Amiodarone hydrochloride is considered to be predominantly a class III antiarrhythmic agent, but the drug also appears to exhibit activity in each of the 4 Vaughn-Williams antiarrhythmic classes, including some class I (membrane-stabilizing) antiarrhythmic action.1, 2, 4, 5, 7, 8, 12, 17, 18, 21, 24, 25, 26, 28, 31, 32, 35, 38, 44, 46, 355, 364
Amiodarone appears to be effective in the management of a wide variety of ventricular as well as supraventricular arrhythmias†.1, 9, 35, 106, 500, 501, 502, 700, 701 Because of amiodarone's potentially life-threatening adverse effects and the management difficulties associated with its use, the drug previously was not considered a first-line antiarrhythmic but generally was reserved for use in life-threatening ventricular arrhythmias.1, 364 The drug also was used infrequently for the suppression or prevention of any type of arrhythmia and only when conventional antiarrhythmic therapy was considered ineffective or was not tolerated.1, 3, 9, 25, 35, 175, 243, 364 However, amiodarone generally appears to exhibit greater efficacy and a lower incidence of proarrhythmic effects than class I or other class III antiarrhythmic drugs and therefore has become a mainstay in the management of various tachyarrhythmias, including expert recommendations for advanced cardiovascular life support (ACLS), despite labeling that continues to recommend more limited use. In addition, although no antiarrhythmic agent given routinely during cardiac arrest has been shown to increase survival to hospital discharge, amiodarone has been shown to increase short-term survival to hospital admission relative to lidocaine or placebo.406, 407, 501 Amiodarone should be used only by clinicians who are familiar with and have access to, either directly or through referral, the use of all currently available modalities for the management of recurrent life-threatening ventricular arrhythmias and who have access to appropriate evaluative and monitoring procedures, including continuous ECG monitoring and electrophysiologic techniques for evaluating the patient in both ambulatory and hospital settings.1, 106
Amiodarone is used orally or IV to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (recurrent ventricular fibrillation and recurrent, hemodynamically unstable ventricular tachycardia) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents are not tolerated.1, 3, 355, 364 Amiodarone is designated an orphan drug by the FDA for use in this condition.356 Amiodarone may be used IV to treat patients with ventricular tachycardia or fibrillation in whom oral amiodarone therapy is indicated, but who are unable to take oral medication.355
It is difficult to assess the overall efficacy of amiodarone since response to the drug depends on many factors, including the specific cardiac arrhythmia being treated, the criteria used to evaluate efficacy, the presence of underlying cardiac disease in the patient, the number of antiarrhythmic agents used prior to amiodarone, the duration of follow-up, and the concomitant use of other antiarrhythmic agents.1, 9, 35, 106 In addition, overall arrhythmia recurrence rates (fatal and nonfatal) appear to be highly variable and depend on many factors, including response to programmed electrical stimulation (PES) or other measures, and whether patients who do not appear to respond initially are included.1 When considering only those patients who responded well enough to amiodarone to be placed on long-term treatment, ventricular arrhythmia recurrence rates have ranged from 20-40% in most studies having an average follow-up period of 1 year or longer.1
Life-Threatening Ventricular Arrhythmias and Advanced Cardiovascular Life Support
There is relatively limited experience from controlled studies with the use of amiodarone for suppression and prevention of recurrent life-threatening ventricular arrhythmias.1, 35, 106, 364 Although comparative data are lacking, the efficacy of amiodarone in the management of severe refractory arrhythmias generally is considered to be at least comparable to and probably better than that of other antiarrhythmic agents (e.g., quinidine, procainamide).5, 26 Data from most clinical studies indicate that the drug is effective in approximately 50-80% of patients with life-threatening ventricular arrhythmias, including those refractory to other antiarrhythmic agents.3, 9, 10, 25, 26, 30, 62, 108, 110, 113, 137, 175, 176 Previously, the potential severity of the drug's adverse effects generally had precluded amiodarone from being considered a first-line† agent in the management of life-threatening ventricular arrhythmias, and use of the drug generally was reserved for patients in whom other antiarrhythmic agents were ineffective or not tolerated.1, 3, 9, 25, 35, 175, 243, 364 Currently, however, amiodarone is considered a preferred† or alternative agent for the management of various life-threatening ventricular arrhythmias, in part because of comparable or better efficacy and its apparent reduced risk of proarrhythmic activity.500, 501, 502
Shock-Resistant Ventricular Fibrillation or Pulseless Ventricular Tachycardia
Amiodarone is used as adjunctive therapy for the treatment of ventricular fibrillation or pulseless ventricular tachycardia resistant to cardiopulmonary resuscitation (CPR), defibrillation, and a vasopressor (e.g., epinephrine).500, 501, 502
