Amiodarone: Clinical uses

INTRODUCTION — Amiodarone is an iodinated benzofuran derivative that was synthesized and tested as an antianginal agent in the 1960s but was later discovered to have antiarrhythmic properties. Amiodarone is widely prescribed, largely due to its efficacy in the management of both supraventricular and ventricular arrhythmias. In addition to the superior efficacy compared with most other antiarrhythmic drugs, amiodarone has very little negative inotropic activity and a low rate of ventricular proarrhythmia, making it advantageous for use in patients with heart failure [1]. Despite these advantages, the use of amiodarone is associated with a relatively high incidence of side effects, making it a complicated drug to use safely.

This topic will review the electrophysiologic properties of amiodarone, clinical indications, and dosing recommendations for oral and intravenous amiodarone. The side effects of amiodarone are discussed in detail elsewhere. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Amiodarone and thyroid dysfunction".)

PHARMACOKINETICS — Slow and wide distribution of amiodarone to tissue (fat, muscle, highly perfused organs) results in a requirement of long loading periods in an effort to accelerate the onset of drug activity. Oral amiodarone is markedly lipophilic, resulting in a very large volume of distribution (average approximately 66 L/kg) and a prolonged time to reach stable plasma levels [1]. It is incompletely absorbed (approximately 30 to 70 percent) after oral administration and is taken up very extensively by tissue, with marked interindividual variation [2]. Because of these characteristics, even with loading, arrhythmia recurrence during the first months of therapy does not necessarily predict long-term efficacy. Conversely, intravenous (IV) amiodarone begins to act within one hour, with rapid onset of action within minutes following an IV bolus.

Estimates of the elimination half-life of amiodarone vary, depending on how the half-life has been measured and the route of amiodarone administration.

●After long-term oral therapy, amiodarone has a true elimination half-life between 60 and 142 days [2,3].

●The relatively short half-life for disappearance of amiodarone from plasma after a single-dose or short-term IV administration is likely a measure of drug redistribution from vascular space into tissue and not true body elimination.

There is little correlation between the plasma concentration of amiodarone or its major active metabolite, desethylamiodarone, and drug efficacy or toxicity [1].

ELECTROPHYSIOLOGIC PROPERTIES — The electrophysiologic properties of amiodarone are complex and incompletely understood. Though classified as a Vaughan-Williams class III antiarrhythmic agent due to its inhibition of outward potassium channels, the drug also has class I sodium channel blocking effects, class II antiadrenergic effects, and class IV calcium channel blocking effects (table 1). The oral and intravenous (IV) forms of amiodarone have important electrophysiologic differences that have an impact on their clinical use (table 2).

Oral amiodarone — Oral amiodarone is classified as a class III antiarrhythmic agent since it prolongs the duration of the action potential and the refractory period of both atrial and ventricular tissue (figure 1). This effect is primarily mediated by blockade of the rapid component of the delayed rectifier current (IKr) that is responsible for phase 3 repolarization of the action potential (figure 2). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

Like other class III agents (sotalol, dofetilide, ibutilide, dronedarone), amiodarone prolongs the QT interval. However, by contrast to most other class III agents, amiodarone has very little proarrhythmic activity. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.)

Oral amiodarone has several other effects that may contribute to its therapeutic efficacy:

●It inhibits inactivated (phase 0) sodium channels, an effect that is primarily seen at rapid heart rates

●It has some class II antiarrhythmic drug activity, inhibiting sympathetic activity, primarily by causing noncompetitive beta receptor blockade

●It also has some class IV antiarrhythmic drug activity by blocking L-type (slow) calcium channels

Intravenous amiodarone — IV amiodarone has a number of important electrophysiologic differences from chronically administered oral amiodarone [4,5]:

●IV amiodarone produces a much smaller increase in the action potential duration in atrial and ventricular myocardium and a minimal increase in the atrial and ventricular refractory periods. As a result, there is little or no increase in QRS duration or the QT interval, respectively.

●IV amiodarone has little effect on sinus cycle length. It has vasodilator activity that triggers an increase in sympathetic activity, and as a result, there is little or no slowing of the sinus rate.

●IV amiodarone may have more potent and more rapid antiadrenergic activity.

Like oral amiodarone, IV amiodarone inhibits inactivated sodium channels, though to a lesser degree than the oral form [4]. This property may account for the efficacy of the agent in the suppression of ventricular tachyarrhythmias [6]. IV amiodarone also prolongs atrioventricular (AV) nodal conduction and refractoriness and may be effective in slowing the ventricular rate in critically ill patients with atrial tachyarrhythmias [7].

