Amiodarone: Clinical uses, administration, and adverse effects

INTRODUCTION — 

Amiodarone is an antiarrhythmic drug that is used to treat atrial and ventricular arrhythmias. Because it can have adverse effects on multiple organ systems, close monitoring is required for patients taking this medication long-term.

The current topic will review the pharmacokinetics, electrophysiologic properties, clinical uses, dosing, monitoring, and adverse effects of amiodarone. Other topics discuss amiodarone pulmonary and thyroid toxicities in detail. (See "Amiodarone pulmonary toxicity" and "Amiodarone and thyroid dysfunction".)

PHARMACOKINETICS — 

Oral and intravenous (IV) amiodarone differ markedly in their pharmacokinetics.

●Oral amiodarone – Oral amiodarone is incompletely absorbed (approximately 30 to 70 percent) after oral administration. It is markedly lipophilic and is taken up extensively by tissue (eg, fat, muscle, highly perfused organs), with marked interindividual variation [1]. The average volume of distribution to tissue is 66 L/kg [2]. Long loading periods are necessary to accelerate the onset of drug activity, and the time to reach stable plasma levels is prolonged. Because of these characteristics, arrhythmia recurrence during the first months of therapy despite loading does not necessarily predict long-term failure. Oral amiodarone has a long true elimination half-life (between 60 and 142 days) [1,3].

●IV amiodarone – Unlike oral amiodarone, IV amiodarone acts quickly, becoming effective within minutes of a bolus. IV amiodarone has a short half-life, likely due to drug redistribution from vascular space into tissue rather than true body elimination.

Plasma concentration of amiodarone or its major active metabolite, desethylamiodarone, does not correlate with drug efficacy or toxicity [2].

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 because 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. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

Like other oral class III agents (eg, sotalol, dofetilide, ibutilide, dronedarone), oral amiodarone prolongs the QT interval. However, in contrast to most other class III agents, amiodarone has very little proarrhythmic activity. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and 'Cardiac effects' below.)

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 by causing noncompetitive beta receptor blockade

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

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 [4].

●Prolongation of the PR interval and the atrioventricular (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 by less than 10 percent), as conduction is slowed in ventricular muscle by the blocking effect on the inactivated sodium channel and resultant slowing of phase 0 depolarization (figure 1) [5]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

●Prolongation of the QT interval (typically by 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) [5,6]. However, unlike with other QT-prolonging drugs, this increased QT seen with amiodarone is rarely proarrhythmic. (See 'Cardiac effects' below.)

Intravenous (IV) amiodarone — IV amiodarone has a number of important electrophysiologic differences from chronically administered oral amiodarone [4,7]:

●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 QT interval.

●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 [7]. This property may account for the efficacy of the agent in the suppression of ventricular tachyarrhythmias [8]. IV amiodarone also prolongs AV nodal conduction and refractoriness and may be effective in slowing the ventricular rate in critically ill patients with atrial tachyarrhythmias [9].

CLINICAL USES IN ADULTS — 

Amiodarone is used for the prevention and treatment of atrial and ventricular arrhythmias in adults.

Atrial fibrillation

●Oral amiodarone – Oral amiodarone is often prescribed for the following reasons:

•To prevent recurrent AF in patients with a history of paroxysmal AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.)

•To prevent postoperative AF in patients undergoing cardiac surgery [10-12]. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Amiodarone'.)

•To prevent postprocedural recurrent AF in patients undergoing elective cardioversion or catheter ablation. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.)

Oral amiodarone is occasionally given for pharmacologic cardioversion (ie, to restore sinus rhythm) but is less effective for this purpose than certain other antiarrhythmic drugs (eg, propafenone, flecainide). It results in pharmacologic cardioversion in only 25 percent of patients with acute or recent-onset AF [13-15].

