Amiodarone: Adverse effects, potential toxicities, and approach to monitoring

INTRODUCTION — Amiodarone has multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. Its primary effect is to block the potassium channels, but it can also block sodium and calcium channels and the beta and alpha adrenergic receptors. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

Long-term use of oral amiodarone has been associated with a relatively high incidence of adverse effects that can range in severity from mild to potentially lethal. While long-term contemporary use of amiodarone has generally been at lower doses (200 to 300 mg/day) than were historically used, even low doses may be associated with significant adverse effects, particularly pulmonary, thyroid, cardiac, skin, and ocular toxicities. Many of these effects are due to the tissue accumulation of amiodarone with long-term oral therapy and are not seen with short-term intravenous therapy.

The major adverse effects of amiodarone, along with the approach to baseline testing and serial monitoring, will be reviewed here. The clinical uses of amiodarone, including recommendations for its use in the treatment of various arrhythmias, are discussed separately. (See "Amiodarone: Clinical uses" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Supportive data for advanced cardiac life support in adults with sudden cardiac arrest", section on 'Amiodarone'.)

RATIONALE FOR MONTORING — The long half-life of oral amiodarone (25 to 100 days) and the potential severity and irreversible nature of some the adverse effects make early recognition of any potential adverse effects important. As a result, baseline testing and careful monitoring of patients taking amiodarone is essential.

The need for baseline testing and monitoring depends on the route of administration and anticipated dose and duration of therapy. Many of the adverse effects associated with oral amiodarone are due to tissue accumulation of the drug with long-term therapy and are not seen with short-term use of intravenous amiodarone [1]. If only short term use is anticipated (eg, to prevent perioperative atrial fibrillation in patient undergoing cardiac surgery, cardioversion in a critically ill patient), no serial monitoring is typically needed, whereas patients in whom long-term use is anticipated should undergo appropriate baseline testing and serial monitoring.

Intravenous (IV) amiodarone is generally used in the management of life-threatening ventricular arrhythmias or in critically ill patients with atrial fibrillation. Patients receiving IV amiodarone are generally on continuous electrocardiographic (ECG) monitoring with frequent assessment of vital signs. Such monitoring is appropriate in all patients due to the potential for hypotension and arrhythmias. If only short-term IV use is anticipated without a plan for long-term oral therapy, no baseline testing is required. However, for patients in whom a transition to long-term oral amiodarone is anticipated, the usual baseline laboratories should be obtained (table 1). (See "Amiodarone: Clinical uses".)

ADVERSE EFFECTS OF ORAL AMIODARONE

Adverse pulmonary effects — Pulmonary toxicity is one of the more common adverse effects of long-term amiodarone and is responsible for most of the rare deaths associated with amiodarone therapy (table 1). While this issue is discussed in detail separately, a brief overview will be presented here, along with recommendations for baseline testing and serial monitoring. (See "Amiodarone pulmonary toxicity".)

Clinical presentation of pulmonary toxicity — Initial reports in which patients were usually treated with amiodarone doses ≥400 mg/day noted a 5 to 15 percent incidence of pulmonary toxicity [2-4]. However, the incidence is less than 2 percent with lower maintenance doses used in contemporary practice [3,5-7].

Pulmonary toxicity is more frequent in those with advanced age or pre-existing lung disease [8], but generally correlates more closely with the total cumulative dose than with serum drug levels [6,8,9]. As a result, pulmonary toxicity usually occurs several months to as late as several years after the initiation of amiodarone therapy [6]. However, there are anecdotal cases of severe pulmonary toxicity developing within two to three weeks of therapy with low cumulative doses [10].

Chronic interstitial pneumonitis is the most common pulmonary toxicity associated with long-term amiodarone therapy. A nonproductive cough and dyspnea are present in 50 of 75 percent of affected individuals at presentation. Pleuritic pain, weight loss, fever (33 to 50 percent of cases), and malaise can also occur. The physical examination often reveals bilateral inspiratory crackles, while clubbing is not seen. (See "Amiodarone pulmonary toxicity", section on 'Clinical manifestations'.)

