropin concentrations has virtually eliminated the need for such a test. Secretion of thyrotropin, induced by exogenous administration of synthetic thyrotropin-releasing hormone (protirelin), is flat or blunted in such patients.

Because clinical manifestations of hyperthyroidism (i.e., cardiac arrhythmias) may be potentially serious in patients receiving amiodarone, aggressive therapy is indicated including dosage reduction or discontinuance of amiodarone, if necessary. Conventional antithyroid agents (e.g., methimazole, propylthiouracil) have been recommended for the management of amiodarone-induced hyperthyroidism; however, these agents appear to be of limited benefit when used alone, since the intrathyroidal thyroglobulin stores generally are fully iodinated in patients receiving long-term amiodarone therapy. High intrathyroidal iodine stores antagonize the inhibitory effects of antithyroid drugs on thyroidal iodine utilization. Combination therapy with methimazole and potassium perchlorate has been used with good results in a limited number of patients with hyperthyroidism and evidence of goiter. The use of β-adrenergic blocking agents (e.g., propranolol) and/or corticosteroids may be of some benefit in the management of hyperthyroidism associated with amiodarone therapy. Radioactive iodine therapy is contraindicated in patients with amiodarone-associated hyperthyroidism because of the low radioiodine uptake due to the high concentrations of circulating iodine from amiodarone therapy and the large intrathyroidal iodine load. In patients in whom aggressive treatment of thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited and could induce thyroid storm. Therefore, careful surgical and anesthetic management is required. Transient hypothyroidism occasionally may occur following resolution of amiodarone-induced hyperthyroidism. Further studies are needed to determine the optimum management of hyperthyroidism in patients receiving amiodarone.

GI Effects

Adverse GI effects, principally nausea, vomiting, constipation, and anorexia, occur in about 25% of patients receiving amiodarone orally but only rarely necessitate discontinuance of the drug. Amiodarone-induced GI disturbances occur most commonly during administration of relatively large oral dosages of the drug (e.g., loading doses) and usually are alleviated by dosage reduction or administration in divided doses with meals.

Nausea and vomiting occur in about 10-33% of patients receiving oral amiodarone; nausea and vomiting occur in approximately 4% and less than 2% of patients receiving IV amiodarone, respectively. Constipation and anorexia have occurred in about 4-9% of patients, and abdominal pain, abnormal salivation, and abnormal taste have occurred in about 1-3% of patients. Epigastric burning or fullness and diarrhea have been reported rarely in patients receiving oral amiodarone; however, a causal relationship to the drug has not been established. Diarrhea has been reported in less than 2% of patients receiving the drug IV. Pancreatitis has been reported during postmarketing experience.

Ocular Effects

Asymptomatic corneal microdeposits are present in practically all adults who receive oral amiodarone for longer than 6 months. These corneal deposits generally are detectable only by slit-lamp ophthalmologic examination and usually are not associated with visual disturbances; however, subjective visual disturbances including halo vision (particularly at night and/or while looking at bright objects), blurred vision, photophobia, and dry eyes may occur in up to 10% of patients receiving the drug.

The development of amiodarone-induced corneal deposits appears to be related to both dosage and duration of therapy. Limited data suggest that more extensive deposits occur in patients receiving amiodarone hydrochloride dosages of 400-1400 mg daily than in patients receiving dosages of 100-200 mg daily. The corneal deposits generally develop within 1-4 months but have occurred as soon as a few weeks after beginning therapy with the drug. Amiodarone keratopathy appears to occur rarely in pediatric patients, possibly because of greater lacrimal secretion and more rapid lacrimal circulation in children than in adults.

Corneal microdeposits generally occur bilaterally and symmetrically. Slit-lamp examination during the early stage of amiodarone keratopathy usually demonstrates fine, punctate, gray to golden brown opacities in a horizontal, linear pattern in the inferior cornea; these deposits then progress gradually into a characteristic, whorl-like pattern with continued therapy. Although the mechanism of amiodarone-induced keratopathy is not known, the presence of complex lipid deposits within lysosome-like intracytoplasmic inclusions suggests possible deposition of amiodarone-phospholipid complexes or lipofuscin within corneal epithelium as well as other epithelial structures of the eye. Corneal microdeposits and visual disturbances are reversible following dosage reduction or discontinuance of amiodarone, usually within about 3 months (range: 2-7 months). Methylcellulose ophthalmic solutions have been used in patients receiving amiodarone in an attempt to decrease the severity of existing microdeposits and progression of the keratopathy, but the efficacy of such therapy has not been established. The presence of asymptomatic corneal microdeposits does not necessitate dosage reduction or withdrawal of amiodarone. If severe and/or persistent visual disturbances occur, they may subside with dosage reduction if continued amiodarone therapy is considered necessary.

Optic neuropathy and/or optic neuritis, which may occur at any time following initiation of amiodarone therapy and usually results in visual impairment, has been reported in patients receiving amiodarone. In some patients, such visual impairment has progressed to permanent blindness. Diplopia, nystagmus, and itching of the eyes have been reported rarely. In addition, papilledema, corneal degeneration, scotoma, lens opacities, ocular discomfort, and macular degeneration have been reported in patients receiving amiodarone therapy. Visual disturbances infrequently impair visual acuity to a substantial degree and rarely require discontinuance of the drug.

Local, Dermatologic, and Sensitivity Reactions

Local injection-site reactions (i.e., pain, erythema, edema, pigment changes, phlebitis, cellulitis, necrosis, skin sloughing) have been reported during postmarketing experience in patients receiving IV injection of amiodarone in recommended dosages.

Adverse dermatologic reactions occur in about 15% of patients receiving oral amiodarone. The most common adverse dermatologic effect associated with amiodarone is photosensitivity, which occurs in about 10% of patients but usually does not require discontinuance of the drug. When photosensitivity occurs, it generally begins within 2 hours of exposure to sunlight, and symptoms may consist of a burning or tingling sensation followed by erythema; blistering occurs infrequently. Swelling of sunlight-exposed areas has been reported rarely. Amiodarone-induced photosensitivity reactions generally last for 1-3 days, but may last as long as a week in severe cases. Photosensitivity reactions may occur up to 4 months following discontinuance of the drug. Enhanced tanning ability has also been reported in some patients receiving the drug.

Since exposure to visible light (wavelengths longer than 400 nm) and/or ultraviolet (UV) wavelengths near the visible spectrum (longer than 320 nm) has resulted in photosensitivity reactions in patients receiving amiodarone, both sunlight and light transmitted through window glass may potentially induce photosensitivity reactions in patients receiving the drug. Sunscreen agents may help to at least partially prevent amiodarone-induced photosensitivity reactions, particularly opaque physical sunscreens (i.e., agents containing zinc oxide, titanium dioxide) and chemical sunscreens that absorb longer UV light wavelengths (i.e., dioxybenzone, oxybenzone). Protective clothing and avoidance of exposure to sunlight are also recommended to at least partially prevent photosensitivity reactions. Although administration of pyridoxine hydrochloride has been recommended for the prevention of photosensitivity in patients receiving amiodarone, in vitro data and data from clinical use suggest that pyridoxine does not prevent and possibly may worsen amiodarone-induced photosensitivity reactions. Reduction in amiodarone dosage may partially alleviate photosensitivity reactions in some patients.