●Intravenous (IV) amiodarone – IV amiodarone is used to treat critically ill patients with atrial fibrillation (AF) who require assistance with one of the following:

•Restoration and maintenance of sinus rhythm – IV amiodarone may be used for the restoration and maintenance of sinus rhythm in patients with AF who are critically ill, especially if the AF is believed to be contributing to hemodynamic compromise [16]. Rates of conversion from AF to sinus rhythm with IV amiodarone are higher when the bolus is followed by a continuous infusion [17]. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.)

•Rate control – IV amiodarone may also be used to control the ventricular rate in critically ill patients with persistent AF, especially when standard rate-controlling therapies (eg, beta blockers, calcium channel blockers) have been ineffective or are contraindicated. In a retrospective study, patients with hemodynamically destabilizing AF or atrial flutter who received IV amiodarone experienced a 37 bpm decrease in ventricular rate and a 24 mmHg increase in systolic blood pressure [9]. While amiodarone is less effective for rate control than diltiazem, it is also less likely to cause hypotension [18].

Ventricular arrhythmias

●Oral amiodarone – Oral amiodarone can be used to suppress ventricular arrhythmias. Examples of clinical scenarios in which amiodarone might be used include the following:

•Prevention of implantable cardioverter-defibrillator (ICD) shocks in patients with a history of sustained ventricular tachycardia (VT). (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".)

•Prevention of sudden cardiac death in patients who do not want to have an ICD placed. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

•Prevention of symptomatic premature ventricular complexes or nonsustained VT. (See "Premature ventricular complexes: Treatment and prognosis", section on 'Antiarrhythmic therapy' and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Persistent symptoms'.)

•Prevention of ventricular arrhythmias in patients with advanced heart failure who have a continuous-flow left ventricular assist device. (See "Management of long-term mechanical circulatory support devices", section on 'Ventricular arrhythmias'.)

●IV amiodarone – IV amiodarone is used for the pharmacologic cardioversion of ventricular arrhythmias (eg, VT) and for the short-term prevention of recurrence. Specific scenarios in which amiodarone might be used and evidence for its use are discussed elsewhere. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis" and "Electrical storm and incessant ventricular tachycardia", section on 'Amiodarone' and "Advanced cardiac life support (ACLS) in adults", section on 'Pulseless ventricular tachycardia and ventricular fibrillation'.)

DOSING AND MONITORING

Oral amiodarone dosing and monitoring

●Dosing – Loading and maintenance dosing recommendations for oral amiodarone are provided in the table (table 3). The recommended loading doses for patients transitioning from intravenous (IV) amiodarone are different than those for patients who are amiodarone-naive. Dose adjustment may be required for patients taking certain medications (see 'Drug-drug interactions' below). Dose adjustment is not required for patients with chronic kidney disease, including those undergoing dialysis. However, because amiodarone is metabolized in the liver, dosage adjustment is probably necessary in substantial hepatic impairment.

●Baseline testing and monitoring – Due to the risk of adverse effects, baseline testing and periodic monitoring are necessary for patients taking long-term oral amiodarone. Specific recommendations can be found in the table (table 4). Adverse effects are discussed below. (See 'Adverse effects of oral amiodarone' below.)

IV amiodarone dosing and administration

●Dosing – Loading and maintenance dosing recommendations for IV amiodarone can be found in the table (table 3). While some guidelines recommend a 300 mg bolus, we prefer the 150 mg dose, which is in agreement with the ACLS tachycardia algorithm [10]. When the drug is being used for rate control, repeated 150 mg boluses can be given over 10 to 30 minutes; no more than six to eight additional boluses should be administered in any 24-hour period. Dose adjustment is not required for patients with chronic kidney disease, including those undergoing dialysis. Adjustment is also unnecessary for patients with chronic liver disease.

●Drug administration – Amiodarone should be mixed in a 5 percent dextrose solution, and the amiodarone concentration should be kept below 2 mg/mL if the infusion is 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. There is substantial interindividual variability in response time; as a result, careful patient observation and dose adjustment are recommended as necessary.