Several other pulmonary toxicities, including eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, alveolar hemorrhage, and pulmonary nodules, have been reported less frequently. (See "Amiodarone pulmonary toxicity".)

Baseline pulmonary testing — Recommended baseline testing for patients who are starting long-term therapy with amiodarone consists of only a chest radiograph. There are differing opinions, and no consensus, of obtaining formal pulmonary function tests (PFTs) with assessment of diffusion capacity (ie, diffusion capacity of the lungs for carbon monoxide [DLCO]) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs (table 1).

Serial pulmonary monitoring and symptomatic follow up — We perform a yearly chest radiograph for asymptomatic patients as long as they are taking amiodarone; however, we do not perform serial PFTs for asymptomatic patients, as PFTs are not helpful for predicting pulmonary toxicity. However, any patient who develops dyspnea or other symptoms suggestive of possible pulmonary toxicity should have both a chest radiograph and formal PFTs (including DLCO) and, as indicated by abnormal PFT findings, chest computed tomography. (See "Amiodarone pulmonary toxicity", section on 'Evaluation'.)

Although DLCO is often decreased in patients with pulmonary toxicity, there is usually no premonitory change in DLCO among asymptomatic patients in whom symptomatic disease subsequently develops. As a result, the DLCO is not useful as a predictive index [11,12]. In one report, for example, most asymptomatic patients with a fall in DLCO of more than 20 percent did not develop pulmonary toxicity over the next year despite continued amiodarone therapy [12].

Treatment of pulmonary toxicity — The treatment of amiodarone pulmonary toxicity typically involves discontinuing the medication and systemic glucocorticoids. Details regarding treatment are presented separately. (See "Amiodarone pulmonary toxicity", section on 'Treatment'.)

Adverse thyroid effects — Thyroid dysfunction (including both hypothyroidism and hyperthyroidism) is considered the most frequent complication of amiodarone treatment (table 1). While this issue is discussed in detail separately, a brief overview will be presented here along with recommendations for baseline testing and serial monitoring. (See "Amiodarone and thyroid dysfunction".)

Clinical presentation of thyroid toxicity — Although initial reports using higher doses noted hyperthyroidism or hypothyroidism in up to 20 percent of patients, the risk is lower (approximately 3 to 4 percent) when lower doses are used [5]. In a large Danish cohort (43,724 patients), the cumulative incidence of thyroid dysfunction following amiodarone in previously untreated patients was 5 percent in patients with heart failure and 4 percent in those without heart failure [13]. In this nationwide study, approximately 5 percent of patients who initiated treatment with amiodarone had thyroid dysfunction at one-year follow-up. In addition, a dose-response relationship was observed between the accumulated dose of amiodarone within the first year and the five-year incidence of thyroid dysfunction. Patients with heart failure who initiated amiodarone received higher accumulated doses of amiodarone and displayed significantly higher associated rates of thyroid dysfunction.

Underlying thyroid status and iodine intake appear to influence the incidence and type of thyroid dysfunction seen with amiodarone therapy [14]. The clinical manifestations of hypothyroidism (eg, fatigue, cold intolerance, constipation, weight gain, coarse hair and skin, etc) and hyperthyroidism (eg, restlessness, unexplained weight loss, low-grade fever, hypertension, tachycardia, etc) are similar to thyroid disease from any etiology, although the intrinsic beta blocking properties of amiodarone may mask some of the hyperthyroid symptoms. (See "Clinical manifestations of hypothyroidism" and "Overview of the clinical manifestations of hyperthyroidism in adults".)