Effects on the ECG — The multiple actions of chronically administered oral amiodarone therapy can produce a variety of changes in the electrocardiogram (ECG). These include:

●Slowing of the sinus rate. Both calcium channel blockade and beta blockade may contribute to this effect, which can lead to sinus bradycardia [5].

●Prolongation of the PR interval and the AV nodal refractory period. Thus, AV conduction block may occur, an effect that may also be related to calcium channel blockade since the AV node is a "slow response" tissue that relies on an inward calcium current for depolarization. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Action potential in slow response tissues'.)

●Widening of the QRS complex (typically less than 10 percent), as conduction is slowed in ventricular muscle by the blocking effect on the inactivated sodium channel, thereby slowing phase 0 depolarization (figure 1) [8]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

●Prolongation of the QT interval (typically less than 10 percent) due to blockade of IKr, the delayed rectifier potassium current that is responsible for phase 3 depolarization of the action potential (figure 1) [8,9]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.)

ORAL AMIODARONE FOR THE TREATMENT OF ATRIAL ARRHYTHMIAS — Amiodarone can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. It is commonly used for several reasons:

●Amiodarone is the most effective medical therapy available for maintaining sinus rhythm

●There is a low risk of ventricular proarrhythmia based on the electrophysiologic properties of amiodarone

●Amiodarone does not increase mortality in heart failure patients

●Therapy can be easily initiated on an outpatient basis

In addition, if AF recurs, amiodarone usually slows the ventricular response at rest and with exercise. It also may reduce symptoms associated with rapid ventricular response to AF, though amiodarone is not recommended solely as a rate-controlling agent. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.)

Amiodarone can be used to treat other atrial arrhythmias such as atrial flutter or atrial tachycardia, but the availability of other antiarrhythmic drugs with lower toxicity rates, and the high success rates of ablative approaches to atrial flutter or atrial tachycardia, often favors these alternatives. The major limiting factor in the use of oral amiodarone for the treatment of AF and other atrial arrhythmias is long-term organ toxicity (eg, thyroid, lung, etc) (table 3). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)

Prevention of recurrent paroxysmal atrial fibrillation — The decision to pursue a strategy of rhythm control in any patient with AF is complex and depends on:

●The presence or absence of symptoms

●Potential adverse effects of persistent AF (ie, uncontrolled ventricular rate)

●Adverse effects of alternative therapies for AF

The choice of which antiarrhythmic drug to use for paroxysmal AF is also complex and based on a variety of factors, most notably the presence and type of structural heart disease. Unlike many other antiarrhythmic drugs, amiodarone has a low risk of ventricular proarrhythmia and does not increase mortality when administered to patients with coronary disease, left ventricular (LV) hypertrophy, LV dysfunction, or congestive heart failure.

While there is no universally accepted dosing regimen, oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used (table 4) [10]. Gastrointestinal side effects may limit loading doses. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can sometimes be as low as 100 mg daily. Doses up to 400 mg/day may also be used but are not recommended for routine maintenance given the higher risk of adverse events. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".)

Pharmacologic cardioversion of atrial fibrillation — Amiodarone is not a first-line therapy for pharmacologic cardioversion given its limited efficacy and long onset of action. If amiodarone is used in this setting, American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines recommend oral loading and maintenance doses to be the same as those described for amiodarone use to prevent recurrence and maintain sinus rhythm in patients with paroxysmal AF. (See 'Prevention of recurrent paroxysmal atrial fibrillation' above.)

Oral amiodarone can result in pharmacologic cardioversion of AF in approximately 25 percent of patients with high ventricular rates from either acute or recent-onset AF [10-12]. Because of the potential for cardioversion following administration of amiodarone, standard precautions need to be considered to prevent thromboembolic events. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".)

Amiodarone and other pharmacologic agents for cardioversion are reviewed separately. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.)