Amiodarone is incompatible with heparin and should not be given through the same infusion line. (See 'Drug-drug interactions' below.)

DRUG-DRUG INTERACTIONS — 

Potential drug-drug interactions may necessitate adjustment of doses of certain medications when used with amiodarone (eg, digoxin, warfarin). Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Additionally, amiodarone can interfere with the hepatic metabolism or excretion of several antiarrhythmic drugs (eg, quinidine, procainamide, digoxin), possibly leading to supratherapeutic plasma concentrations if the dose of those drugs is not reduced. These interactions are particularly worrisome because they may persist for as long as three months after the cessation of therapy due to the long elimination half-life of amiodarone. Amiodarone is hepatically metabolized, primarily by CYP3A4. Inhibitors and inducers of CYP3A4 can increase or decrease amiodarone serum concentrations, which may contribute to increased toxicity or decreased efficacy, respectively. Specific interactions may be checked using the drug interactions program included with UpToDate.

Examples of medications that interact with amiodarone include the following:

●Digoxin – Amiodarone can reduce the excretion of digoxin, raising the plasma digoxin concentration and potentially leading to digoxin toxicity. The dose of digoxin should be reduced by 30 to 50 percent at the time of amiodarone initiation or the need for digoxin should be reevaluated altogether. Digoxin levels should be measured within three days after amiodarone initiation. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Dose adjustment with concomitant medications'.)

●Warfarin – Amiodarone may interfere with the metabolism of warfarin via inhibition of CYP2C9, resulting in an elevation in the international normalized ratio (INR) and potential bleeding complications [19,20]. Thus, the INR level should be checked more frequently in the first two weeks after amiodarone is initiated. In a retrospective cohort study of 754 patients treated with chronic warfarin therapy in whom amiodarone was started, the average INR increased from 2.6 to 3.1, leading to an average reduction in warfarin dose of 24.6 percent [20].

The interaction between amiodarone and warfarin is further complicated by the potential effects of amiodarone on thyroid function. The effect of warfarin is potentiated by thyrotoxicosis and attenuated in hypothyroidism [21]. Thyroid function should be reassessed in any patient on a stable warfarin and amiodarone regimen if the INR changes unexpectedly. (See 'Hypothyroidism and thyrotoxicosis' below.)

●Direct oral anticoagulants (DOACs) – There are limited data concerning drug-drug interactions between DOACs and amiodarone, but retrospective data suggest an association between amiodarone use and major bleeding in older adults taking DOACs [22,23]. For patients receiving both amiodarone and a DOAC, some UpToDate contributors to this topic would decrease the DOAC dose to minimize the risk of bleeding, while others would not [24,25].

●Simvastatin – Amiodarone alters the metabolism of simvastatin, likely due to inhibition of CYP3A4, resulting in a significantly higher risk of rhabdomyolysis when both drugs are used concurrently. If amiodarone and simvastatin are required in the same patient, the dose of simvastatin should be no higher than 20 mg daily.

●Other drugs – Amiodarone can increase the plasma concentration of many other medications, including cyclosporine, colchicine, and other drugs subject to hepatic metabolism or P-glycoprotein transport. Amiodarone is subject to adverse cardiac effects such as sinus bradycardia and QT prolongation, which may be additive with other agents. (See 'Cardiac effects' below.)

Heparin and IV amiodarone should not be given through the same IV line because they can precipitate.

ADVERSE EFFECTS — 

The adverse effects of intravenous (IV) and oral amiodarone differ.

Adverse effects of oral amiodarone — Long-term oral amiodarone has many possible adverse effects, including toxicities involving the lungs, thyroid, heart, liver, eyes, and skin, necessitating monitoring (table 4).

Pulmonary toxicity — Amiodarone-induced pulmonary toxicity historically occurred in 5 to 15 percent of patients on chronic amiodarone. However, the incidence has decreased to 1 to 5 percent because lower maintenance doses are used in contemporary practice [26-29]. Risk factors for developing pulmonary toxicity include a high cumulative dose, daily dose >400 mg/day, duration of therapy exceeding two months, older age, and preexisting lung disease [30,31].