Baseline thyroid testing and serial monitoring — Patients should undergo thyroid function testing prior to initiating treatment with amiodarone, again within three to four months of initiating amiodarone, and every 12 months during chronic amiodarone therapy (table 1). The onset of amiodarone-induced hypothyroidism two years after initiating therapy is rare; thus, the drug might be continued according to underlying indication with low concern of hypothyroidism induction. However, hyperthyroidism resulting from amiodarone can still be possible, and appropriate assessments are required individually. Typically, a thyroid-stimulating hormone (TSH) level can be ordered and, if normal, testing is complete. Follow-up for an abnormal TSH varies depending upon the direction of the TSH abnormality:

●Elevated TSH (suggesting hypothyroidism) – free T4 level

●Decreased TSH (suggesting hyperthyroidism) – free T4 level and total T3 level

Consultation with an endocrinologist is often warranted to determine the optimal course of action following abnormal thyroid function testing.

Treatment of thyroid dysfunction — The treatment of amiodarone-induced thyroid dysfunction is reviewed briefly here but discussed in detail separately. (See "Amiodarone and thyroid dysfunction".)

●Patients with hypothyroidism can usually be treated with thyroid hormone replacement and maintained on amiodarone.

●Patients with amiodarone-induced hyperthyroidism should be evaluated by, and treated in conjunction with, an endocrinologist. Such patients may benefit from discontinuing amiodarone if no life-threatening arrhythmias are present and other antiarrhythmic options are available.

Adverse cardiac effects

Clinical presentation of cardiac toxicity — Multiple cardiac effects can be seen in patients taking chronic amiodarone therapy (table 1). Sinus bradycardia is an expected result from amiodarone treatment, but excessive bradycardia or AV block often represents toxicity. Amiodarone does generally lead to prolongation of the QT interval, but this is rarely proarrhythmic. Finally, amiodarone can alter the defibrillation thresholds for patients with implantable cardioverter-defibrillators (ICDs).

●Bradycardia and AV block – Amiodarone can directly cause both sinus bradycardia and AV nodal block, due primarily to its calcium channel blocking activity. The overall incidence of bradycardic events has been approximately 3 to 5 percent [15]. In the meta-analysis of chronic low-dose amiodarone (mean 150 to 330 mg/day), the incidence of bradycardic events was significantly greater than with placebo (3.3 versus 1.4 percent; odds ratio [OR] 2.2, 95% CI 1.1-4.3) [5]. Typically sinus bradycardia results in few or no symptoms, but patients with second or third degree AV block are usually symptomatic with one or more of lightheadedness, presyncope, syncope, dyspnea, or fatigue.

●QT prolongation and proarrhythmia – As with most antiarrhythmic drugs, amiodarone can result in prolongation of the QT interval [16]. However, the incidence of proarrhythmia is lower with amiodarone than other class III drugs (eg, sotalol, ibutilide, and dofetilide), with an incidence of torsades de pointes ≤1 percent [7]; the exact electrophysiologic mechanisms responsible for the low proarrhythmic activity of amiodarone remain incompletely understood [4,5,17-19]. In the meta-analysis of low-dose therapy, there were no cases of torsades de pointes in the 738 patients treated with amiodarone for at least one year [5]. Several factors contribute to the rarity of torsades de pointes with amiodarone: 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 women due to slightly longer average baseline QT intervals in women, and is much more likely to occur with other factors that can cause QT prolongation such as hypokalemia, hypomagnesemia, and concomitant use of other drugs that prolong the QT interval [20]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced long QT syndrome'.)

●Interaction with ICDs – Amiodarone may have important interactions with ICDs. It may slow the ventricular tachycardia rate, possibly precluding its recognition by the device by decreasing the rate of the VT below the VT detection zone, and its major metabolite desethylamiodarone increases the defibrillation threshold in a dose-dependent fashion; this effect is seen with monophasic and biphasic waveforms [21-24]. If amiodarone is initiated in a patient with known elevated defibrillation thresholds (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 [15].

Baseline cardiac testing and serial monitoring — All patients should have an ECG prior to starting amiodarone therapy and annually for the duration of therapy, or more frequently in response to a change in symptoms (table 1). Patients with an ICD are followed in accordance with standard practice for device monitoring. (See "Cardiac implantable electronic devices: Patient follow-up".)