Pretreatment before elective cardioversion or catheter ablation for persistent atrial fibrillation — In patients who did not remain in sinus rhythm following cardioversion or in patients at high risk for recurrent AF after planned cardioversion, we often pretreat with an antiarrhythmic drug, including amiodarone [13]. Given the prolonged half-life of oral amiodarone, the loading time is extended, so the drug should be started two to six weeks prior to elective cardioversion to reduce the risk of recurrence. Dosing regimens vary (table 4) but generally aim for an oral load of 6 to 10 grams over a period of two to six weeks prior to cardioversion, with a decrease in dose to maintenance levels (usually 100 to 200 mg daily) following cardioversion or shortly thereafter. Given the unique pharmacologic properties of amiodarone, AF recurrences in the first two to three months following cardioversion do not necessarily predict long-term failure of the drug. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.)

Oral amiodarone has also been investigated in patients undergoing catheter ablation for persistent AF.

●In the AMIO-CAT trial, in which 212 patients undergoing AF ablation were randomized to begin therapy with amiodarone or placebo for eight weeks following catheter ablation, there was a nonsignificant trend toward fewer recurrences of AF in the amiodarone group (39 versus 48 percent), but significantly fewer patients receiving amiodarone required hospitalization or cardioversion for recurrent AF [14].

●In the SPECULATE trial, in which 112 patients with long-standing persistent AF were randomized to discontinuation of chronic amiodarone therapy four months prior to ablation or continuation of therapy and then followed for an average of 32 months, significantly more patients who continued amiodarone had successful termination of AF at the time of ablation (79 versus 57 percent); however, late AF recurrence was significantly greater in the group who continued amiodarone [15].

Further investigation is needed to determine the optimal role for amiodarone in patients undergoing AF ablation.

Prophylaxis against atrial fibrillation following cardiac surgery — Amiodarone lowers the incidence of postoperative AF in patients undergoing cardiac surgery [10]. Various dosing regimens for oral amiodarone have been used in clinical trials [16,17]. In general, however, we recommend beta blockers rather than amiodarone; however, for patients who cannot take beta blockers, amiodarone may be used. The approach to prevention of AF following cardiac surgery is discussed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Amiodarone'.)

INTRAVENOUS AMIODARONE FOR THE TREATMENT OF ATRIAL ARRHYTHMIAS — Intravenous (IV) amiodarone is primarily used for the treatment of atrial arrhythmias in two settings:

●Restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable atrial fibrillation (AF).

●Rate control in critically ill patients with AF with rapid ventricular response in whom the tachycardia is contributing to hemodynamic compromise.

The administration of IV amiodarone requires attention to a specific dosing schedule to minimize side effects, which are largely different from those seen with chronic oral therapy. In addition, there is substantial interindividual variability in response time; as a result, careful patient observation and dose adjustment are recommended as necessary.

Amiodarone should be mixed in a 5 percent dextrose solution and the amiodarone concentration kept below 2 mg/mL if given through a peripheral vein to minimize the development of local phlebitis. Higher drug concentrations must be delivered through an indwelling catheter in a central vein.

Amiodarone is physically incompatible with a number of drugs, including heparin, which should not be given in the same solution. (See 'Side effects with IV administration' below.)

Restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable atrial fibrillation — AF is common in critically ill patients and may contribute to hemodynamic instability. IV amiodarone can be used in this situation but has not been sufficiently studied in this population to allow for specific recommendations. When administered (table 4), an initial IV loading dose of 150 mg is given over a minimum of 10 minutes. More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter [1]. This regimen delivers 1050 mg of amiodarone in the first 24 hours.

In general, the reported efficacy of IV amiodarone in restoring and maintaining sinus rhythm is inconsistent, though professional society guidelines list IV amiodarone as an option for pharmacologic cardioversion [10]. (See "Atrial fibrillation: Cardioversion", section on 'Indications'.)

Several meta-analyses have been published evaluating the efficacy of IV amiodarone in restoration of normal sinus rhythm in critically ill patients [18-20]. The meta-analyses have included studies with widely varying methodologies, leading to some conflicting results.

●The largest meta-analysis included studies comparing amiodarone with other antiarrhythmic drugs or placebo [19]. IV amiodarone was as efficacious as other antiarrhythmic drugs and more effective than placebo, but amiodarone was associated with a higher rate of adverse events compared with placebo.

●Another meta-analysis, which included only studies comparing amiodarone with placebo or class Ic antiarrhythmic drugs, determined that conversion from AF to sinus rhythm was greater at 8 and 24 hours, but not at one or two hours [20].

Conversion rates from AF to sinus rhythm following IV amiodarone are higher when the bolus (3 to 7 mg/kg) is followed by continuous infusion (900 to 3000 mg daily) [18].