Long-term administration of amiodarone is associated with pigment deposition resulting in a blue-gray discoloration of the skin. The manufacturer states that blue-gray skin pigmentation occurred in less than 1% of patients who had received the drug for an average of about 440 days (range: 2-1515 days); however, in clinical studies, blue-gray skin pigmentation was reported in approximately 2-5% of patients. The incidence appears to be related to both the cumulative dosage and duration of therapy. Pigmentary changes of the skin generally are restricted to exposed areas of the body, particularly the face and hands, and may be mistaken for cyanosis. Exposure to sunlight or visible light and fairness of complexion appear to be risk factors. Although not clearly established, limited data suggest that photosensitivity reactions may predispose to the development of blue-gray pigmentation. The mechanism(s) of amiodarone-induced blue-gray discoloration is not known; however, histologic examination in a limited number of patients has revealed lysosomal, membrane-bound bodies containing amiodarone, N-desethylamiodarone, lipids, and possibly lipofuscin. Blue-gray pigmentation is of cosmetic importance only. The pigmentation usually is slowly reversible following discontinuance of the drug, although this may require up to a year in some cases. Occasionally, the pigmentation may not be completely reversible. Skin cancer has been reported during postmarketing experience with amiodarone.

Rash and hair loss have been reported in less than 1% of patients receiving oral amiodarone. Toxic epidermal necrolysis (sometimes fatal) and generalized pustular psoriasis also have been reported in patients receiving amiodarone. Exfoliative dermatitis and erythema multiforme also have been reported. Stevens-Johnson syndrome has been reported in less than 2% of patients receiving the drug IV and also has been reported during postmarketing experience with amiodarone. Pruritus has been reported during postmarketing experience with amiodarone.

Angioedema, urticaria, eczema, or bronchospasm has been reported during postmarketing experience with amiodarone therapy; anaphylactic/anaphylactoid reactions, including shock, also have been reported during postmarketing experience in patients receiving amiodarone.

Granuloma has been reported through postmarketing experience in patients receiving amiodarone.

Cardiovascular Effects

New or worsened heart failure reportedly occurs in about 3% or about 2% of patients receiving oral or IV amiodarone therapy, respectively; however, it is often difficult to distinguish between spontaneous and amiodarone-induced depression of left ventricular function. Congestive heart failure rarely requires discontinuance of the drug.

Hypotension was the most frequent adverse effect observed in clinical trials of IV amiodarone, occurring in approximately 16% of patients. Hypotension has occurred in less than 1% of patients receiving oral amiodarone. Hypotension refractory to treatment and resulting in death has been reported during postmarketing experience with IV amiodarone. The relationship to amiodarone is not known, but hypotension (probably resulting from decreased cardiac output and/or decreased peripheral vascular resistance) has occurred rarely during open-heart surgery (during and/or following cardiopulmonary bypass) in patients receiving the drug.(See Cautions: Precautions and Contraindications.) An interaction between amiodarone and various anesthetic agents has been suggested but not clearly established. Some manufacturers and clinicians state that close perioperative monitoring is recommended in amiodarone-treated patients undergoing general anesthesia, since amiodarone may sensitize patients to the myocardial depressant and conduction effects of halogenated hydrocarbon general anesthetics.

Flushing and edema have occurred in about 1-3% of patients receiving oral amiodarone. In patients receiving IV amiodarone, cardiac arrest and shock have been reported in 2.9% and less than 2% of patients, respectively; asystole also has been reported. Venous thrombosis and thrombophlebitis have been reported with IV amiodarone during postmarketing experience.

Effects on Cardiac Conduction and Sinus Node Function

Clinically important conduction disturbances, mainly AV and intraventricular block, occur infrequently in patients receiving amiodarone and are reversible following discontinuance of the drug. Sinoatrial block has also been reported. Rarely, amiodarone-induced QT prolongation has been associated with arrhythmogenicity.

Amiodarone generally depresses sinus node function. SA node dysfunction, including symptomatic sinus bradycardia or sinus arrest with suppression of escape foci, has occurred in approximately 1-5% of patients. Concomitant administration of a cardiac glycoside, β-adrenergic blocking agent, and/or calcium-channel blocking agent may increase the risk of sinus bradyarrhythmias. The relationship to amiodarone is not known, but atropine-resistant sinus bradycardia, sinus arrest, and/or AV block have also occurred in some amiodarone-treated patients undergoing general anesthesia, mainly for open-heart surgery.(See Cautions: Precautions and Contraindications.) Patients with preexisting sinus bradycardia or sinus node disease may have an increased risk of amiodarone-induced sinus bradyarrhythmias. Sinus bradycardia induced by amiodarone generally is not fully responsive to atropine.Bradycardia usually responds to dosage reduction, but administration of a β-adrenergic agonist (e.g., isoproterenol) and/or insertion of an artificial ventricular pacemaker may be necessary in patients with severe amiodarone-induced sinus bradyarrhythmias; amiodarone has been discontinued in several patients because of bradycardia.

Hematologic Effects

Coagulation abnormalities have occurred in about 1-3% of patients receiving oral amiodarone, and spontaneous ecchymosis has occurred in less than 1% of patients receiving the drug. Severe thrombocytopenia, resulting in ecchymoses and petechiae, has occurred in a few patients receiving the drug. Following discontinuance of amiodarone and initiation of corticosteroid therapy, platelet counts gradually increased to normal values over a period of 12-16 days; subsequent administration of the drug resulted in recurrence of thrombocytopenia. Thrombocytopenia has been reported in less than 2% of patients receiving IV amiodarone. Although not clearly established, positive lymphocyte stimulation test results suggest that a delayed hypersensitivity reaction may be responsible for the thrombocytopenia. Hemolytic anemia, aplastic anemia, pancytopenia, agranulocytosis, and neutropenia have been reported during postmarketing experience in patients receiving amiodarone.

Other Adverse Effects

Noninfectious epididymitis or epididymo-orchitis and/or scrotal pain have occurred in some patients receiving high oral dosages of amiodarone and/or long-term therapy with the drug. In patients who developed epididymitis, epididymal enlargement initially occurred unilaterally but later progressed bilaterally. Epididymitis subsided in some patients with reduction of amiodarone dosage but resolved in other patients despite continued therapy without dosage adjustment. Abnormal kidney function has been reported in less than 2% of patients receiving the drug IV. Renal insufficiency/impairment or acute renal failure has been reported with IV amiodarone during postmarketing experience. Impotence also has been reported during postmarketing experience with amiodarone therapy.

Gynecomastia, which was reversible following withdrawal of amiodarone but recurred upon rechallenge, has been reported. Hyperglycemia, symptomatic hypoglycemia, and vasculitis have been reported rarely. Myopathy, rhabdomyolysis, and muscle weakness have been reported during postmarketing experience in patients receiving amiodarone.(See HMG-CoA Reductase Inhibitors (Statins), under Drug Interactions: Drugs, Foods, and Dietary or Herbal Supplements Affecting Hepatic Microsomal Enzymes.) Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported during postmarketing experience in patients receiving amiodarone therapy.

Symptomatic bradycardia, sometimes requiring pacemaker intervention, has been reported in patients receiving amiodarone concomitantly with a hepatitis C virus (HCV) treatment regimen containing sofosbuvir in conjunction with another HCV direct-acting antiviral (DAA), including ledipasvir, simeprevir, or daclatasvir. Fatal cardiac arrest was reported in a patient receiving amiodarone concomitantly with the fixed combination containing ledipasvir and sofosbuvir (ledipasvir/sofosbuvir). In most reported cases, bradycardia occurred within hours to days after HCV treatment containing sofosbuvir with another DAA was initiated in patients receiving amiodarone, but has been observed up to 2 weeks after initiation of such HCV treatment regimens in patients receiving amiodarone. Bradycardia generally resolved after the HCV treatment regimen was discontinued. The mechanism for this adverse cardiovascular effect is unknown. Patients who may be at increased risk for symptomatic bradycardia if amiodarone is used concomitantly with an HCV treatment regimen containing sofosbuvir and another DAA include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease. Because of these reports of symptomatic bradycardia, concomitant use of amiodarone with an HCV treatment regimen containing sofosbuvir with another DAA (e.g., ledipasvir, simeprevir, daclatasvir) is not recommended.(See Drug Interactions: HCV Antivirals.)