Antiarrhythmic drugs are used during cardiac arrest to facilitate the restoration and maintenance of a spontaneous perfusing rhythm in patients with refractory (i.e., persisting or recurring after at least one shock) ventricular fibrillation or pulseless ventricular tachycardia; however, there is no evidence that these drugs increase survival to hospital discharge when given routinely during cardiac arrest.500 High-quality CPR and defibrillation are integral components of ACLS and the only proven interventions to increase survival to hospital discharge.500, 501 Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.500, 501 The principal goal of pharmacologic therapy during cardiac arrest is to facilitate return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use.500, 501 (See Uses: Advanced Cardiovascular Life Support and Cardiac Arrhythmias, in Epinephrine 12:12.12.) If an antiarrhythmic agent is needed for the treatment of refractory ventricular fibrillation or pulseless ventricular tachycardia during adult cardiac arrest, the American Heart Association (AHA) recommends amiodarone as the first-line drug of choice because of its proven benefits in improving rates of ROSC and hospital admission; lidocaine may be used as an alternative.500, 501 Results of several studies suggest that amiodarone is more effective than lidocaine in improving rates of ROSC and hospital admission in patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.500, 501 In pediatric advanced life support (PALS), current evidence supports the use of either amiodarone or lidocaine for these arrhythmias.502
Results of a randomized, double-blind, placebo-controlled study in patients with out-of-hospital cardiac arrest due to defibrillation-refractory ventricular arrhythmias (i.e., ventricular fibrillation, pulseless ventricular tachycardia) who received a single 300-mg dose of IV amiodarone hydrochloride (after at least 3 precordial electrical shocks were administered) indicate that the drug improved the rate of survival to hospital admission by 29%.395, 398 In a randomized, double-blind, comparative study with lidocaine, approximately 23% of patients with out-of-hospital cardiac arrest due to defibrillation-refractory ventricular arrhythmias who received IV amiodarone hydrochloride (5 mg/kg) or its matching placebo survived to hospital admission compared with 12% of those who received IV lidocaine (1.5 mg/kg) or its matching placebo following at least 3 precordial electrical shocks, IV epinephrine, and an additional precordial electrical shock.420 Among patients for whom the time from dispatch of the ambulance to the administration of the drug was equal to or less than the median time (24 minutes), approximately 28% of those given amiodarone and 15% of those given lidocaine survived to hospital admission.420 Despite these results, only about 5% of patients receiving IV amiodarone who survived to hospital admission lived to be discharged from the hospital compared with about 3% of those receiving IV lidocaine.420 Evidence supporting the use of amiodarone and lidocaine in pediatric cardiac arrest is more limited and principally based on extrapolation of data from the adult population.459, 502 In a retrospective cohort study that included data from 889 pediatric patients with in-hospital cardiac arrest, improved ROSC was observed with lidocaine compared with amiodarone.459, 502 Neither drug was associated with improved survival to hospital discharge.459, 502
IV amiodarone also may be used for the treatment of regular wide-complex tachycardias during the periarrest period and is included as a recommended antiarrhythmic agent in current ACLS guidelines for both adult and pediatric tachycardia.500, 501, 503
Monomorphic and Polymorphic Ventricular Tachycardia
Some experts recommend that sustained monomorphic ventricular tachycardia not associated with angina, pulmonary edema, or hypotension (blood pressure less than 90 mm Hg)† be treated with amiodarone or synchronized electrical cardioversion.364, 442 Other experts recommend amiodarone for control of hemodynamically stable monomorphic ventricular tachycardia†.501 Drug regimens including amiodarone or procainamide may be used initially† for the treatment of patients with episodes of sustained ventricular tachycardia that are associated with myocardial infarction and somewhat better tolerated hemodynamically.364, 442 If IV antiarrhythmic therapy is used for ventricular fibrillation or tachycardia, it probably should be discontinued (at least temporarily) after 6-24 hours so that the patient's ongoing need for antiarrhythmic drugs can be reassessed.364, 442
Amiodarone also may be used for the treatment of polymorphic (irregular) ventricular tachycardia† associated with myocardial ischemia in the absence of QT interval prolongation.501 Although rare, episodes of drug-refractory sustained polymorphic ventricular tachycardia (electrical storm) have been reported in cases of acute myocardial infarction.364, 442 Some experts state that these episodes should be managed by aggressive attempts at reducing myocardial ischemia†, including therapies such as an IV β-adrenergic blocking agent, IV amiodarone, left stellate ganglion blockade, intra-aortic balloon counterpulsation (IABP), or emergency revascularization (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft [CABG] surgery); IV magnesium also may be used.364, 442 Polymorphic ventricular tachycardia associated with QT interval prolongation usually is treated with IV magnesium sulfate.501
Prevention of Ventricular Arrhythmias and Death Associated with Cardiac Arrest
Oral amiodarone has been used for primary prevention† of sustained ventricular tachycardia (i.e., ventricular tachycardia lasting greater than 30 seconds and/or associated with hemodynamic compromise),364 ventricular fibrillation, or sudden cardiac death in patients with nonsustained ventricular arrhythmia following myocardial infarction.344, 368, 370, 384, 394 Such use of the drug was once thought to prevent sudden cardiac death because ventricular premature complexes (VPCs) were believed to be harbingers of more serious ventricular arrhythmias (e.g. ventricular fibrillation or tachycardia).364, 418 However, conflicting results have been reported in studies evaluating the efficacy of antiarrhythmic agents on the risk of sudden death from cardiac causes in post-myocardial infarction patients.419