Ventricular rate control in critically ill patients with atrial fibrillation and rapid ventricular response — IV amiodarone may be used as a rate-controlling agent in critically ill individuals with hemodynamically destabilizing AF who cannot be maintained in sinus rhythm and in whom standard rate-controlling therapies have been either unsuccessful or are contraindicated due to hypotension. An initial IV loading dose of 150 mg is given over a minimum of 10 minutes (table 4). More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter [1]. This regimen delivers 1050 mg of amiodarone in the first 24 hours. Repeated 150 mg boluses can be given over 10 to 30 minutes, but no more than six to eight additional boluses should be administered in any 24-hour period.

AF with rapid ventricular response may contribute to hemodynamic compromise. Furthermore, ventricular rates >120 beats/minute for prolonged periods of time may contribute to left ventricular dysfunction. In a retrospective study, intensive care unit patients with hemodynamically destabilizing AF or atrial flutter resistant to conventional therapy experienced a significant 37 beat/minute decrease in ventricular rate and an increase in systolic blood pressure of 24 mmHg with no associated adverse effects [7].

IV amiodarone may also be used for rate control in patients with congestive heart failure [10].

AMIODARONE FOR VENTRICULAR ARRHYTHMIAS — Amiodarone is useful in a variety of ventricular arrhythmias including ventricular premature beats (VPBs), nonsustained ventricular tachycardia (VT), and sustained VT or ventricular fibrillation (VF). Most commonly, amiodarone is used for the secondary prevention of recurrent ventricular arrhythmias in patients with an implantable cardioverter-defibrillator (ICD) to reduce the frequency of ICD shocks. Typically, a beta blocker is co-administered with amiodarone.

Treatment of ventricular arrhythmias — Amiodarone suppresses VPBs and episodes of nonsustained VT. This is clearly demonstrated in several of the primary prevention trials of amiodarone in post-myocardial infarction (MI) and congestive heart failure patients in whom baseline and follow-up 24-hour ambulatory ECGs were performed. As examples:

●The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) pilot study enrolled patients with frequent or repetitive asymptomatic ventricular premature depolarizations (VPDs) [21]. When compared with placebo, patients receiving amiodarone had much greater suppression of VPDs and nonsustained VT (86 compared with 50 percent of placebo patients).

●The CHF-STAT trial compared amiodarone versus placebo in patients with heart failure, left ventricular (LV) ejection fraction of 40 percent or less, and frequent VPBs (more than 10/hour) [22]. Following two weeks of treatment, significantly fewer patients on amiodarone had VT on Holter monitor (33 versus 76 percent). Despite the reduction in ventricular arrhythmias and ectopy, amiodarone did not reduce mortality.

Additional trials are reviewed in detail elsewhere. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

Amiodarone is also one of the few antiarrhythmic drugs that does not increase mortality when given to patients with moderate to severe LV dysfunction. The apparent efficacy and safety of amiodarone for the treatment of ventricular tachyarrhythmias in patients with structural heart disease have led to several studies evaluating the impact of amiodarone on survival in patients at high risk of arrhythmic death.

Primary prevention of sudden cardiac death — Amiodarone for primary prevention of sudden cardiac death (SCD) is generally considered only for patients with LV dysfunction who are not candidates for, or refuse to have, ICD implantation [23]. When administered (table 4), the recommended loading dose for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [1]. Higher loading dose regimens have been evaluated but do not appear to provide greater efficacy. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects.

Ventricular arrhythmias are responsible for a large proportion of SCDs, especially in those individuals with underlying structural heart disease. The ability of amiodarone to suppress ventricular arrhythmias led to several trials designed to assess its effect on patients deemed high risk for ventricular arrhythmias either because they have already survived a sustained ventricular tachyarrhythmia or were believed to be at high risk of developing such arrhythmias due to the presence of LV dysfunction.

Earlier studies comparing amiodarone with standard medical therapy generally enrolled patients with either recent MI or congestive heart failure [2]. A 2015 Cochrane systematic review and meta-analysis (based on low to moderate quality evidence) concluded that, compared with placebo or no intervention, amiodarone reduced SCD (risk ratio [RR] 0.76, 95% CI 0.66-0.88), total cardiac death (RR 0.86, 95% CI 0.77-0.96), and all-cause mortality (RR 0.88, 95% CI 0.78-1.00) [24]. In trials comparing amiodarone with ICD therapy, ICD therapy was superior in the primary prevention of SCD [25,26]. Because of this, amiodarone for primary prevention of SCD is rarely used without concurrent use of an ICD. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

Secondary prevention of sudden cardiac death — In view of the superiority of ICD compared with antiarrhythmic drugs, including amiodarone, for the secondary prevention of SCD, amiodarone should not be used alone for secondary prevention except in those who do not meet ICD criteria, or in those who meet criteria but cannot receive a device or refuse device implantation. When administered (table 4), the recommended loading dose for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [1]. Higher loading dose regimens have been evaluated but do not appear to provide greater efficacy. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects.