Management of adverse cardiac effects — 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, then urgent treatment (eg, pacing) may be required as the amiodarone tissue concentrations decrease.

●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, options include reducing the dose of amiodarone or other medications that cause AV block. 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 arrythmias are rare and that amiodarone is generally safe despite mild prolongation of the QT interval. When the QT interval is above 550 milliseconds, we avoid concomitant use of medications that interact with amiodarone metabolism or intrinsically prolong the QT interval [25]. A detailed discussion of amiodarone-induced arrhythmias can be found separately. (See "Amiodarone: Clinical uses", section on 'Electrophysiologic properties'.)

●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.

Adverse hepatic effects

Clinical presentation of hepatotoxicity — A transient rise in serum aminotransferase concentrations occurs in approximately 25 percent (range 15 to 50 percent) of patients soon after amiodarone is begun; most patients are asymptomatic with this [26]. Symptomatic hepatitis occurs in less than 3 percent of patients; potential complications include cirrhosis and hepatic failure [26,27]. Jaundice is an unusual adverse effect that may be due to intrahepatic cholestasis [28,29]. Serum bilirubin concentrations may first increase or continue to increase for a period of time after the drug is discontinued [28,29]. These findings are consistent with the long half-life of amiodarone (25 to 100 days). Both direct hepatotoxicity and metabolic idiosyncrasy are thought to contribute to amiodarone-induced hepatic injury [26,30].

Baseline hepatic function assessment and serial monitoring — Prior to beginning chronic amiodarone therapy, baseline testing (table 1) should include serum transaminase levels (ALT and AST). These tests should be repeated every 12 months for the duration of therapy for following the development of signs or symptoms suggesting liver disease [15].

Treatment of hepatic toxicity — Although the relation of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity and, therefore, that maintenance doses should be kept as low as possible. In the meta-analysis of chronic low-dose amiodarone (mean 150 to 330 mg/day), the incidence of hepatotoxicity was low and not significantly different from placebo (1.2 versus 0.8 percent; OR 1.2, 95% CI 0.4-3.3) [5].

Amiodarone should be discontinued in most cases if there is more than a twofold elevation in serum transaminase levels from baseline, or in patients diagnosed with hepatitis [15].

Adverse ocular effects — Corneal microdeposits are an expected finding in patients on chronic oral amiodarone, typically with minimal to no impact on vision. In contrast, rare cases of optic neuropathy have been reported, with the potential to progress to blindness if undiagnosed and untreated. All patients should have a baseline eye examination prior to (or shortly after) initiating chronic oral amiodarone therapy (table 1). 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.

Corneal microdeposits — Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities [31-33]. 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 [31]. The formation of microdeposits is dose-dependent; the changes are reversible within seven months after amiodarone is discontinued [32].

Corneal microdeposits do not reduce visual acuity. However, ocular symptoms occur in a small number of patients [31,32]. These include halo vision (colored rings around lights), particularly at night, photophobia, and blurred vision. The incidence has been reported as 1.5 percent in a meta-analysis of trials of chronic low-dose amiodarone (mean dose 150 to 330 mg/day), compared with 0.1 percent seen with placebo (OR 3.4, 95% CI 1.2-9.6) [5,32].

The presence of microdeposits is not considered a contraindication to continued amiodarone therapy, since visual acuity is rarely affected [31,32]. In any patient with visual symptoms who is taking amiodarone, other common factors (a change in refractive correction, progression of age-related cataract, or increased intraocular pressure) should be considered before attributing the change to the drug.

Optic neuropathy — Amiodarone has been reported to cause optic nerve injury, with unilateral or bilateral visual loss that can rarely progress to permanent blindness [31,34,35]. Whether the prevalence of this adverse effect increases with time is unclear, although some survey data have reported that the prevalence may increase over time [31].