●Clinical manifestations – The most common form of amiodarone pulmonary toxicity is interstitial pneumonitis. Patients usually present with a gradual onset of nonproductive cough and/or dyspnea, often with fever. The symptoms typically begin within 6 to 12 months; however, some patients develop symptoms within the first few weeks or after several years of treatment. (See "Amiodarone pulmonary toxicity", section on 'Clinical manifestations'.)

Organizing pneumonia represents 25 percent of pulmonary toxicity cases and has a more acute presentation than interstitial pneumonitis, occurring over a few weeks or months. Presenting symptoms are similar to those of interstitial pneumonitis.

Less common forms of pulmonary toxicity include organizing pneumonia, eosinophilic pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules, and pleural effusions.

●Baseline testing and serial monitoring – A baseline chest radiograph is recommended prior to initiation of long-term amiodarone to uncover evidence of undiagnosed underlying interstitial lung disease (table 4). Some experts obtain baseline pulmonary function tests (PFTs) with diffusion capacity for patients with underlying lung disease, while others rarely do so. For long-term monitoring, annual chest radiographs are indicated, whereas repeat PFTs are indicated only for patients who have symptoms that are concerning for pulmonary toxicity.

●Management – Patients who develop pulmonary toxicity should immediately stop amiodarone; however, due to the long elimination half-life, pulmonary symptoms may initially progress despite drug discontinuation. Patients with interstitial pneumonitis who have significant symptoms may benefit from systemic glucocorticoids. (See "Amiodarone pulmonary toxicity", section on 'Treatment'.)

A detailed discussion of amiodarone pulmonary toxicity can be found elsewhere. (See "Amiodarone pulmonary toxicity".)

Hypothyroidism and thyrotoxicosis — Thyroid toxicity (eg, hypothyroidism, thyrotoxicosis) is the most frequent complication of amiodarone treatment. Similar to pulmonary toxicity, rates of thyroid toxicity have decreased (from 20 percent to approximately 3 to 4 percent) with the use of lower amiodarone doses in contemporary clinical practice [27].

●Clinical manifestations – The clinical manifestations of hypothyroidism (eg, fatigue, cold intolerance, constipation, weight gain, coarse hair and skin) and thyrotoxicosis (eg, restlessness, unexplained weight loss, low-grade fever, hypertension, tachycardia) are similar to thyroid disease from any etiology, although the intrinsic beta-blocking properties of amiodarone may mask some of the hyperthyroid symptoms. Hypothyroidism may develop earlier than thyrotoxicosis; in one study, the median time to onset of amiodarone-induced hypothyroidism was 183 days, while the median onset of hyperthyroidism was 720 days [32]. (See "Clinical manifestations of hypothyroidism" and "Overview of the clinical manifestations of hyperthyroidism in adults".)

●Baseline testing and serial monitoring – Patients should undergo thyroid function testing (ie, thyroid-stimulating hormone with reflex free T4) prior to initiating treatment with amiodarone. The test should be repeated within three to four months of initiating amiodarone, and then every 12 months during chronic amiodarone therapy (table 4).

●Management – For patients whose thyroid function becomes abnormal, consultation with an endocrinologist is warranted to determine the optimal course of action. For most patients with amiodarone-induced hypothyroidism, the drug can be continued provided that levothyroxine is initiated. For patients with thyrotoxicosis, management depends on the indication for amiodarone and the severity of symptoms. (See "Amiodarone and thyroid dysfunction", section on 'Treatment of AIT'.)

A detailed discussion of amiodarone thyroid toxicity can be found elsewhere. (See "Amiodarone and thyroid dysfunction".)

Cardiac effects — Amiodarone can lead to bradyarrhythmias and tachyarrhythmias. In addition, the drug can cause electrophysiologic changes that impact implantable cardioverter-defibrillation (ICD) function (table 4).