Precautions and Contraindications

Patients should be instructed to read the medication guide provided by the manufacturer before initiating therapy with amiodarone and each time the prescription is refilled, since new information may be available.

Amiodarone is a highly toxic drug and exhibits several potentially fatal toxicities, notably pulmonary toxicity. Because of its pharmacokinetic properties, difficult dosing schedule, and severity of adverse effects in patients who are improperly monitored, amiodarone should be administered only by clinicians who are experienced in the management of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits associated with amiodarone therapy, and who have access to laboratory facilities necessary to adequately monitor the efficacy and adverse effects of the drug, including continuous ECG monitoring and electrophysiologic techniques for evaluating the patient in both ambulatory and hospital settings. Because of the risks of substantial toxicity, amiodarone therapy currently is reserved principally for the management of documented life-threatening ventricular arrhythmias. Even in patients at high risk of death from arrhythmia, in whom the risks of toxicity are acceptable, use of amiodarone poses major management difficulties that could be life-threatening in a patient population at risk of sudden death, and maximum efforts should be made to utilize alternative antiarrhythmic agents initially.

Because of the life-threatening nature of the arrhythmias treated, lack of a predictable time course of antiarrhythmic effect, and the risks of arrhythmogenic effects and potential interactions with previous drug therapy, the loading-dose phase of oral amiodarone therapy should be performed in a hospital setting. Close monitoring of patients during the loading-dose phase of therapy is necessary, especially until the risk of recurrent ventricular tachycardia or fibrillation has abated. The difficulties associated with using amiodarone effectively and safely pose substantial risks to the patient. Even with an oral loading-dose regimen, a response to orally administered drug generally requires at least 1 week and usually 2 or more weeks of therapy. Because absorption and elimination of amiodarone are variable, adjustment of maintenance dosage is difficult, it is not unusual to require dosage reduction or temporary withdrawal or discontinuance of the drug. Patients who experience serious adverse effects during therapy with amiodarone should immediately contact their clinician or seek medical attention; in addition, patients should contact their clinician before discontinuance of the drug.

The time at which a previously controlled life-threatening arrhythmia will recur after reduction of amiodarone dosage or discontinuance of the drug is unpredictable, ranging from weeks to months. During this period, the patient is at great risk and may need prolonged hospitalization or intensive ambulatory monitoring (e.g., via telemetric ECG), possibly with periodic determination of plasma concentrations of the drug. Attempts to substitute other antiarrhythmic agents when amiodarone must be discontinued because of inefficacy or intolerance are difficult because of the gradually, but unpredictably, changing body burden of the drug, the drug's residual effects, and its potential interactions with subsequent treatment.

Because amiodarone may cause pulmonary toxicity that is potentially fatal, baseline pulmonary function tests, including diffusion capacity, should be performed prior to initiation of oral amiodarone therapy, and periodic chest radiographs and clinical evaluation should be performed every 3-6 months during therapy with the drug. Periodic pulmonary function testing also should be considered. Preoperative pulmonary function tests are recommended for patients undergoing cardiothoracic surgery since ARDS may develop postoperatively in patients receiving the drug. Until further studies have been performed, some manufacturers recommend that FiO2 and tissue oxygenation (as determined by SaO2 or PaO2) be closely monitored in patients receiving amiodarone.(See Cautions: Pulmonary Effects.) Amiodarone should be used with caution, if at all, in patients with preexisting pulmonary disease, including chronic obstructive disease, or reduced pulmonary diffusion capacity. Patients should inform their clinician of preexisting lung or breathing disorders prior to initiation of amiodarone therapy. The possibility of amiodarone-induced pulmonary toxicity should be considered in any patient developing a new respiratory symptom during therapy with the drug. Patients should contact their clinician if dyspnea, wheezing, coughing, chest pain, hemoptysis, or any other breathing disorders occur during therapy with amiodarone. Clinical and radiographic evaluation, as well as scintigraphic and pulmonary function testing (including diffusion capacity), if necessary, are recommended in such patients. Respiratory symptoms should be carefully assessed and other causes of respiratory impairment (e.g., congestive heart failure, pulmonary embolism, malignancy) should be ruled out before discontinuance of the drug. Measurement of pulmonary capillary wedge pressure may help exclude congestive heart failure as a cause of symptoms or radiographic findings. Since amiodarone-induced pulmonary toxicity may mimic infection, possible infectious causes should be excluded; bronchoalveolar lavage, transbronchial lung biopsy, and/or open lung biopsy may aid in the diagnosis, especially in patients in whom alternative antiarrhythmic therapy is not available. The manufacturer states that the presence of suppressor/cytotoxic (CD8, T8) T-cell lymphocytosis in bronchoalveolar lavage specimens should be considered confirmatory of hypersensitivity pneumonitis. If hypersensitivity pneumonitis occurs, corticosteroid therapy should be initiated and amiodarone should be discontinued. If evidence of interstitial pneumonitis (alveolitis) is present, dosage of amiodarone should be reduced and, preferably, therapy with the drug withdrawn in an attempt to determine whether the toxicity is reversible; however, amiodarone should be discontinued with caution in patients with life-threatening arrhythmias, since sudden cardiac death is common in these patients.

Because amiodarone can alter results of thyroid function tests and/or cause clinical hypothyroidism or hyperthyroidism, thyroid function tests should be performed prior to initiating amiodarone therapy and at periodic intervals (approximately every 3-6 months) thereafter, particularly in geriatric patients and/or in patients with a prior history of thyroid nodules, goiter, or other thyroid dysfunction. Patients should inform their clinician if they have thyroid dysfunction or a history of such dysfunction prior to initiation of therapy. In addition, patients receiving amiodarone should be instructed to report episodes of chest pain, weight loss or gain, weakness, heat or cold intolerance, hair thinning, diaphoresis, menstrual cycle changes, swelling in the neck (e.g., goiter), nervousness, irritability, restlessness, decreased concentration, depression in geriatric patients, tremor, or aggravation of cardiovascular disease to their clinician, since such manifestations may indicate amiodarone-induced thyroid dysfunction. If any new signs of cardiac arrhythmias appear, the possibility of hyperthyroidism should be considered. The risks and benefits of amiodarone therapy in patients with thyroid dysfunction should be carefully considered because of the potential for arrhythmia breakthrough or exacerbation of arrhythmias, which may result in death, in such patients.

Because amiodarone may cause elevations in serum hepatic enzyme concentrations and may rarely cause severe, potentially fatal, hepatic injury, serum hepatic enzyme concentrations should be monitored at regular intervals in patients receiving the drug, particularly those receiving relatively high maintenance dosages. Patients should inform their clinician of preexisting liver dysfunction prior to initiation of amiodarone therapy. Patients should contact their clinician if nausea or vomiting, dark urine, fatigue, jaundice, or stomach pain occurs during amiodarone therapy. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of IV amiodarone therapy. If serum hepatic enzyme concentrations increase to more than 3 times normal values in patients with normal pretreatment values or twice baseline pretreatment values in patients with elevated values prior to amiodarone therapy, or if hepatomegaly or progressive hepatic injury occurs, a reduction in oral amiodarone dosage, a decrease in the infusion rate during parenteral amiodarone therapy, or discontinuance of the drug should be considered. Because the risk of hepatic necrosis during IV amiodarone therapy may be related to the use of rapid infusion rates and excessive drug concentrations in the initial loading dose, the initial amiodarone concentration and IV infusion rate should be monitored closely and should not exceed those recommended by the manufacturer. Liver biopsy with ultrastructural study by electron microscopy may aid in the diagnosis of amiodarone-induced hepatic toxicity.