Survivors of SCD due to arrhythmia carry a high risk of recurrence. With the possible exception of amiodarone, attempts to significantly reduce SCD rates by using antiarrhythmic drugs have yielded disappointing results, most likely related to the proarrhythmic effects of many antiarrhythmic drugs. The recognition of the limitations of antiarrhythmic drugs for secondary prevention was paralleled by the development of smaller, transvenous ICDs with tiered therapies, bradycardia pacing, and success rates of >95 percent in terminating VT and VF.

Several randomized trials and meta-analyses have compared ICDs with antiarrhythmic drugs for secondary prevention of SCD in patients with resuscitated VF, sustained VT with syncope, or sustained VT with ejection fraction ≤40 percent, and evidence of hemodynamic compromise. All showed superior efficacy of ICD compared with antiarrhythmic drugs. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

Prevention of ventricular arrhythmias in patients with ICDs — Shocks delivered by an ICD, especially when repetitive, can be painful and impact quality of life [27]. Amiodarone may be used to decrease the risk of ICD shocks. When administered (table 4), the recommended loading dose for the prevention of ICD shocks is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [23,28]. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects.

The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Study evaluated amiodarone plus beta blocker, sotalol alone, and beta blocker alone for the prevention of ICD shocks in 412 patients [29]. Amiodarone plus beta blocker significantly reduced the risk of shock compared with beta blocker alone (hazard ratio [HR] 0.27, 95% CI 0.14-0.52) or sotalol alone (HR 0.43, 95% CI 0.22-0.85). In the SURVIVE-VT trial, patients with ischemic cardiomyopathy and appropriate ICD shocks who were randomly assigned antiarrhythmic drugs, including amiodarone, were more likely to experience the composite endpoint (including cardiovascular death, appropriate ICD shock, heart failure hospitalization, or severe treatment-related complications), compared with those treated with ablation (HR 0.52, 95%CI 0.30-0.90). (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Antiarrhythmic drugs'.)

When using amiodarone in patients with ICDs, reassessment of defibrillation threshold may be necessary in those individuals with marginally acceptable defibrillation threshold prior to drug initiation [30]. Additionally, care must be taken in device programming as amiodarone may slow the rate of VT such that the cycle length of spontaneous VT falls outside of the programmed limits (heart rate or cycle length) for detection of VT. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Increased defibrillation threshold'.)

IV amiodarone for the treatment of electrical storm and incessant ventricular tachycardia — The use of IV amiodarone in the treatment of electrical storm and incessant VT is discussed separately. (See "Electrical storm and incessant ventricular tachycardia".)

IV amiodarone during resuscitation from cardiac arrest — The administration of IV amiodarone as part of the advanced cardiac life support protocol for resuscitation of cardiac arrest is discussed separately. (See "Advanced cardiac life support (ACLS) in adults".)

SPECIAL CONSIDERATIONS

Side effects with IV administration — A major problem noted with the intravenous (IV) preparation is hypotension, which occurs in as many as 26 percent of patients and has been attributed to faster loading rates as well as the solvents used in the preparation [6,31]. Hypotension does not appear to occur with a preparation of amiodarone that employs an aqueous base [32]. Patients who develop hypotension may benefit from a decrease in the infusion rate, while additional IV boluses may be beneficial in patients with recurrent arrhythmias during the early phase of therapy [1,7].

Proarrhythmia has been noted in 2 to 3 percent of patients treated with intravenous amiodarone; it usually manifests as torsades de pointes, but ventricular fibrillation can occur [4,6]. In a multicenter study in which 6 of 342 patients developed proarrhythmia, all had an exacerbating factor such as acute ischemia or an electrolyte imbalance [6].

Other cardiac side effects (bradycardia, asystole, heart failure, and shock), nausea, vomiting, and abnormal liver function tests occurred in 1 to 5 percent of patients each [4,6].