●Clinical and electrophysiologic manifestations

•Bradyarrhythmias – Amiodarone can directly cause both sinus bradycardia and atrioventricular (AV) nodal block, due primarily to its calcium channel-blocking activity. The overall incidence of bradycardic events is approximately 3 to 5 percent [33]. In a meta-analysis of four trials (1465 patients) comparing chronic low-dose amiodarone (mean 150 to 330 mg/day) with placebo, the incidence of bradycardic events was greater with low-dose amiodarone than with placebo (3.3 versus 1.4 percent; odds ratio [OR] 2.2, 95% CI 1.1-4.3) [27]. Age ≥75 years is a risk factor for this adverse effect [34]. Sinus bradycardia does not usually cause symptoms, but patients with second- or third-degree AV block may experience lightheadedness, presyncope, syncope, dyspnea, or fatigue.

•QT prolongation and proarrhythmia – As with most antiarrhythmic drugs, amiodarone can result in prolongation of the QT interval [35]. However, the incidence of proarrhythmia is lower with amiodarone than with other class III drugs (eg, sotalol, ibutilide, dofetilide), with torsades de pointes occurring in ≤1 percent [29]. The electrophysiologic mechanisms responsible for the low proarrhythmic activity of amiodarone remain incompletely understood [27,36-39]; however, several factors may contribute to the lower rate of torsades de pointes with amiodarone than with other class III antiarrhythmic drugs, including lack of reverse use dependence, concurrent blockade of the L-type calcium channels, and less heterogeneity of ventricular repolarization (less QT dispersion). Torsades de pointes associated with amiodarone therapy is more likely to occur in female individuals and is much more likely to occur in patients who have another risk factor for QT prolongation (eg, hypokalemia, hypomagnesemia, concomitant use of certain drugs) [40]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced long QT syndrome'.)

•Interaction with ICDs – Amiodarone can impact ICD function in two distinct ways. First, it may decrease the rate of ventricular tachycardia (VT) below the VT detection zone, precluding its recognition by the ICD. Second, its major metabolite, desethylamiodarone, increases the defibrillation threshold (DFT) in a dose-dependent fashion [41-44]. The higher DFT increases the likelihood that ICD-delivered shocks will be unsuccessful in terminating a ventricular arrhythmia.

●Baseline testing and serial monitoring – All patients should have an electrocardiogram (ECG) prior to starting amiodarone therapy and annually for the duration of therapy, or more frequently in response to a change in symptoms (table 4). If amiodarone is initiated in a patient with an ICD who is known to have elevated DFTs or risk factors for elevated DFTs, a noninvasive ICD evaluation should be performed to test for adverse drug-device interactions once loading is complete [33]. (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Tachycardia therapies'.)

●Management – The management of adverse cardiac effects related to amiodarone varies depending upon the adverse effect and may require dose reduction or discontinuation of amiodarone. Despite dose modification or cessation of amiodarone, cardiac adverse effects may persist due to the drug’s long half-life. If the effects are clinically significant, urgent treatment (eg, pacing) may be required. Management of specific cardiac effects is as follows:

•Sinus bradycardia – If sinus bradycardia occurs during therapy, amiodarone and other drugs with negative chronotropic effects should be discontinued or dose-reduced, if possible. If amiodarone therapy is necessary and sinus bradycardia persists after medications have been modified, placement of a permanent pacemaker capable of atrial pacing may be required.

•High-grade AV block – If high-grade (second- or third-degree) AV block develops during therapy, we reduce the dose of amiodarone (or a concurrent medication that may be contributing, such as a beta blocker). If AV block does not resolve despite medication changes, placement of a permanent pacemaker may be necessary.