Because amiodarone causes corneal microdeposits in almost all patients and optic neuropathy occasionally may result in visual disturbances, the manufacturer and some clinicians recommend that a baseline ophthalmologic examination (e.g., a slit-lamp evaluation) be performed before initiating therapy with the drug and then possibly at periodic intervals during long-term therapy (e.g., after the first 6 months and then annually and/or as necessary). Patients experiencing visual disturbances or those receiving long-term therapy should be monitored carefully. Patients experiencing visual disturbances (e.g., blurred vision, visual halos, ocular photosensitivity) should contact their clinician. The presence of nonprogressive, asymptomatic corneal microdeposits does not necessitate dosage reduction or discontinuance of amiodarone. In addition, optic neuropathy and/or optic neuritis (usually resulting in visual impairment, which sometimes may progress to permanent blindness) has been reported in patients receiving amiodarone and although a causal relationship to the drug has not been clearly established, some manufacturers state that if visual impairment occurs (e.g., changes in visual acuity, decreases in peripheral vision), a prompt ophthalmologic examination should be performed. If optic neuropathy and/or optic neuritis has developed, amiodarone therapy should be reevaluated and the described risks and complications should be weighed against the possible benefits of antiarrhythmic therapy. Routine ophthalmologic examinations, including slit-lamp and funduscopic tests, should performed in patients receiving amiodarone therapy. Most manufacturers of corneal refractive laser surgery devices consider the procedure to be contraindicated in patients receiving amiodarone.

The use of sunscreen agents and protective clothing and avoidance of excessive exposure to sunlight are recommended to help prevent photosensitivity reactions associated with amiodarone therapy. Patients with fair complexions or excessive exposure to sunlight or those who have received prolonged amiodarone therapy and/or relatively large cumulative doses appear to be more susceptible to amiodarone-induced blue-gray skin discoloration.

Hypotension has been reported during open-heart surgery (during and/or following cardiopulmonary bypass) in amiodarone-treated patients. Patients should inform their clinician of blood pressure abnormalities prior to initiating amiodarone therapy. Atropine-resistant sinus bradycardia, sinus arrest, and/or AV block also have occurred in some amiodarone-treated patients undergoing general anesthesia for major surgery. The relationship of these effects to amiodarone is not known. An interaction between the antiarrhythmic agent and various anesthetic agents has been suggested but not clearly established. The hypotension may be severe in some patients and require larger than usual dosages of sympathomimetic agents and/or intra-aortic balloon counterpulsation. Sinus bradyarrhythmias and/or AV block may require insertion of an artificial pacemaker. Pending further evaluation, the anesthesiologist should be aware of potential complications in patients undergoing general anesthesia who are currently receiving amiodarone or who have previously received the drug within the past 1-2 months. In addition, close perioperative monitoring is recommended in patients undergoing general anesthesia while receiving amiodarone, since amiodarone may sensitize patients to the myocardial depressant and conduction effects of halogenated hydrocarbon general anesthetics.

Because IV amiodarone therapy is associated with bradycardia, patients with a known predisposition to bradycardia or AV block should be treated with IV amiodarone in a setting where a temporary pacemaker is available. Patients should contact their clinician if they experience heart pounding, irregular heart beat, very fast or slow heartbeat, lightheadedness, or faintness during amiodarone therapy. Also, because of the risk of proarrhythmia during parenteral amiodarone therapy, patients should be monitored for QTc prolongation during infusion of amiodarone. The need to coadminister amiodarone with other drugs that are known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits in individual patients.(See Drugs Affecting the QT Interval, under Drug Interactions.)

Since antiarrhythmic agents, including amiodarone, may be less effective and/or more arrhythmogenic in patients with hypokalemia or hypomagnesemia, the possibility of a potassium or magnesium deficiency should be evaluated and, if present, corrected prior to initiation of amiodarone therapy. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

Because of the possibility of clinically important interactions when amiodarone is used concomitantly with other drugs, patients should inform their clinicians of their use of other drugs, including prescription and nonprescription drugs, or of dietary and herbal supplements such as St. John's wort.(See Drug Interactions.) Grapefruit juice is known to inhibit cytochrome P-450 (CYP) 3A4-mediated metabolism of oral amiodarone, resulting in increased plasma concentrations of the drug; therefore, patients should be instructed not to consume grapefruit juice during treatment with oral amiodarone.(See Grapefruit Juice under Drug Interactions: Drugs, Foods, and Dietary or Herbal Supplements Affecting Hepatic Microsomal Enzymes.)

Amiodarone is contraindicated in patients with cardiogenic shock, in patients with severe sinus node dysfunction resulting in marked sinus bradycardia, in patients with second- or third-degree AV block, and in patients with episodes of bradycardia that have caused syncope, except when used concomitantly with an artificial pacemaker. Amiodarone also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation, including iodine; IV amiodarone is contraindicated in patients with known hypersensitivity to any components of the parenteral formulation, including iodine.

Pediatric Precautions

Safety and efficacy of amiodarone in children have not been established. In a clinical trial in pediatric patients 30 days to 15 years of age, hypotension (36%), bradycardia (20%), and atrioventricular block (15%) were common dose-related adverse effects, and in some cases were severe or life-threatening. In this trial, injection-site reactions were observed in 5 of 20 patients receiving IV amiodarone through a peripheral vein. Limited data suggest that the drug may be useful in carefully selected cases for the management of refractory supraventricular or ventricular tachycardias in children, and current guidelines for pediatric advanced life support (PALS) recommend the use of amiodarone or lidocaine for the treatment of shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. This recommendation is based principally on extrapolation of data from adult studies as well as an observational study in pediatric patients suggesting improved return of spontaneous circulation (ROSC) with lidocaine compared with amiodarone.

Each mL of the commercially available amiodarone hydrochloride IV injection contains 20.2 mg of benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates. Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.

In addition, the commercially available amiodarone hydrochloride IV injection has been found to leach diethylhexyl phthalate (DEHP) plasticizer from IV tubing (e.g., PVC tubing). Leaching of DEHP is increased when IV amiodarone hydrochloride is infused at higher concentrations and slower infusion rates than those recommended by the manufacturer. After reviewing data from animal studies and limited experience in humans, an expert panel of the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) concluded that exposure to DEHP may adversely affect male reproductive tract development during fetal, infant, and toddler stages of development if the exposure at these stages is severalfold higher than that in adults, a situation that might be associated with intensive medical procedures such as those performed in critically ill infants. In studies in sexually mature rats, an oral amiodarone hydrochloride dosage of 3.7-14 mg/kg daily was associated with no observable adverse effects; however, in rats at the postnatal stage, a dosage level associated with no observable adverse effects was not identified. The maximum anticipated exposure to DEHP following IV administration of amiodarone hydrochloride in pediatric patients has been calculated to be about 1.9 mg/kg daily for a 3-kg infant, which provides about a 2- to 7-fold margin of safety. In pediatric patients requiring therapy with IV amiodarone hydrochloride, dosing methods that may reduce potential exposure to DEHP (e.g., IV loading dose of 5 mg/kg given in 5 divided doses of 1 mg/kg, with each incremental dose infused over 5-10 minutes) may be considered.

Geriatric Precautions

While clinical experience to date has not revealed age-related differences in response to amiodarone, clinical studies evaluating the drug have not included sufficient numbers of adults 65 years of age and older to determine whether geriatric patients respond differently than younger adults. The manufacturers state that dosage in general for geriatric patients should be selected carefully, usually starting at the low end of the dosage range, because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. In addition, geriatric patients may be more susceptible to bradycardia and conduction disturbances induced by the drug.