●In a report of 296 cases of optic neuropathy identified through the US Food and Drug Administration adverse event reporting system, 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 [36].

●In a Taiwanese nationwide cohort study, which included 6175 patients who started treatment with amiodarone between 2005 and 2009 (along with 24,700 matched controls) and were followed for an average of 1.9 years, significantly more amiodarone-treated patients developed optic neuropathy (17 [0.3 percent] versus 30 [0.1 percent] of controls; adjusted hazard ratio 2.1, 95% CI 1.1-3.9) [35].

●In a post hoc report from the SCD-HeFT trial in which patients were randomized to amiodarone (n = 837) or placebo (n = 832), there were no reported cases of bilateral vision loss over a relatively short duration of follow-up (median 45.5 months) [37].

Additional long-term data are needed to clarify the incidence of optic neuropathy and potential causation from amiodarone. However, 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 [31].

Other — Long-term amiodarone therapy has several other potential toxicities.

Adverse skin reactions — Various skin reactions, previously more common when higher doses of amiodarone were used, were reported in 2.3 percent of patients (compared with 0.7 percent in placebo recipients; OR 2.5, 95% CI 1.1-6.2) in the meta-analysis of chronic low-dose amiodarone therapy (mean dose 150 to 300 mg/day) [5]. Types of skin reactions include:

●Photosensitivity, which can be treated with avoidance of sun exposure and the use of sunblock.

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

●Other reported adverse effects include hyperpigmentation, pseudoporphyria, and bullous dermatitis [38].

The bluish-slate gray discoloration of the skin occurs in 1 to 3 percent of patients on chronic amiodarone therapy and appears to be due to the deposition of lipofuscin in the dermis [39-41]. There may be a tissue threshold for amiodarone in individual patients above which skin discoloration appears and below which it fades [42]. Thus, patients disturbed by skin pigmentation who are taking large doses (more than 400 mg/day) may notice improvement in skin discoloration by reducing the dose.

There is no specific therapy for the skin discoloration, but affected patients are advised to avoid sun exposure. Complete resolution after cessation of amiodarone therapy may take one year or more [43].

Adverse gastrointestinal effects — Gastrointestinal adverse effects associated with amiodarone therapy, which include nausea, vomiting, anorexia, diarrhea, and constipation, occur mostly during the initial loading phase of therapy [5,15]. While previously reported in up to 30 percent of patients, findings from the meta-analysis of chronic low-dose amiodarone therapy suggest that gastrointestinal adverse effects are not significantly more frequent than with placebo (4.2 versus 3.3 percent) [5]. Taking the medication with food or reducing the dose when possible can reduce GI side effects.

Adverse neurologic function — 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 [5,15,44]. In the meta-analysis of chronic low-dose amiodarone therapy (mean dose 150 to 330 mg/day), neurologic side effects were much less common than what was reported in early studies that utilized higher doses of amiodarone, but still significantly more frequent than with placebo (4.6 versus 1.9 percent; OR 2.0, 95% CI 1.1-3.7) [5]. We recommend stopping amiodarone to see if symptoms resolve.

Adverse drug interactions — 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 of several antiarrhythmic drugs (such as quinidine, procainamide, and digoxin), possibly leading to supratherapeutic plasma concentrations if the dose 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 (25 to 100 days). See the drug interactions program for additional information including specific dose adjustments or limits and management suggestions.

●Digoxin – Amiodarone can interfere with the metabolism of digoxin, raising the plasma digoxin concentration and potentially leading to digoxin toxicity. The dose of digoxin should be empirically reduced by 50 percent at the time of amiodarone initiation or the need for digoxin 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 can also interfere with the metabolism of warfarin, which often necessitates approximately a 25 percent reduction in warfarin dose to prevent an elevation in the international normalized ratio (INR) and potential bleeding complications [45,46]. 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, with an average reduction in warfarin dose of 24.6 percent [46]. The INR level should be checked more frequently in the one to two weeks after amiodarone is initiated.