•QT prolongation – While amiodarone prolongs the QT interval, the authors and editors of this topic agree that amiodarone-induced arrhythmias are rare and that amiodarone is generally safe despite mild prolongation of the QT interval. If the QT interval is above 550 milliseconds, we avoid concomitant use of medications that interact with amiodarone metabolism or intrinsically prolong the QT interval [45].

•Increased ICD defibrillation threshold – If ongoing treatment with amiodarone is required and results in an unacceptably high defibrillation threshold, options include using a high-output device, reprogramming the shock waveform (eg, duration, amplitude), repositioning the lead, or adding a subcutaneous array.

Abnormal liver tests and hepatitis — Amiodarone commonly causes abnormal serum aminotransferase concentrations but rarely causes hepatitis.

●Clinical manifestations – A transient rise in serum aminotransferase concentrations (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) occurs in approximately 25 percent (range 15 to 50 percent) of patients soon after amiodarone is begun [46]. Most patients with a rise in AST and/or ALT are asymptomatic. Symptomatic hepatitis occurs in fewer than 3 percent of patients, with cirrhosis and hepatic failure being rare [46,47]. Jaundice is an unusual adverse effect that may be due to intrahepatic cholestasis [48,49]. Both direct hepatotoxicity and metabolic idiosyncrasy are thought to contribute to amiodarone-induced hepatic injury [46,50]. Lab abnormalities may continue or worsen for a period of time after amiodarone is discontinued [48,49] due to the long half-life of the drug.

●Baseline testing and serial monitoring – Prior to beginning chronic amiodarone therapy, baseline testing (table 4) should include serum aminotransferase levels (ALT and AST). These tests should be repeated every 12 months for the duration of therapy, or following the development of signs or symptoms suggesting liver disease [33]. On follow-up liver enzyme testing, if hepatic enzymes exceed three times the upper limit of normal (or two times the upper limit of normal in patients with elevated enzymes at baseline), the dose should be decreased or amiodarone discontinued. Although the relationship of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity; therefore, maintenance doses should be kept as low as possible.

●Management – Amiodarone should be discontinued if there is more than a twofold increase in serum transaminase levels from baseline, or if a patient is diagnosed with hepatitis [33].

Corneal microdeposits and optic neuropathy — Corneal microdeposits, which are usually benign, have been reported in the majority of patients taking chronic amiodarone [51,52]. Optic neuropathy, which can cause blindness, is rare.

●Clinical manifestations

•Corneal microdeposits – Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities [51-53]. The corneal microdeposits are caused by the secretion of amiodarone by the lacrimal gland with accumulation on the corneal surface. They are identifiable on ophthalmologic examination as a brownish whorl at the juncture of the lower one-third and upper two-thirds of the cornea and have been described as resembling a cat's whiskers [51]. The formation of microdeposits is dose-dependent; the changes are reversible within seven months after amiodarone is discontinued [52].

Corneal microdeposits do not reduce visual acuity. However, ocular symptoms occur in a small number of patients [51,52]. These include halo vision (colored rings around lights), particularly at night, photophobia, and blurred vision.

•Optic neuropathy – Amiodarone has been reported to cause optic nerve injury, with unilateral or bilateral visual loss that can rarely progress to permanent blindness [51,54,55]. In a report of 296 cases of optic neuropathy, the mean duration of amiodarone treatment prior to visual loss was nine months (ranging from 1 to 84 months); nearly one-third of cases were asymptomatic [56].

●Baseline testing and serial monitoring – All patients should have a baseline eye examination prior to (or shortly after) initiating chronic oral amiodarone therapy (table 4). Annual eye examinations are recommended but not required if patients remain asymptomatic while taking amiodarone; however, patients with visual symptoms while on amiodarone should be promptly referred for a repeat eye examination.

●Management – The presence of corneal microdeposits is not considered a contraindication to continued amiodarone therapy, since visual acuity is rarely affected [51,52]. In any patient with visual symptoms who is taking amiodarone, other common factors (eg, a change in refractive correction, progression of age-related cataract, increased intraocular pressure) should be considered before attributing the change to the drug.