Mutagenicity and Carcinogenicity

No evidence of amiodarone-induced mutagenicity was seen with an in vitro microbial test system (Ames test). Amiodarone also was not mutagenic in the micronucleus or lysogenic test.

Long-term studies in rats indicated that oral amiodarone caused a substantial, dose-related increase in thyroid tumors (follicular adenoma and/or carcinoma), with an increase in tumors occurring even at dosages as low as 5 mg/kg daily (approximately 0.08 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]). No carcinogenicity studies were conducted with IV amiodarone.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in pregnant rats or rabbits receiving oral amiodarone hydrochloride dosages of 25 mg/kg daily (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]) revealed no evidence of harm to the fetus. However, in pregnant rabbits receiving oral amiodarone hydrochloride dosages of 75 mg/kg daily (approximately 2.7 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]), abortions occurred in more than 90% of these rabbits. Slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones were reported in pregnant rats receiving oral amioda

Drug Interactions

While only a limited number of drug interactions with amiodarone have been investigated, most drugs studied to date have been shown to interact with amiodarone. Few data are available on drug interactions with parenteral amiodarone therapy; most of the information on drug interactions with amiodarone comes from experience with oral administration of the drug. The possibility of interactions with any concomitantly administered drug and amiodarone should be anticipated, particularly for drugs with potentially serious toxic effects such as other antiarrhythmic agents. If such drugs are needed, their dosage should be carefully reassessed and adjusted as necessary, and plasma concentrations of such drugs should be measured, if appropriate.

Because of the long and variable elimination half-life of amiodarone, the potential for interactions exists not only with concomitantly administered drugs but also with drugs administered after discontinuance of amiodarone therapy.

Drugs Affecting the QT Interval

Amiodarone prolongs the QTc interval, and clinicians should consider the possibility that potentially serious cardiac arrhythmias, including torsades de pointes, could occur if amiodarone were used concomitantly with other drugs that prolong the QTc interval (e.g., cisapride [no longer commercially available in the US], halofantrine [no longer commercially available in the US], dolasetron, pimozide, disopyramide, fluoroquinolones, loratadine, macrolide antibiotics, trazodone, ziprasidone, azole antifungal agents). Use of amiodarone with any other agent known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of such combination therapy. Some manufacturers state that such combined use should be avoided or is contraindicated. If dolasetron and amiodarone are used concomitantly, caution should be exercised and cardiac function should be monitored.

Drugs with P-Glycoprotein-mediated Clearance

Amiodarone inhibits the P-glycoprotein transport system, which may result in unexpectedly high plasma concentrations of drugs that are substrates for this transport system.

Drugs, Foods, and Dietary or Herbal Supplements Affecting Hepatic Microsomal Enzymes

Amiodarone is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally the isoenzymes CYP3A4 and CYP2C8. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors, or inducers of CYP3A4 and CYP2C8. Amiodarone also inhibits CYP2D6, CYP1A2, CYP2C9, and CYP3A4 isoenzymes. Inhibition of these isoenzymes by amiodarone may result in unexpectedly high plasma concentrations of other drugs which are metabolized by these isoenzymes.(See Cyclosporine and see HMG-CoA Reductase Inhibitors (Statins) under Drug Interactions: Drugs, Food, and Dietary or Herbal Supplements Affecting Hepatic Microsomal Enzymes.)

Antiarrhythmic Agents

The use of amiodarone in conjunction with other antiarrhythmic agents generally should be reserved for patients with life-threatening arrhythmias who do not respond completely to either a single antiarrhythmic agent or amiodarone alone. When combination therapy with amiodarone is employed, it is generally recommended that dosage of the currently administered antiarrhythmic agent(s) be reduced by 30-50% several days after initiation of amiodarone therapy, since the onset of amiodarone's antiarrhythmic effect may be delayed. The necessity of continuing the other antiarrhythmic agent(s) should be assessed after the antiarrhythmic effect of amiodarone has been established, and discontinuance of the other antiarrhythmic agent(s) usually should be attempted. If combination therapy with the other antiarrhythmic agent(s) is continued, patients should be monitored with particular care for possible adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias. In patients already receiving amiodarone, the initial dosage of other antiarrhythmic agents should be reduced to approximately 50% of their usual recommended initial dosages.

Atypical ventricular tachycardia (torsades de pointes) has been reported rarely when amiodarone was administered concomitantly with various antiarrhythmic agents, including disopyramide, mexiletine, propafenone, and quinidine. Pending further accumulation of data, amiodarone should be used with caution when administered concomitantly with other antiarrhythmic agents, particularly class IA antiarrhythmic agents.

Flecainide

Plasma flecainide concentrations adjusted for daily dosage increased by an average of about 60% (range: 5-190%) when amiodarone therapy was initiated in a limited number of patients receiving flecainide. Although the mechanism(s) of this interaction is not known, it has been suggested that amiodarone may inhibit the hepatic metabolism and/or decrease the renal clearance of flecainide. Pending further accumulation of data, it is recommended that the dosage of flecainide be reduced by 30-50% several days after initiation of amiodarone therapy; subsequently, the patient and plasma flecainide concentrations should be monitored closely and flecainide dosage adjusted as necessary.

Procainamide

Concomitant use of amiodarone and procainamide may result in increased plasma procainamide and N-acetylprocainamide (NAPA) concentrations and subsequent toxicity. In a limited number of patients receiving 2-6 g of procainamide hydrochloride daily, initiation of amiodarone hydrochloride (1200 mg daily for 5-7 days and then 600 mg daily) increased plasma procainamide and NAPA concentrations by about 55 and 33%, respectively, during the first week of amiodarone therapy. The exact mechanism(s) has not been elucidated, but it has been suggested that amiodarone may decrease the renal clearance of procainamide or NAPA and/or inhibit the hepatic metabolism of procainamide. In addition to a pharmacokinetic interaction, additive electrophysiologic effects, including increased QTc and QRS intervals, occur during concomitant use; adverse electrophysiologic effects (e.g., acceleration of ventricular tachycardia) may also occur. Pending further accumulation of data, it is recommended that procainamide dosage be reduced by 20-33% when amiodarone therapy is initiated in patients currently receiving procainamide or that procainamide therapy be discontinued.

Quinidine

Serum quinidine concentrations may increase following initiation of amiodarone therapy in patients currently receiving quinidine, with subsequent toxicity occurring in some patients. Administration of amiodarone hydrochloride (1200 mg daily for 5-7 days then reduced to 600 mg daily) to a limited number of patients receiving quinidine gluconate or sulfate (average dose of about 3 g daily) resulted in an increase in serum quinidine concentrations of about 33%. Serum quinidine concentrations may begin to increase within a couple days after initiation of amiodarone therapy. The mechanism of the interaction is not fully established, but it has been suggested that amiodarone may inhibit hepatic clearance or decrease renal clearance of quinidine and/or displace quinidine from tissue- and/or protein-binding sites. Although not clearly established, combination therapy with amiodarone and quinidine may also cause marked QT prolongation, predisposing patients to atypical ventricular tachycardia (torsades de pointes). It is generally recommended that quinidine dosage be reduced by 33-50% when amiodarone therapy is initiated in patients currently receiving quinidine or that quinidine therapy be discontinued. Serum quinidine concentrations should be monitored carefully and quinidine dosage reduced as necessary in patients receiving concomitant amiodarone and quinidine therapy; patients should be observed closely for signs of toxicity, including QT prolongation.