Results of 2 multicenter, randomized, placebo-controlled studies in patients with frequent or repetitive ventricular premature complexes (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [CAMIAT]) or with left ventricular dysfunction (European Myocardial Infarct Amiodarone Trial [EMIAT]) indicate that therapy with oral amiodarone in patients who had survived a recent myocardial infarction appeared to reduce resuscitated cardiac arrest or ventricular fibrillation or arrhythmic death but was not associated with reduction of total mortality after 1-2 years of follow-up.1, 364, 368, 370, 376, 377, 378, 379, 380, 381, 382, 383, 384, 391, 394 These data are consistent with results of pooled analysis of small controlled trials in patients with structural heart disease, including post-myocardial infarction patients.1 However, in a smaller study (Basel Antiarrhythmic Study of Infarct Survival [BASIS]) comparing amiodarone with usual care in patients with persisting asymptomatic complex arrhythmias (multiform or repetitive ventricular arrhythmias [Lown class 3 or 4b]) after acute myocardial infarction, long-term therapy with amiodarone was associated with a reduction in mortality at 1 year compared with no antiarrhythmic therapy,344 possibly as a result of a decreased incidence of sudden death from ventricular tachycardia and fibrillation.343, 344 In addition, analysis of pooled data369, 374, 383 from several other randomized studies344, 368, 370, 372, 373, 385, 386, 387 in patients at risk of sudden cardiac death (e.g., those with congestive heart failure or left ventricular dysfunction, recent myocardial infarction, prior cardiac arrest) suggested that amiodarone therapy may reduce total mortality by 10-19%, and such risk reduction associated with the drug may be similar in the mentioned patient populations.369, 374
Findings from the National Heart, Lung, and Blood Institute (NHLBI)'s Cardiac Arrhythmia Suppression Trial (CAST) study indicated a substantially increased rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild to moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent VPC) who received encainide or flecainide (class I antiarrhythmic drugs) compared with placebo after an average of 10 months of follow-up, which resulted in considerably modified clinicians' use of not only class IC antiarrhythmics, but also class I antiarrhythmic agents in general, in post-myocardial infarction patients.1, 358, 359, 360, 418, 419 Although it has been suggested that the applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or to predominantly class III antiarrhythmic agents such as amiodarone (a drug that has some characteristics of class IA and IC antiarrhythmic agents)5, 7, 8, 21, 25, 32 is uncertain, the American College of Cardiology (ACC) and AHA state that β-adrenergic blocking agents are preferred over amiodarone for general prophylaxis.364 In addition, results of prospective, randomized clinical studies indicate improved survival following use of implantable cardioverter defibrillator (ICD) therapy compared with conventional drug therapy, including amiodarone, in patients with nonsustained ventricular tachycardia, reduced ejection fraction (less than 40%), and/or a history of myocardial infarction.419, 421, 422, 427 However, preliminary reports suggest that only a small proportion of patients with a previous myocardial infarction would benefit from ICD therapy and it remains unclear whether routinely screening patients with impaired left ventricular function for prophylactic ICD therapy is clinically feasible and cost-effective.419
Amiodarone hydrochloride is used orally or IV to suppress or prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., recurrent ventricular fibrillation and recurrent, hemodynamically unstable ventricular tachycardia) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents cannot be tolerated.1, 3, 364 The effectiveness of IV amiodarone in suppressing recurrent ventricular fibrillation or hemodynamically unstable (destabilizing) ventricular tachycardia is supported by 2 randomized, parallel, dose-response studies of approximately 300 patients each.355 In patients with recurrent ventricular fibrillation or destabilizing ventricular tachycardia that was refractory to first-line (e.g., lidocaine) therapy, amiodarone produced a dose-dependent decrease in arrhythmia recurrence, although not in mortality.364, 365 Patients with at least 2 episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia within the preceding 24 hours were randomly assigned to receive IV amiodarone hydrochloride doses of 125 mg or 1 g over 24 hours;355 one study also evaluated a dose of 500 mg.355 After 48 hours, patients were eligible to receive open access to any treatment deemed necessary (including IV amiodarone) to control their arrhythmias.355 Amiodarone was administered in a 3-phase sequence, with an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and a subsequent 18-hour maintenance infusion.355 Maintenance infusion was continued up through hour 48.355 Additional supplemental 10-minute infusions of 150 mg were administered for breakthrough arrhythmias;355 these occurred more frequently in patients receiving the 125-mg dosage regimen.355 Fewer patients receiving the 1-g IV amiodarone hydrochloride regimen required supplemental infusions.355 During treatment with IV amiodarone, median episodes of ventricular tachycardia or ventricular fibrillation were 0.02/hour in the group receiving the 1-g dosage regimen and 0.07/hour in the group receiving the 125-mg dosage regimen, or approximately 0.5 versus 1.7 episodes daily in patients receiving the 1-g versus 125-mg dosage regimen, respectively.355 In one study, the time to first episode of ventricular tachycardia or ventricular fibrillation was approximately 10 or 14 hours in patients receiving the 125- or 1000-mg amiodarone hydrochloride dosage regimens, respectively.355 Mortality rate was not affected by treatment in either of these studies.355