When given through peripheral intravenous lines, amiodarone may cause local phlebitis [33,34]. The risk of amiodarone-induced phlebitis increases with higher infusion rates and higher concentrations (eg, >2 mg/mL). The risk of phlebitis can be reduced by using lower infusion rates (when possible), lower concentrations (<2 mg/mL), or an in-line filter [35].

Transition from IV to oral therapy — The bioavailability of oral compared with intravenous amiodarone ranges from 30 to 70 percent and is increased in the presence of food. Additionally, an increase in plasma levels may not be seen for four to five hours after the ingestion of oral amiodarone. We suggest the following approach to converting IV to oral amiodarone dosing:

●Patients who have been on IV therapy for more than two weeks can be started on maintenance oral amiodarone. The maintenance dose should be determined according to antiarrhythmic effect as assessed by patient tolerance as well as symptoms, Holter recordings, and/or programmed electrical stimulation. Whereas some patients can be controlled on lower doses (eg, 100 mg/day), others may require up to 400 to 600 mg/day for refractory arrythmias. The most common maintenance doses are between 100 and 400 mg/day.

●Patients who have been on IV therapy for one to two weeks can be started on an intermediate amiodarone dose of 400 to 800 mg/day. This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to their maintenance dose.

●Patients who have been on IV therapy for one week or less should probably receive the usual oral amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to their maintenance dose.

●Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function.

Dose adjustment — Amiodarone is metabolized in the liver. The major metabolite is desethylamiodarone, which is active and has a longer elimination half-life than amiodarone [1]. Dose reduction is probably necessary in patients with significant hepatic disease. By comparison, there is minimal elimination of both amiodarone and desethylamiodarone by the kidneys due both to the large volume of distribution and extensive protein binding; the latter effect also minimizes drug removal by dialysis. As a result, the dose of amiodarone does not have to be reduced in patients with renal disease or in patients undergoing dialysis.

Drug interactions — Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Interactions with other drugs, such as digoxin and warfarin, must be considered. A few key drug interactions are discussed separately in UpToDate. Additionally, specific interactions of amiodarone with other medications may be determined using the drug interactions program. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.)

Use in children — The overall safety and efficacy of amiodarone in children have not been fully established. Use of amiodarone in the treatment of tachyarrhythmias in children has been reported in several small series and one small clinical trial [36]. Although amiodarone is effective for number of arrhythmias, its use in children is often limited by toxicities. Adverse events are common with IV amiodarone use in children and may be severe. Consultation with a pediatric cardiologist is advised. Severe adverse effects may include cardiovascular collapse, hypotension, bradycardia, and AV block. Nausea and vomiting are also common. ECG and blood pressure monitoring should be performed during administration of IV amiodarone.

Amiodarone appears to be effective in the following circumstances:

●Supraventricular tachycardia (SVT) – In children with refractory SVT, IV amiodarone is an option as second-line therapy for conversion to sinus rhythm. Use of IV amiodarone in this setting is generally limited to treatment of SVT that is refractory to other agents (adenosine, procainamide), and oral amiodarone is a second-line therapy for the prevention of recurrent arrhythmia. In children with frequent or symptomatic SVT episodes, oral amiodarone is sometimes used for chronic management if there is a poor response to first- and second-line agents (eg, beta blockers, digoxin, and sotalol). (See "Management of supraventricular tachycardia (SVT) in children".)

●Wide QRS complex tachycardia – IV amiodarone has also been used, alone or in combination with other antiarrhythmic drugs, in infants and children with resistant, life-threatening ventricular tachyarrhythmias [37,38]. (See "Management and evaluation of wide QRS complex tachycardia in children", section on 'Shock-resistant tachyarrhythmia'.)

Optimal dosing of amiodarone in children is not well established.

●For oral therapy, dosing is based upon body weight or, in children less than one year of age, upon body surface area. The loading dose, which can be given in one or two divided doses per day, is 10 to 15 mg/kg per day or 600 to 800 mg/1.73 m² per day for 4 to 14 days or until adequate control of the arrhythmia is attained or prominent adverse effects occur. The dose should then be reduced to 5 mg/kg per day or 200 to 400 mg/1.73 m² per day once daily for several weeks. If the arrhythmia does not recur, the lowest effective dose should be used for maintenance. The usual minimal dose is 2.5 mg/kg per day.