Lidocaine

Sinus bradycardia was observed in a patient receiving oral amiodarone who was given lidocaine for local anesthesia. Seizures associated with increased lidocaine concentrations were observed in one patient receiving concomitant IV amiodarone therapy.

HIV Protease Inhibitors

HIV protease inhibitors inhibit CYP3A4 to varying degrees, which may result in a decrease in the metabolism of amiodarone. Concomitant use of amiodarone and an HIV protease inhibitor used with low-dose ritonavir (ritonavir-boosted) or without low-dose ritonavir (unboosted) may result in increased plasma concentrations of amiodarone and the HIV protease inhibitor.

Concomitant use of amiodarone and ritonavir-boosted saquinavir or ritonavir-boosted tipranavir is not recommended. If amiodarone is used concomitantly with other ritonavir-boosted HIV protease inhibitors or with unboosted HIV protease inhibitors, some experts recommend caution and state that the patient should be monitored for amiodarone toxicity and consideration given to monitoring ECG and amiodarone plasma concentrations.

Histamine H2-Receptor Antagonists

Cimetidine inhibits CYP3A4 and can increase plasma amiodarone concentrations.

Histamine H1-Receptor Antagonists

Use of amiodarone with loratadine may result in a decrease in the metabolism of loratadine, a substrate of CYP3A4. QT-interval prolongation and torsades de pointes have been reported with concomitant use of amiodarone and loratadine.

Cyclosporine

Amiodarone inhibits CYP3A4, which may result in a decrease in the metabolism of cyclosporine, a substrate of CYP3A4. Concomitant use of amiodarone and cyclosporine has been reported to produce persistently elevated plasma concentrations of cyclosporine, resulting in elevated serum creatinine concentrations despite reduction in the dose of cyclosporine.

HMG-CoA Reductase Inhibitors (Statins)

Potent inhibitors of CYP3A4 can increase plasma concentrations of HMG-CoA reductase inhibitory activity and increase the risk of myopathy. Because the risk of myopathy/rhabdomyolysis is increased following concomitant use of amiodarone with higher dosages of certain HMG-CoA reductase inhibitors (e.g., simvastatin dosages exceeding 20 mg daily), the daily dosage of lovastatin or simvastatin should not exceed 40 or 20 mg, respectively, during concomitant therapy with amiodarone.

Rifampin

Concomitant administration of amiodarone and rifampin has been associated with decreases in plasma concentrations of amiodarone and desethylamiodarone because of induction of CYP3A4 by rifampin.

St. John's Wort (Hypericum perforatum)

St. John's wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2. Since amiodarone is a substrate for CYP3A4, concomitant use of amiodarone and St. John's wort has the potential to result in decreased plasma concentrations of amiodarone.

Other Drugs Affecting Hepatic Microsomal Enzymes

Concomitant administration of fentanyl and amiodarone may result in hypotension, bradycardia, and decreased cardiac output. Prolonged (exceeding 2 weeks) administration of oral amiodarone impairs the metabolism of dextromethorphan, phenytoin, and methotrexate.

Use of amiodarone concurrently with trazodone may result in a decrease in the metabolism of trazodone, a substrate of CYP3A4. QT-interval prolongation and torsades de pointes have been reported with concomitant use of amiodarone and trazodone.

Clopidogrel undergoes biotransformation through the CYP3A4 isoenzyme, and concomitant use with amiodarone may decrease the biotransformation of clopidogrel to the active form. Ineffective inhibition of platelet aggregation has been reported during concomitant use of clopidogrel and amiodarone.

Grapefruit Juice

Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in intestinal mucosa, resulting in increased plasma concentrations of amiodarone. In healthy individuals receiving grapefruit juice and oral amiodarone concurrently, the area under the plasma concentration-time curve (AUC) and peak plasma concentration of amiodarone increased by 50 and 84%, respectively, and desethylamiodarone plasma concentrations decreased to below the detection limits of the assay. Therefore, grapefruit juice should not be consumed during treatment with oral amiodarone. This interaction should be considered when switching from IV to oral amiodarone therapy.

Phenytoin

Concomitant use of amiodarone and phenytoin has resulted in a twofold to threefold increase in steady-state serum concentrations of phenytoin and subsequent signs of phenytoin toxicity (e.g., nystagmus, ataxia, lethargy) in a limited number of patients. The increase in serum phenytoin concentrations occurred within 3-4 weeks of initiating amiodarone therapy. Although the exact mechanism(s) has not been clearly established, amiodarone may inhibit hepatic metabolism of phenytoin. Patients receiving phenytoin should be monitored closely for signs of phenytoin toxicity when amiodarone is administered concomitantly; serum phenytoin concentrations also should be monitored and dosage of phenytoin reduced as necessary.

Phenytoin has been reported to decrease plasma amiodarone concentrations.

Anticoagulants

An increase in prothrombin time (PT) appears to occur in almost all patients treated with amiodarone and a coumarin or indandione anticoagulant concomitantly and can result in serious or fatal hemorrhage. The increase in PT usually begins within 3-4 days, although onset of the effect may be delayed for 1-3 weeks in some patients. Bleeding episodes generally have been reported to occur 1-4 weeks following initiation of amiodarone therapy. The magnitude of the increase in PT appears to average 100%. Because of amiodarone's long elimination half-life, the PT may not return to normal for 1-4 months following discontinuance of the antiarrhythmic agent. The exact mechanism is not fully established, but amiodarone appears to decrease the hepatic clearance of warfarin. If amiodarone therapy is initiated in patients receiving warfarin or another coumarin or indandione anticoagulant, a reduction in anticoagulant dosage of 33-50% is recommended. In patients receiving amiodarone and an oral anticoagulant concomitantly, the PT should be determined frequently and patients should be observed closely for adverse effects; dosage of the anticoagulant should be adjusted as necessary.

Cardiac Glycosides

Concomitant use of amiodarone and digoxin regularly results in increased serum digoxin concentrations, which may reach toxic levels with subsequent digoxin toxicity. Serum digoxin concentrations generally increase by an average of 70-100% in adults, but substantial variability exists in the magnitude of the increase. Limited data suggest that the magnitude of the increase may be much greater in children than in adults (i.e., 70-800%).

The amiodarone-induced increase in serum digoxin concentrations usually begins within 1-7 days and progresses gradually over a period of several weeks or even months. The exact mechanism(s) of this interaction appears to be complex and remains to be fully established, but data indicate that amiodarone may decrease the renal and/or nonrenal clearance of digoxin. It has also been suggested that amiodarone may increase the oral bioavailability of digoxin or displace digoxin from tissue binding sites. When initiating amiodarone therapy in patients receiving digoxin, the need for continued cardiac glycoside therapy should be reassessed, and digoxin discontinued if appropriate; if concomitant therapy is considered necessary in patients receiving digoxin, a 50% reduction in digoxin dosage is recommended when amiodarone therapy is begun. Serum digoxin concentrations should be monitored carefully and digoxin dosage reduced as necessary in patients receiving amiodarone and digoxin concomitantly; patients should be observed closely for signs of cardiac glycoside toxicity. In addition, thyroid function should be monitored carefully in patients receiving concurrent amiodarone and digoxin therapy, since amiodarone-induced changes in thyroid function may increase or decrease serum digoxin concentrations or alter sensitivity to the therapeutic and toxic effects of the cardiac glycoside.

Other Cardiovascular Drugs

Amiodarone should be used with caution in patients receiving calcium-channel blocking agents (e.g., diltiazem, verapamil) and/or β-adrenergic blocking agents (e.g. propranolol), since possible potentiation of sinus bradycardia, sinus arrest, and AV block may occur. If amiodarone therapy is considered necessary, the drug may continue to be used in patients with severe sinus bradycardia or sinus arrest following insertion of an artificial pacemaker and institution of cardiac monitoring.