Because there has been no evidence of improved survival with use of antiarrhythmic agents, including amiodarone and β-adrenergic blocking agents,419 whereas such evidence does exist for ICD therapy,419, 423, 424, 425 ICDs have increasingly been used in the secondary prevention of life-threatening ventricular arrhythmias.418, 421, 427 In comparative studies, ICD therapy has been shown to be superior to antiarrhythmic drugs, principally amiodarone, for increasing overall survival of patients who had been resuscitated from near-fatal ventricular fibrillation or sustained ventricular tachycardia.423, 424 Analysis of pooled data indicates that ICD therapy prolongs life by 2.1 or 4.4 months compared with amiodarone after a follow-up period of 3 or 6 years, respectively.423 Subgroup analysis of patients enrolled in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study indicates that patients with an isolated episode of ventricular fibrillation in the absence of cerebrovascular disease or history of prior arrhythmia who have undergone revascularization or who have moderately preserved left ventricular function (i.e., left ventricular ejection fraction greater than 27%) are not likely to benefit from ICD therapy compared with amiodarone therapy.426 However, results of this analysis must be considered speculative because the specific criteria used in defining the subgroups were not planned prior to collection of data, and additional studies are needed to verify these findings.426
Prediction of the efficacy of any antiarrhythmic agent in the long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial.1, 35 Many authorities currently recommend the use of ambulatory ECG monitoring, programmed electrical stimulation (PES), or a combination of both to assess patient response to amiodarone.1 There is no consensus on many aspects of how best to assess patient response to the drug; however, there is reasonable agreement on some aspects.1 If a patient with a prior history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during ECG monitoring prior to treatment, some provocative approach such as exercise or PES is required to assess the efficacy of amiodarone.1 The need for provocation in patients who do manifest life-threatening arrhythmias spontaneously remains to be established, although there are reasons to consider PES or other means of provocation in such patients.1 In patients whose PES-induced arrhythmia is made noninducible by amiodarone, the prognosis is almost uniformly excellent, with very low rates of arrhythmia recurrence or sudden death.1 The meaning of continued inducibility during therapy with the drug is controversial.1 Although not clearly established, increased difficulty of arrhythmia induction by PES and/or the ability to tolerate the induced ventricular tachycardia without severe symptoms may be useful criteria for identifying patients who may benefit from amiodarone therapy despite continued inducibility of the arrhythmia during therapy with the drug.1, 303 Generally, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of the need to revise treatment.1, 293 Other criteria for predicting the efficacy of amiodarone therapy, including complete suppression of nonsustained ventricular tachycardia determined by ambulatory ECG monitoring and the documentation of very low rates of VPCs, also have been suggested.1 These issues remain unsettled for amiodarone as well as for other antiarrhythmic agents.1 Specialized references should be consulted for additional information.
Combination Antiarrhythmic Regimens
Amiodarone has been used in combination with numerous other antiarrhythmic agents for the management of severe refractory ventricular arrhythmias; however, such combination therapy has not been evaluated in well-controlled studies and is associated with an increased risk of adverse cardiovascular effects.5, 9, 25, 30, 108, 109, 110, 113, 122, 125, 126, 137
Amiodarone has been used with good results in a limited number of patients experiencing life-threatening ventricular arrhythmias associated with post-infarction aneurysm†26, 72 or with chronic myocarditis induced by Chagas' disease.†26, 72, 172 IV amiodarone has been used with some success in a limited number of patients for the management of ventricular tachycardia and ventricular fibrillation associated with cardiac glycoside intoxication†.135, 257
Supraventricular Tachyarrhythmias
Amiodarone appears to be effective in the suppression and prevention of various supraventricular tachycardias (SVTs)†;3, 4, 5, 9, 10, 12, 25, 26, 27, 35, 62, 66, 71, 72, 92, 109, 110, 111, 113, 116, 119, 120, 122, 125, 126, 402, 501, 701 because of a higher risk of toxicity and proarrhythmic effects, antiarrhythmic agents generally should be reserved for patients who do not respond to or cannot be treated with AV nodal blocking agents (β-adrenergic blocking agents and nondihydropyridine calcium-channel blocking agents).501, 700 Some experts state that amiodarone may be useful in situations where ventricular rate control is needed but AV nodal blocking agents are contraindicated, such as in patients with preexcited atrial arrhythmias associated with an accessory pathway†.501, 701 However, IV amiodarone is potentially harmful when used for the acute treatment of patients with preexcited atrial fibrillation since it has the potential to accelerate the ventricular response and precipitate fatal arrhythmias.700, 701
Atrial Fibrillation and Flutter
Amiodarone has been used orally and IV in the management of atrial fibrillation† or flutter† .402, 501, 700, 701