●For IV therapy in critically ill children with tachyarrhythmias who have not responded to standard therapy, a variety of regimens have been used. We typically give a slow bolus infusion of 5 mg/kg (maximum dose 300 mg) IV over 20 to 60 minutes. If the patient does not convert to sinus rhythm, additional bolus doses of 1 to 5 mg/kg (up to a total of 15 mg/kg) can be given if there are no signs of toxicity (eg, hypotension, prolonged QT interval). This can be followed, if necessary, by a continuous infusion at a rate of 5 to 10 mcg/kg per minute.

Use in pregnancy — Amiodarone has unique characteristics that mandate cautious use in pregnancy. The complications that can occur with the use of amiodarone during pregnancy are:

●Hypothyroidism or hyperthyroidism in the mother or fetus because of the iodine in amiodarone

●Fetal bradycardia

●Fetal QT interval prolongation

●Premature labor

●Low birth weight

In addition, amiodarone is found in fetal tissue and breast milk. For these reasons, the use of amiodarone in pregnancy should be reserved for maternal and fetal arrhythmias not responding to agents with known safety. Concomitant beta-blocker therapy should be avoided. Breast feeding is not recommended when the mother is taking amiodarone. (See "Supraventricular arrhythmias during pregnancy" and "Maternal conduction disorders and bradycardia during pregnancy".)

Neonates of mothers taking amiodarone should have complete thyroid function tests and developmental follow-up. (See "Clinical features and detection of congenital hypothyroidism".)

SIDE EFFECTS — While amiodarone does have many potential benefits, side effects are a serious concern. Of greatest concern are potential toxicities involving the lungs, thyroid, liver, eyes, and skin (table 3). The potential side effects related to amiodarone use are discussed in detail separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".)

SUMMARY AND RECOMMENDATIONS

●Electrocardiographic actions – Amiodarone has various electrophysiologic properties that are favorable in the treatment of tachyarrhythmias. There are important differences in these properties between the oral and intravenous (IV) preparations. (See 'Electrophysiologic properties' above.)

Amiodarone can slow the sinus heart rate, prolong the PR interval, widen the QRS complex, and prolong the QT interval on surface electrocardiogram. (See 'Effects on the ECG' above.)

●Treatment of atrial arrythmias

•Oral amiodarone – This can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. While there is no universally accepted dosing regimen (table 4), oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can sometimes be as low as 100 mg daily. (See 'Oral amiodarone for the treatment of atrial arrhythmias' above.)

•IV amiodarone – This is primarily used for the treatment of atrial arrhythmias in two settings: restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable AF, and rate control in critically ill patients with AF with rapid ventricular response in whom the tachycardia is contributing to hemodynamic compromise. An initial IV loading dose of 150 mg is given over a minimum of 10 minutes (table 4). More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter. (See 'Intravenous amiodarone for the treatment of atrial arrhythmias' above.)

●Treatment of ventricular arrythmias – Amiodarone is useful in a variety of ventricular arrhythmias but is most commonly used for the secondary prevention of recurrent ventricular arrhythmias in patients, including patients with an implantable cardioverter-defibrillator (ICD) to reduce the frequency of ICD shocks. The recommended loading dose (table 4) for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams (except for secondary prevention of ICD shocks, when the loading dose is typically 8 to 10 grams). The maintenance dose should be determined according to antiarrhythmic effect as assessed by patient tolerance as well as symptoms, Holter recordings, and/or programmed electrical stimulation. Whereas some patients can be controlled on lower doses (eg, 100 mg/day), others may require up to 400 to 600 mg/day for refractory arrythmias. (See 'Amiodarone for ventricular arrhythmias' above.)

●In the context of implantable cardioverter-defibrillators – Despite its effectiveness in reducing ventricular tachyarrhythmias, amiodarone has been shown to be inferior to ICDs in reducing mortality in both primary and secondary prevention studies of patients at high risk for sudden cardiac death. Thus, the use of amiodarone in this setting should be reserved for patients who are candidates for an ICD but who cannot or refuse to have an ICD implanted. (See 'Primary prevention of sudden cardiac death' above and 'Secondary prevention of sudden cardiac death' above.)

●Transition from IV to oral dosing – The dosing of amiodarone following conversion from IV to oral administration varies according to the duration of IV treatment prior to conversion. (See 'Transition from IV to oral therapy' above.)

●Drug interactions and side effects – Amiodarone has the potential for numerous drug interactions and side effects (table 3) that require monitoring. (See 'Drug interactions' above and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)