General Anesthetics

The effects of concomitant administration of amiodarone and anesthetic agents have not been fully evaluated. However, potentially serious adverse cardiovascular and cardiac effects have occurred in some amiodarone-treated patients undergoing general anesthesia, suggesting the possibility of an interaction between the antiarrhythmic agent and various anesthetic agents. (See Cautions: Precautions and Contraindications.) In addition, close perioperative monitoring is recommended in patients undergoing general anesthesia while receiving amiodarone, since amiodarone may sensitize patients to the myocardial depressant and conduction effects of halogenated hydrocarbon general anesthetics.

HCV Antivirals

Concomitant use of amiodarone and a hepatitis C virus (HCV) treatment regimen containing sofosbuvir with another HCV direct-acting antiviral (DAA), including ledipasvir, simeprevir, or daclatasvir, may result in serious symptomatic bradycardia and is not recommended. The mechanism for this adverse cardiovascular effect is unknown; the effect of concomitant use of amiodarone with these HCV treatment regimens on plasma concentrations of the drugs is unknown. If there are no alternative HCV treatment options and a regimen of sofosbuvir with another DAA (e.g., ledipasvir, simeprevir, daclatasvir) must be used in a patient receiving amiodarone, the patient should be advised about the risk of serious symptomatic bradycardia before HCV treatment is initiated. Cardiac monitoring should be performed in an inpatient setting during the first 48 hours of concomitant use of amiodarone and a regimen containing sofosbuvir with another DAA; heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use. Similar cardiac monitoring is recommended in patients who discontinued amiodarone just prior to initiation of a regimen that includes sofosbuvir with another DAA or if an alternative antiarrhythmic agent cannot be used and amiodarone must be initiated in a patient already receiving such sofosbuvir regimens. Patients receiving amiodarone concomitantly with a regimen containing sofosbuvir with another DAA should be advised about the risk of serious symptomatic bradycardia and the importance of immediately contacting a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur.

Concomitant use of oral amiodarone and simeprevir is expected to result in modestly increased amiodarone concentrations due to intestinal CYP3A4 inhibition by simeprevir. If amiodarone is used concomitantly with a simeprevir-containing HCV treatment regimen that does not include sofosbuvir, caution is warranted and therapeutic drug monitoring of the antiarrhythmic agent, if available, is recommended.

Concomitant use of amiodarone and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir is expected to increase plasma concentrations of amiodarone. If amiodarone is used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir, caution is warranted and therapeutic drug monitoring of the antiarrhythmic agent, if available, is recommended.

Cholestyramine Resin

Limited data indicate that administration of cholestyramine resin following a single oral dose of amiodarone may decrease the elimination half-life and plasma concentrations of amiodarone, possibly by interfering with enterohepatic circulation of the antiarrhythmic agent. Further evaluation of this potential interaction is needed.

Agalsidase Beta

Some clinicians state that because of a theoretical risk of inhibited intracellular α-galactosidase activity with amiodarone, it should not be administered concurrently with agalsidase beta, a biosynthetic form of α-galactosidase.

Pharmacokinetics

Absorption

Amiodarone hydrochloride is slowly and variably absorbed from the GI tract following oral administration. The absolute bioavailability of commercially available amiodarone hydrochloride tablets averages approximately 50%, but varies considerably, ranging from 22-86%. The sometimes low and often variable bioavailability of amiodarone may possibly result from N-dealkylation or other metabolism in the intestinal lumen and/or GI mucosa, from first-pass metabolism in the liver, and/or from poor dissolution characteristics of the drug. Food increases the rate and extent of absorption of amiodarone. Results of a study in healthy adults indicate that administration of a single 600-mg oral dose of amiodarone hydrochloride after a high-fat meal increases the area under the plasma concentration-time curve (AUC) and the peak plasma concentration of amiodarone by 2.3 (range: 1.7-3.6) and 3.8 (range: 2.7-4.4) times, respectively, compared with administration in the fasting state. Food also increases the rate of absorption of amiodarone; when administered with food, the time to achieve peak plasma concentration of unchanged drug is decreased by about 37% to 4.5 hours. The mean AUC and mean peak plasma concentrations of N-desethylamiodarone (the major metabolite) increase by about 55 and 32%, respectively; however, the time to peak plasma concentration of this metabolite remains unchanged in the presence of food. Limited data suggest that the drug may undergo enterohepatic circulation.

Following oral administration, peak plasma amiodarone concentrations usually occur within 3-7 hours (range: 2-12 hours). Following oral administration of a single 400-mg dose of amiodarone hydrochloride in fasting, healthy adults, peak plasma amiodarone concentrations of approximately 0.15-0.7 mcg/mL are attained. Within the oral dosage range of 100-600 mg daily, steady-state plasma concentrations of the drug are approximately proportional to dosage, increasing by an average of 0.5 mcg/mL per 100-mg increment in dosage; however, there is considerable interindividual variation in plasma concentrations attained with a given dosage. Following continuous oral administration of the drug in the absence of an initial loading-dose regimen, steady-state plasma amiodarone concentrations would not be attained for at least 1 month and generally not for up to 5 months or longer. Following chronic oral administration of amiodarone, plasma concentrations of N-desethylamiodarone, the major metabolite of the drug, are approximately 0.5-2 times those of unchanged drug.

In a study of single-dose IV amiodarone hydrochloride (5 mg/kg over 15 minutes) in healthy individuals, peak drug concentration ranged from 5-41mcg/mL. Following 10-minute IV infusions of amiodarone hydrochloride at a dose of 150 mg in patients with ventricular fibrillation or hemodynamically unstable ventricular tachycardia, peak drug concentration ranged from 7-26 mcg/mL. Because of a rapid distribution phase, the concentration of amiodarone declines to 10% of peak values within 30-45 minutes after the end of the infusion. In clinical trials after 48 hours of continuous IV infusions (125, 500, or 1000 mg daily) plus supplemental infusions (150 mg) as needed for recurrent arrhythmias, mean plasma concentrations of amiodarone ranged from 0.7-1.4 mcg/mL.Following administration of a single IV dose of amiodarone in patients with cirrhosis, lower peak and mean plasma concentrations of N-desethylamiodarone are observed; mean amiodarone concentration remains unchanged.

Following oral administration of amiodarone, the onset of antiarrhythmic activity is highly variable. A therapeutic response may begin within 2-3 days in some patients but generally is not evident until 1-3 weeks after beginning therapy with the drug, even when loading doses are administered. Limited data suggest that the onset of action occurs earlier in patients receiving loading doses of the drug and in pediatric patients. Although not clearly established, the time of maximal antiarrhythmic effect usually occurs within 1-5 months after initiating oral amiodarone therapy. Antiarrhythmic effects generally persist for 10-150 days following withdrawal of long-term amiodarone therapy; however, duration of antiarrhythmic activity is variable and unpredictable and appears to depend on the length of therapy as well as the type of cardiac arrhythmia being treated. In general, when amiodarone therapy is resumed after prior discontinuance of the drug and subsequent recurrence of the arrhythmia, control of the arrhythmia occurs relatively rapidly compared to the initial response, presumably because tissues are not fully depleted of the drug at the time therapy is resumed.