Amiodarone is one of several antiarrhythmic agents that may be used to maintain sinus rhythm in patients with atrial fibrillation or flutter.700, 701 Long-term therapy with oral amiodarone alone4, 5, 9, 10, 12, 25, 26, 27, 35, 62, 66, 71, 72, 92, 109, 110, 111, 113, 116, 119, 120, 122 or in combination with other antiarrhythmic agents125, 126 has been effective for suppression and prevention of refractory atrial fibrillation†. Limited data indicate that long-term amiodarone therapy may be effective in about 70% (range: 35-95%) of patients with atrial fibrillation†, including those whose arrhythmia is refractory to conventional therapy.25, 26, 62, 66, 71, 109, 110, 113, 116, 119, 120, 122, 402 Although not clearly established, the efficacy of amiodarone in the suppression of atrial fibrillation† may result from the drug's ability to maintain normal sinus rhythm (probably by increasing atrial refractoriness), suppress atrial premature complexes (which may precipitate atrial fibrillation), and control ventricular rate.27, 109, 110, 119, 122, 123 There is some evidence that amiodarone may be substantially more effective than sotalol or propafenone for long-term prevention of recurrent atrial fibrillation.402 Whether maintaining sinus rhythm in patients with recurrent atrial fibrillation will result in improved survival or a reduction in the risk of thromboembolic complications remains to be established.402
Oral4, 9, 71, 118 or IV†9, 114, 123 amiodarone may be effective for conversion of atrial fibrillation† to normal sinus rhythm (i.e., rhythm control).701 In current expert guidelines, amiodarone is considered a reasonable option for pharmacological conversion of atrial fibrillation; however, other antiarrhythmic agents (e.g., flecainide, dofetilide, propafenone, ibutilide) are preferred.701 IV amiodarone may be harmful, and therefore should not be used, in patients with Wolff-Parkinson-White (WPW) syndrome who have preexcited atrial fibrillation because the drug can accelerate ventricular rate and potentially cause life-threatening ventricular arrhythmias.701 Conversion of atrial fibrillation to normal sinus rhythm may be associated with embolism, particularly when atrial fibrillation has been present for more than 48 hours, unless the patient is adequately anticoagulated.701 (See Uses: Cardioversion of Atrial Fibrillation/Flutter, in Heparin 20:12.04.16.)
Further studies are needed to evaluate the comparative efficacy and safety of oral amiodarone, other antiarrhythmic agents, and cardioversion (direct-current countershock).4, 118 Although cardioversion has been used safely and effectively following oral9, 38, 110, 124 or IV124, 301 amiodarone administration, decreased efficacy of cardioversion in patients receiving the drug has also been reported.1, 25, 122, 175, 304 Further studies are needed to evaluate the effect of amiodarone therapy on the efficacy of cardioversion.9
Paroxysmal Supraventricular Tachycardia
Limited data suggest that IV amiodarone is effective in terminating paroxysmal supraventricular tachycardia (PSVT)†, including atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) (e.g., WPW syndrome).9, 38, 48, 501, 700 Some experts state that IV amiodarone may be considered for the acute treatment of hemodynamically stable patients with AVNRT when other therapies are ineffective or contraindicated.700 However, IV use of amiodarone can be potentially harmful in patients with preexcited atrial fibrillation because the drug may accelerate ventricular rate and cause life-threatening ventricular arrhythmias.700
Long-term oral amiodarone therapy appears to be particularly effective in the suppression and prevention of paroxysmal reentrant supraventricular tachycardias† (AVNRT and AVRT [e.g., WPW syndrome])4, 5, 8, 9, 25, 26, 27, 28, 29, 37, 39, 41, 47, 48, 66, 71, 72, 109, 110, 112, 113, 122, 128, 318 including those refractory to other antiarrhythmic agents.5, 26, 27, 39, 66, 71, 110, 113, 122, 128, 318, 700 Some experts state that oral amiodarone may be reasonable for ongoing management of AVNRT or AVRT in patients who are not candidates for, or prefer not to undergo, catheter ablation and in whom first-line drugs (e.g., β-adrenergic blocking agents, diltiazem, verapamil) are not effective or contraindicated.700 Oral amiodarone also has been effective in some patients for the suppression and prevention of atrial fibrillation or flutter associated with WPW syndrome†.26, 27, 37, 38, 39, 41, 66, 71, 127, 318 Although amiodarone also has been used IV in such patients,117, 165 IV use of the drug has resulted in acceleration of ventricular rate.165, 284, 701
IV amiodarone may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia† (i.e., regular SVT arising from a localized atrial site), and oral amiodarone may be reasonable for the ongoing management of such patients.700
While evidence is more limited, amiodarone also has been used in patients with multifocal atrial tachycardia† (i.e., rapid, irregular rhythm with at least 3 distinct P-wave morphologies).700 However, such arrhythmia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic therapy.700 Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of chronic obstructive pulmonary disease or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity).700
Amiodarone may be used for the treatment of junctional tachycardia† (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia; however, efficacy data is available only for pediatric patients.700β-Adrenergic blocking agents generally are considered the drugs of choice for terminating and/or reducing the incidence of junctional tachycardia.700
Bradycardia-Tachycardia Syndrome
Amiodarone has been effective in the prevention of supraventricular arrhythmias associated with bradycardia-tachycardia syndrome† in a limited number of patients;4, 9, 25, 110, 129, 130, 131 however, the drug should be used with caution in such patients, since it may depress sinoatrial node function, possibly resulting in marked bradycardia.4, 9, 20, 25, 30, 129, 130, 131 Some clinicians recommend insertion of a temporary or permanent artificial pacemaker prior to initiation of amiodarone therapy in patients with bradycardia-tachycardia syndrome†.4, 9, 25, 130, 132