Given the potential for permanent visual loss, immediate cessation of amiodarone or dose reduction is recommended for patients who develop optic neuropathy unless the arrhythmia is life-threatening and an alternative antiarrhythmic drug is not available [51].

Skin reactions — A meta-analysis of patients receiving chronic low-dose amiodarone therapy (mean dose 150 to 300 mg/day) reported various skin reactions in 2.3 percent of patients (compared with 0.7 percent in patients receiving placebo) [27].

●Clinical manifestations – Types of skin reactions include:

•Photosensitivity.

•Bluish-slate gray discoloration of the skin (so-called "blue man syndrome"), which is usually most prominent on the face (picture 1).

•Less common reactions include hyperpigmentation, pseudoporphyria, and bullous dermatitis [57].

The bluish-slate gray discoloration of the skin appears to be due to the deposition of lipofuscin in the dermis [58-60]. There may be a tissue threshold for amiodarone above which skin discoloration appears and below which it fades [61].

●Management – Patients with skin discoloration who are taking amiodarone >400 mg/day may notice improvement if they reduce the dose. Patients with photosensitivity should avoid sun exposure and/or use sunscreen. Complete resolution of skin reactions after cessation of amiodarone therapy may take one year or more [62].

Gastrointestinal effects — While higher doses (>300 mg/day) of amiodarone were historically associated with gastrointestinal (GI) side effects (eg, nausea, vomiting, anorexia, diarrhea, constipation) in up to 30 percent of patients during the initial loading phase of therapy [33], a meta-analysis of patients on chronic low-dose amiodarone therapy suggested that GI adverse effects are comparable to amiodarone and placebo [27]. Nonetheless, patients on amiodarone who develop GI side effects may be instructed to take the medication with food; if this does not help, reducing the dose may be reasonable.

Neurologic toxicity — Neurologic toxicity associated with amiodarone therapy may take many forms, including tremor, ataxia, peripheral neuropathy with paresthesias, and sleep disturbances. Similar to other toxicities, these appear to be dose-related in patients requiring higher doses [27,33,63]. In a meta-analysis of patients on chronic low-dose amiodarone therapy (mean dose 150 to 330 mg/day), neurologic side effects were much less common than previously reported in early studies that utilized higher doses of amiodarone; however, they are still more frequent than with placebo (4.6 versus 1.9 percent; OR 2.0, 95% CI 1.1-3.7) [27]. Patients taking amiodarone who develop new neurologic symptoms should be referred to a specialist for evaluation.

Adverse effects of IV amiodarone — Hypotension is the most common adverse effect of IV amiodarone, occurring in up to a quarter of patients. This side effect has been attributed to fast loading rates as well as the benzyl alcohol and polysorbate 80 used in the preparation [8,64]. Hypotension does not appear to occur with a preparation of amiodarone that employs an aqueous base [65]. Patients who develop hypotension may benefit from a decrease in the infusion rate [2,9]. Alternatively, fluid administration or judicious use of an inotrope or vasopressor may be appropriate.

Proarrhythmia has been noted in 2 to 3 percent of patients treated with IV amiodarone. It usually manifests as torsades de pointes, but ventricular fibrillation can occur [7,8]. It appears that an exacerbating factor is necessary to provoke an arrhythmia; in a multicenter study in which 6 of 342 patients on IV amiodarone developed proarrhythmia, all had a contributing factor such as acute ischemia or an electrolyte imbalance [8].

Other cardiac side effects (eg, bradycardia, asystole, heart failure, shock), nausea, vomiting, and abnormal liver function tests may occur in 1 to 5 percent of patients each [7,8].

When given through peripheral IV lines, amiodarone may cause local phlebitis [66,67]. 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, lower concentrations (<2 mg/mL), or an in-line filter [68].

SPECIAL POPULATIONS

Children

●Clinical uses – Amiodarone is used infrequently in children. Consultation with a pediatric cardiologist is advised whenever amiodarone is being considered.