There is considerable interindividual variation in the relationship between plasma amiodarone concentrations and antiarrhythmic effects. Limited data suggest that prolongation of the QTc interval is correlated with plasma amiodarone concentrations. Based on suppression of arrhythmias, plasma amiodarone concentrations of approximately 1-2.5 mcg/mL are usually necessary for optimum therapeutic effect, although therapeutic response may be apparent at lower concentrations in some patients; plasma concentrations higher than 2.5 mcg/mL are generally not necessary. There is no established relationship between drug concentration and therapeutic response for short-term IV amiodarone therapy. Although considerable overlap exists between therapeutic and toxic plasma concentrations, certain adverse reactions including adverse hepatic, ocular, and neuromuscular effects appear to occur more frequently when plasma amiodarone concentrations exceed 2.5 mcg/mL.

Distribution

Distribution of amiodarone into human body tissues and fluids has not been fully characterized. Following IV administration in rats, amiodarone is distributed extensively into many tissues, including adipose tissue, liver, kidneys, heart, and, to a lesser extent, the CNS. Following chronic oral administration of the drug in humans, amiodarone and N-desethylamiodarone are distributed extensively into many body tissues and fluids, including adipose tissue, liver, lung, spleen, skeletal muscle, bone marrow, adrenal glands, kidneys, pancreas, testes, semen, saliva, lymph nodes, myocardium, thyroid gland, skin, and brain. Amiodarone is also distributed into bile. Limited data indicate that peak biliary concentrations of the drug may be approximately 50 times greater than peak plasma concentrations. Tissue concentrations of amiodarone generally exceed concurrent plasma concentrations of the drug.N-Desethylamiodarone appears to accumulate in the same body tissues as amiodarone; however, after long-term therapy, concentrations of the metabolite are usually substantially higher than concentrations of unchanged drug in almost all tissues, except adipose tissue, which mainly contains amiodarone.N-Desethylamiodarone and, to a lesser extent, amiodarone also distribute into erythrocytes. Ratios of erythrocyte-to-plasma concentrations of amiodarone and N-desethylamiodarone were 0.33 and 0.67, respectively, after a single oral dose of amiodarone and 0.38-0.48 and 1.3-1.76, respectively, after long-term oral therapy with the drug. Following a single IV dose, the mean blood-to-plasma ratio for amiodarone is 0.73.

Following IV administration, amiodarone is rapidly and widely distributed. The apparent volume of distribution of the drug or its major metabolite, N-desethylamiodarone, in healthy adults reportedly averages 65.8 L/kg (range: 18.3-147.7 L/kg) or ranges from 68-168 L/kg, respectively, following a single IV dose.

In vitro, amiodarone is approximately 96% bound to plasma proteins, mainly to albumin and, to a lesser extent, a high-density lipoprotein that is probably β-lipoprotein.

Amiodarone and N-desethylamiodarone cross the placenta to a limited extent. In pregnant women receiving amiodarone, ratios of umbilical venous to maternal venous plasma concentrations of amiodarone and N-desethylamiodarone were 0.1-0.28 and 0.25-0.55, respectively. Amiodarone and its major metabolite are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations. Limited data in a lactating woman indicate amiodarone and N-desethylamiodarone milk-to-plasma ratios ranging from 2.3-9.1 and 0.8-3.8, respectively.

Elimination

Plasma concentrations of amiodarone appear to decline in at least a biphasic manner, although more complex, multicompartmental pharmacokinetics have been described. Following a single IV dose in healthy adults, the half-life of the drug in the terminal elimination phase (t½β) has been reported to average 25 days (range: 9-47 days). The elimination half-life of the major metabolite, N-desethylamiodarone, is equal to or longer than that of the parent drug. Following single-dose administration of amiodarone in a limited number of healthy individuals, amiodarone exhibits multicompartmental pharmacokinetics; the mean apparent terminal plasma elimination half-life of amiodarone and N-desethylamiodarone were 58 (range: 15-142) and 36 (range: 14-75) days, respectively. The half-life of amiodarone appears to be substantially more prolonged following multiple rather than single doses. It has been suggested that differences in reported elimination half-lives may result in part from misinterpretation of slow distribution phases as elimination phases following IV administration of the drug. Following chronic oral administration of amiodarone hydrochloride in patients with cardiac arrhythmias (200-600 mg daily for 2-52 months), the drug appears to be eliminated in a biphasic manner with an initial elimination half-life of about 2.5-10 days, which is followed by a terminal elimination half-life averaging 53 days (range: 26-107 days), with most patients exhibiting a terminal elimination half-life in the range of 40-55 days. The elimination half-life of the major metabolite, N-desethylamiodarone, averages 57-61 days (range: 20-118 days) following long-term oral administration of amiodarone. The elimination profile of amiodarone probably reflects an initial elimination of the drug from well-perfused tissues followed by prolonged elimination from poorly perfused tissues such as adipose tissue.

In a study of single-dose amiodarone hydrochloride (5 mg/kg over 15 minutes) in healthy individuals, clearance of the drug and its major active metabolite, N-desethylamiodarone, ranged from 90-158 and 197-290 mL/hour per kg, respectively. In clinical studies lasting 2-7 days, clearance of IV amiodarone in patients with ventricular fibrillation or ventricular tachycardia ranged from 220-440 mL/hour per kg. Clearance of the drug in healthy geriatric individuals (i.e., older than 65 years of age) was decreased to approximately 100 mL/hour per kg, as compared with clearance of approximately 150 mL/hour per kg in younger individuals; in addition, the elimination half-life of the drug was increased in these geriatric individuals to 47 days, as compared with 20 days in younger individuals.

The exact metabolic fate of amiodarone has not been fully elucidated, but the drug appears to be extensively metabolized, probably in the liver and possibly in the intestinal lumen and/or GI mucosa, to at least one major metabolite. The major metabolite, N-desethylamiodarone, is formed by N-deethylation. Although not clearly established, limited data in animals indicate that the desethyl metabolite possesses substantial electrophysiologic and antiarrhythmic activity similar to amiodarone's. Following IV administration of a single dose of N-desethylamiodarone in animals, the metabolite prolonged atrial and ventricular refractoriness and decreased conduction within the AV node; however, further studies are needed to determine the effects of the desethyl metabolite following chronic administration. The precise role of N-desethylamiodarone in the antiarrhythmic activity of amiodarone has not been clearly established. The development of maximal ventricular class III antiarrhythmic effects after oral amiodarone administration in humans correlates more closely with N-desethylamiodarone accumulation over time than with amiodarone accumulation. A minor metabolite of amiodarone, di-N-desethylamiodarone, has been identified in animals following chronic administration of the drug. Amiodarone and N-desethylamiodarone may undergo deiodination to form deiodoamiodarone and deiodo-N-desethylamiodarone, respectively; iodine (in the form of iodide); and possibly other iodine-containing metabolites. It is not known whether deiodinated metabolites are pharmacologically active.

The excretory patterns of amiodarone and its metabolite have not been well characterized. Following oral or IV administration, amiodarone appears to be excreted almost completely in feces as unchanged drug and N-desethylamiodarone, presumably via biliary elimination. Although not clearly established, limited data suggest that amiodarone may undergo enterohepatic circulation. Renal excretion of amiodarone and N-desethylamiodarone appears to be negligible.

Following IV administration of amiodarone in healthy individuals, total plasma clearance of the drug averages approximately 1.9 mL/minute per kg (range: 1.4-2.5 mL/minute per kg). Although not clearly established, total apparent plasma clearance of the drug appears to decrease with time. Clinical experience suggests that clearance of amiodarone may be more rapid in pediatric patients; however, further studies are needed to fully determine the effects of age on clearance of the drug. Factors of age, gender, or renal or hepatic disease appear to have no effect on the disposition of amiodarone or its major metabolite, N-desethylamiodarone.

In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered; however, the terminal elimination half-life of N-desethylamiodarone is prolonged in these patients.

Amiodarone and N-desethylamiodarone are not appreciably removed by hemodialysis or peritoneal dialysis.

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