Amiodarone has been used in a limited number of patients for the management of chronic stable angina pectoris†.17, 50, 133, 229 Limited data suggest that amiodarone is as effective as diltiazem and more effective than sublingual nitroglycerin in increasing exercise tolerance and decreasing ST-segment depression in patients with chronic stable angina pectoris†.133 Amiodarone also has been used with good results in some patients with Prinzmetal variant angina†.17, 134 Because of the potential toxicity associated with amiodarone, the drug generally is not considered a first-line agent for the management of chronic stable angina pectoris† or Prinzmetal variant angina†284 but may have a beneficial antianginal effect in patients receiving the drug for the management of arrhythmias.229
Amiodarone has been used with good results in some patients for the management of ventricular and supraventricular arrhythmias associated with hypertrophic cardiomyopathy†.25, 258, 259, 278, 292 In addition to its antiarrhythmic effects,258, 259, 278, 292 the drug may also relieve symptoms258, 278 and increase exercise capacity258, 259, 278 in some patients, including those whose arrhythmias are refractory to conventional treatment.258, 259, 278 Pending further accumulation of data, some clinicians recommend that treatment with amiodarone be considered only in patients with refractory hypertrophic cardiomyopathy†.258, 278
Reconstitution and Administration
Amiodarone hydrochloride is administered orally or by IV infusion.1, 3, 9, 10, 25, 35, 355 Amiodarone also has been administered by intraosseous (IO) injection† in the setting of advanced cardiovascular life support (ACLS); however, there is limited experience with the drug given by this route.501
For the management of life-threatening ventricular arrhythmias, oral amiodarone hydrochloride usually is administered once daily.1, 3 When dosages of 1 g or more daily are administered (e.g., during the loading-dose phase of therapy) or when intolerable adverse GI effects occur with once-daily dosing, it is recommended that the drug be given in divided doses (e.g., twice daily) with meals.1, 3 Because food can increase the rate and extent of absorption of amiodarone, the drug should be administered in a consistent manner relative to food intake.1, 431
Patients should be advised not to stop taking amiodarone without their clinician's knowledge, even if they feel better, as their condition may worsen.431 If a patient misses an oral dose of amiodarone, a double dose should not be taken to make up for the missed dose; instead, the next dose should be taken at the regularly scheduled time.431 If additional oral doses of amiodarone are ingested, patients should seek medical attention urgently by contacting their clinician or immediately proceeding to the nearest hospital emergency department.431
Extemporaneous Oral Suspension
Extemporaneous oral suspensions of amiodarone have been prepared using the tablets and a commercially available vehicle.463, 464
Standardized concentrations for an extemporaneously prepared oral suspension of amiodarone have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 462Multidisciplinary expert panels were convened to determine recommended standard concentrations. 462Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 462 For additional information on S4S (including updates that may be available), see [Web]
Concentration Standards |
|---|
5 mg/mL 20 mg/mL for doses of 75 mg or greater |
aAmiodarone needs to have a pH very close to 8 to assure particle consistency
Commercially available amiodarone hydrochloride concentrate for injection containing 50 mg of the drug per mL must be diluted prior to administration.355 To produce the solution required for the first rapid loading infusion or for supplemental amiodarone infusions, 3 mL of amiodarone hydrochloride concentrate should be added to 100 mL of 5% dextrose, resulting in a final concentration of 1.5 mg/mL.355 To produce the solution for slow infusion and the maintenance infusion, 18 mL of amiodarone hydrochloride concentrate should be added to 500 mL of 5% dextrose, resulting in a final amiodarone concentration of 1.8 mg/mL.355 For subsequent maintenance infusions, solutions containing a final amiodarone hydrochloride concentration of 1-6 mg/mL may be used.355 Parenteral amiodarone hydrochloride solutions should be inspected visually for particulate matter whenever solution and container permit.355
For IV infusion, the recommended dose of the diluted amiodarone hydrochloride solution is administered in a 3-phase sequence: a rapid loading phase, a slow loading phase, and a maintenance infusion phase.355 Parenteral amiodarone therapy should be used for acute antiarrhythmic therapy until the patient's cardiac rhythm is stabilized and oral therapy can be initiated.355 The manufacturer states that most patients will require IV therapy for 48-96 hours, but that parenteral therapy may be administered safely for longer periods of time.355
Solutions containing an amiodarone hydrochloride concentration of 2 mg/mL or more should be administered via a central venous catheter,355 although the manufacturer states that parenteral amiodarone solutions should be administered via a central venous catheter dedicated to administration of the drug whenever possible.355 An in-line filter also should be used for administration of IV amiodarone hydrochloride solutions.355 Amiodarone hydrochloride infusions that will exceed 2 hours must be administered in glass or polyolefin bottles.355 (See Chemistry and Stability: Stability.) Although amiodarone hydrochloride adsorbs to polyvinyl chloride (PVC), the drug dosages used in clinical trials were designed to take this factor into account;355 therefore, the manufacturer recommends that solutions containing amiodarone hydrochloride injection be administered through PVC tubing.355 Polysorbate (Tween®) 80, a component of IV amiodarone, can cause leaching of diethylhexylphthalate (DEHP) from IV tubing, including PVC tubing.355 Leaching of DEHP increases at lower than recommended flow rates and at higher than recommended infusion concentrations.355 Therefore, the manufacturer's dosage recommendations should be followed closely.355