•Supraventricular tachycardia (SVT) – In children with refractory SVT, intravenous (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). 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 [69,70]. (See "Management and evaluation of wide QRS complex tachycardia in children", section on 'Shock-resistant tachyarrhythmia'.)

●Safety – Use of amiodarone in the treatment of tachyarrhythmias in children has been reported in several small series and one small clinical trial [71]. Adverse events are common with IV amiodarone use in children and may be severe, including cardiovascular collapse, hypotension, bradycardia, and atrioventricular (AV) block. Nausea and vomiting are common. Electrocardiography (ECG) and blood pressure monitoring should be performed during the administration of IV amiodarone.

●Dosing

•Oral amiodarone – 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.

•IV amiodarone – 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.

Pregnancy and lactation — Amiodarone has unique characteristics that mandate cautious use in pregnancy. The most concerning complications that can occur with the use of amiodarone during pregnancy are thyroid dysfunction (especially neonatal hypothyroidism) and neurodevelopmental abnormalities [72]. Other possible effects include fetal bradycardia, fetal QT interval prolongation, premature labor, and low birth weight.

When amiodarone is taken during pregnancy and when lactating, amiodarone can be found in fetal tissue and human milk. 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 due to the risk of fetal bradycardia. Neonates should not ingest human milk produced by an individual taking amiodarone. (See "Supraventricular arrhythmias during pregnancy" and "Maternal conduction disorders and bradycardia during pregnancy".)

Neonates born to individuals taking amiodarone should have complete thyroid function tests and developmental follow-up.

SUMMARY AND RECOMMENDATIONS

●General principles – Amiodarone is an effective antiarrhythmic drug for atrial and ventricular arrhythmias. The oral formulation has a slow onset of action, a large volume of distribution, and a long half-life. (See 'Introduction' above and 'Pharmacokinetics' above.)

●Electrophysiologic properties – Amiodarone is a class III antiarrhythmic agent but also has class I, II, and IV effects. Oral amiodarone slows the sinus rate, prolongs the PR and QT intervals, and widens the QRS. (See 'Electrophysiologic properties' above.)

●Clinical uses

•Atrial arrhythmias – Oral amiodarone is used primarily to prevent atrial fibrillation (AF). Intravenous (IV) amiodarone is used for restoration and maintenance of sinus rhythm in patients with AF who are critically ill, as well as to control the ventricular rate in critically ill patients with persistent AF. (See 'Atrial fibrillation' above.)

•Ventricular arrhythmias – Oral amiodarone is used to prevent ventricular arrhythmias. IV amiodarone is used for the pharmacologic conversion of ventricular arrhythmias and for the short-term prevention of recurrence. (See 'Ventricular arrhythmias' above.)

●Dosing and monitoring – Details regarding dosing, baseline testing, and monitoring can be found in the tables (table 3 and table 4) and above. (See 'Dosing and monitoring' above.)

●Drug-drug interactions – Oral amiodarone interacts with many medications, including digoxin and warfarin. (See 'Drug-drug interactions' above.)

●Adverse effects of oral amiodarone – Oral amiodarone can cause many adverse effects, including toxicities involving the lungs, thyroid, heart, liver, eyes, and skin. (See 'Adverse effects of oral amiodarone' above.)

●Adverse effects of IV amiodarone – Hypotension occurs in up to a quarter of patients given IV amiodarone. Arrhythmias (eg, torsades de pointes) are uncommon. (See 'Adverse effects of IV amiodarone' above.)

●Use in children – Amiodarone is used infrequently in children to treat supraventricular tachycardia (SVT) and wide QRS complex tachycardia. (See 'Children' above.)

●Pregnancy and lactation – Amiodarone can have adverse effects on the fetus and should be avoided in pregnancy unless no alternative exists. Neonates should not ingest human milk produced by an individual taking amiodarone. (See 'Pregnancy and lactation' above.)