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 [47]. Thyroid function should be reassessed in any patient on a stable warfarin and amiodarone regimen if the INR changes unexpectedly. (See 'Adverse thyroid effects' above.)

●Direct oral anticoagulants (DOACs) – There are limited data concerning drug-drug interactions of DOACs and amiodarone. It is currently recommended that clinicians consider alternative combinations or adjust the DOAC dose to minimize the risk of bleeding [48]. A retrospective, population-based, nested case-control study found a significant association between major bleeding and current use of amiodarone among older patients with atrial fibrillation on a DOAC (ie, there was 53 percent increased odds of major bleeding with current use of amiodarone) [49]. Accordingly, caution should be used in the coprescription of amiodarone and DOACs, and the risk of major bleeding should be considered in determining the risks of a drug-drug interaction between amiodarone and DOACs.

●Simvastatin – Amiodarone alters the metabolism of simvastatin, 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 other medications including sildenafil, cyclosporine, and other hepatically metabolized drugs including some antidepressants.

SUMMARY AND RECOMMENDATIONS

●Rationale for monitoring – The long half-life of amiodarone (25 to 100 days) and the potential severity of some of the adverse effects make early recognition important. Thus, baseline testing and careful monitoring of patients taking amiodarone is essential (table 1). (See 'Rationale for montoring' above.)

●Adverse pulmonary effects – Pulmonary toxicity is a common adverse effect of long-term amiodarone and is rarely fatal. Pulmonary toxicity generally correlates more closely with the total cumulative dose than with serum drug levels.

•Several different types of adverse pulmonary effects may occur, including chronic interstitial pneumonitis, the most common.

•Symptoms include a nonproductive cough and dyspnea.

•Physical examination often reveals bilateral inspiratory crackles.

•The diagnosis of amiodarone pulmonary toxicity is one of exclusion.

•Treatment consists primarily of stopping amiodarone, with corticosteroid therapy administered in patients with symptomatic pulmonary toxicity. (See 'Adverse pulmonary effects' above and "Amiodarone pulmonary toxicity".)

●Thyroid dysfunction – This includes both hypothyroidism and hyperthyroidism and is another common complication of amiodarone therapy, occurring in approximately 3 to 4 percent of patients when lower doses (<400 mg/day) are used. Underlying thyroid status and iodine intake appear to influence the incidence and type of thyroid dysfunction seen with amiodarone therapy. (See 'Adverse thyroid effects' above and "Amiodarone and thyroid dysfunction".)

●Adverse cardiac effects – These can include excessive sinus bradycardia, AV block, and QT interval prolongation (usually not arrhythmogenic). Finally, amiodarone can alter the defibrillation thresholds for patients with an implantable cardioverter-defibrillators (ICDs). Management varies depending upon the adverse effect. (See 'Adverse cardiac effects' above.)

●Adverse hepatic effects – Symptomatic hepatitis occurs in less than 3 percent of patients on amiodarone, and potential complications such as cirrhosis and hepatic failure occur very infrequently. However, a transient asymptomatic rise in serum aminotransferase concentrations occurs in approximately 25 percent of patients soon after beginning amiodarone. Although the relation of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity. While patients are usually asymptomatic, the drug should be discontinued if there is more than a twofold elevation in serum aminotransferases. (See 'Adverse hepatic effects' above.)

●Adverse ocular effects – Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities. While corneal microdeposits do not reduce visual acuity, ocular symptoms may occur, including halo vision (colored rings around lights), photophobia, and blurred vision. The presence of microdeposits is not considered a contraindication to continued amiodarone therapy since visual acuity is rarely affected. (See 'Corneal microdeposits' above.)

●Adverse drug interactions – 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 of several antiarrhythmic drugs (such as quinidine, procainamide, and digoxin), possibly leading to supratherapeutic plasma concentrations if the dose is not reduced. (See 'Adverse drug interactions' above.)