The surface properties of solutions containing amiodarone hydrochloride injection are altered such that the drop size may be reduced.355 This reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used.355 Therefore, the manufacturer states that solutions containing amiodarone hydrochloride injection must be administered by a volumetric infusion pump.355
Standardized concentrations for IV amiodarone have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 460, 461Multidisciplinary expert panels were convened to determine recommended standard concentrations. 460, 461Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 460, 461 For additional information on S4S (including updates that may be available), see [Web].460, 461
Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
Adults | 1.8 mg/mL | mg/min |
Pediatric patients (<50 kg) | 1.8 mg/mL | mcg/kg/mina |
A uniform and optimal dosage schedule for amiodarone hydrochloride has not been established.1, 35 Amiodarone is a highly toxic drug, and the lowest effective dosage should be used to minimize the risk and occurrence of adverse effects .1 Dosage of amiodarone hydrochloride must be carefully adjusted according to individual requirements and response, patient tolerance, and the general condition and cardiovascular status of the patient.1, 355 Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring) and/or programmed electrical stimulation (PES), as appropriate, is recommended during therapy with the drug.1 When dosage adjustment is necessary, the patient should be monitored closely for an extended period of time because of the long and variable elimination half-life of amiodarone and the difficulty in predicting the length of time required to attain a new steady-state plasma concentration of the drug.1 When feasible, monitoring of plasma amiodarone concentrations may be helpful in evaluating patients who are not responding to the drug or who experience unexpectedly severe toxicity.1, 2, 3, 5, 25, 35, 62, 63, 64, 70, 71, 75, 81 Monitoring of plasma amiodarone concentrations may also be useful in identifying patients whose concentrations are unusually low and who might benefit from an increase in dosage1, 35 or those whose concentrations are unusually high in whom dosage reduction might minimize the risk of adverse effects.1
Patients should be advised not to double the next dose if a dose is missed.431
Although amiodarone dosage requirements generally appear to be similar in geriatric and younger adults, relatively high dosages should be used with caution in geriatric patients since they may be more susceptible to bradycardia and conduction disturbances induced by the drug.301 In addition, some manufacturers state that dosage in general for geriatric patients should be selected carefully, usually starting at the low end of the dosage range, because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1, 355
Life-threatening Ventricular Arrhythmias in Adults
For the management of life-threatening ventricular arrhythmias, loading doses of amiodarone hydrochloride are required to ensure an antiarrhythmic effect without waiting several months.1, 2, 3, 5, 23, 25, 35, 42, 59, 64, 68, 72, 73 The loading-dose phase of therapy should be performed in a hospital setting.1, 35 Close monitoring of patients is necessary, especially until the risk of recurrent ventricular tachycardia or fibrillation has abated.1 Upon initiating amiodarone therapy in patients receiving other antiarrhythmic agents, an attempt should be made to gradually discontinue the other antiarrhythmic agents.1
In adults, oral amiodarone hydrochloride loading dosages of 800-1600 mg daily generally are required for 1-3 weeks (and occasionally for longer periods of time) until an initial therapeutic response occurs.1 Some clinicians have used oral loading dosages exceeding 1600 mg daily35, 64, 73 or IV† loading-dose regimens.64, 250 Clinicians should consult published protocols for specific information on oral loading-dose regimens using dosages greater than 1600 mg daily or on IV loading-dose regimens. If an IV loading-dose regimen is used, oral therapy should be initiated as soon as possible after an adequate response is obtained and IV amiodarone therapy gradually eliminated.301 If adverse effects become excessive during the loading-dose phase of therapy, a reduction in dosage is recommended.1 Elimination of recurrent ventricular tachycardia and recurrent ventricular fibrillation as well as reduction in VPCs and total ventricular ectopic beats usually occur within about 1-3 weeks.1, 2, 3, 5, 23, 25, 42, 59, 64, 68, 72
When adequate control of ventricular arrhythmias is achieved or adverse effects become prominent, the dosage of amiodarone hydrochloride should be reduced to 600-800 mg daily for about 1 month and then reduced again to the lowest effective maintenance dosage, usually 400 mg daily.1, 3, 284 Further cautious reductions in maintenance dosage (e.g., to 200 mg daily) may be possible in some patients.70, 284 Adequate maintenance dosages generally range from less than 400 mg daily up to 600 mg daily.1 Because absorption and elimination of amiodarone are variable, adjustment of maintenance dosage is difficult, and it is not unusual to require dosage reductions or temporary withdrawal or discontinuance of the drug.1, 284
For the management of life-threatening ventricular arrhythmias, the recommended starting dose of IV amiodarone hydrochloride over the first 24 hours is approximately 1000 mg.355 The amiodarone hydrochloride dose for the first rapid loading infusion is 150 mg administered at a rate of 15 mg/minute (i.e., over 10 minutes);355, 364 the initial infusion rate should not exceed 30 mg/minute.355, 364, 397 The slow loading phase of the infusion is 360 mg of amiodarone hydrochloride administered at a rate of 1 mg/minute (i.e., over 6 hours).355, 364, 397 The first maintenance phase of the infusion is 540 mg of amiodarone hydrochloride administered at a rate of 0.5 mg/minute (i.e., over 18 hours).355, 364, 397 The first 24-hour dose of amiodarone hydrochloride may be individualized for each patient; however, in controlled clinical trials, mean daily dosages exceeding 2.1 g were associated with an increased risk of hypotension.355
After the first 24 hours, the maintenance infusion rate of 0.5 mg/minute (i.e., 720 mg over 24 hours) should be continued;355 however, the rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.355 In the event of breakthrough episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia, supplemental amiodarone hydrochloride infusions of 150 mg administered at a rate of 15 mg/minute (i.e., over 10 minutes) may be given.355 Based on experience from clinical trials of IV amiodarone hydrochloride, a maintenance infusion of up to 0.5 mg/minute can be administered with caution for 2-3 weeks, regardless of the patient's age, renal function, or left ventricular function.355 The manufacturer states that there is limited experience in patients receiving parenteral amiodarone hydrochloride for longer than 3 weeks.355
For cardiac arrest secondary to pulseless ventricular tachycardia or ventricular fibrillation, experts recommend an initial adult loading dose of amiodarone hydrochloride of 300 mg, given by rapid IV or IO† injection; an additional dose of 150 mg may be considered.500, 501
Supraventricular Arrhythmias in Adults
For acute treatment of supraventricular tachycardia (SVT) in adults, an IV amiodarone hydrochloride loading dose of 150 mg over 10 minutes is recommended.700 The drug should then be administered at a rate of 1 mg/minute for 6 hours, then 0.5 mg/minute for the remaining 18 hours or until oral dosing is initiated.700 For ongoing management of SVT, some experts recommend an oral amiodarone hydrochloride loading dosage of 400-600 mg daily (in divided doses) in adults for approximately 2-4 weeks, followed by a maintenance dosage of 100-200 mg daily.700 Clinicians should consult published protocols for specific information on oral loading-dose regimens using higher dosages.
When used for rate control of atrial fibrillation, some experts recommend an initial IV amiodarone hydrochloride dose of 300 mg over 1 hour, followed by 10-50 mg/hr over 24 hours; the usual oral maintenance dose is 100-200 mg daily.701
For the long-term management of recurrent atrial fibrillation† in adults, an oral dosage regimen that includes an initial amiodarone hydrochloride loading dose of 10 mg/kg daily for 14 days, followed by 300 mg daily for 4 weeks, and then by a maintenance dosage of 200 mg daily has been used effectively to prevent recurrences.402
Pediatric dosage of oral amiodarone hydrochloride has not been established, and dosage may vary considerably.201, 280, 281 For the management of ventricular and supraventricular arrhythmias in children†, some clinicians have recommended oral amiodarone hydrochloride loading dosages of 10-15 mg/kg daily40, 242 or 600-800 mg/1.73 m2 daily9, 69, 189, 242 for approximately 4-14 days40, 69, 189, 242 and/or until adequate control of cardiac arrhythmias is achieved or adverse effects become prominent.40, 242 Dosage of the drug is then reduced to 5 mg/kg daily40, 242 or 200-400 mg/1.73 m29, 69, 189, 242 for several weeks. If possible, dosage is then reduced gradually to the lowest effective level.69, 189, 242 Children younger than 1 year of age appear to require higher loading and maintenance dosages of amiodarone hydrochloride than older children when dosage of the drug is calculated on the basis of body weight, but not on the basis of body surface area.280, 282
The manufacturer states that pediatric dosage of IV amiodarone hydrochloride has not been established.242, 355 For the management of refractory ventricular fibrillation or pulseless ventricular tachycardia† during pediatric resuscitation, the recommended amiodarone hydrochloride IV or IO† dose is 5 mg/kg as a rapid bolus injection.502, 503 Some experts recommend that if adequate control of cardiac arrhythmia is not achieved, the dose may be repeated twice (maximum single dose of 300 mg) up to a total dosage of 15 mg/kg.502, 503 If used for the management of wide-complex tachycardias or SVT in pediatric patients who are not in cardiac arrest, an IV amiodarone hydrochloride dose of 5 mg/kg is recommended (infused slowly over 20-60 minutes depending on the urgency).503 Alternative methods of dosing IV amiodarone hydrochloride (e.g., loading dose of 5 mg/kg given in 5 divided doses of 1 mg/kg, with each incremental dose infused over 5-10 minutes)416 may be considered in order to minimize pediatric exposure to the plasticizer DEHP.408
Conversion from IV to Oral Dosage
Patients whose arrhythmias have been controlled successfully with IV amiodarone hydrochloride may be switched to oral therapy.355 The manufacturer states that since there are some differences in the safety and efficacy profiles of the oral and IV preparations of amiodarone, clinicians should review the prescribing information for oral amiodarone when switching from IV to oral therapy.355 The optimal dose of oral amiodarone hydrochloride will depend on the dose and duration of IV therapy, as well as the bioavailability of the oral drug.355 The manufacturer suggests that for patients receiving a daily dose of 720 mg of amiodarone hydrochloride IV (assuming an infusion rate of 0.5 mg/minute) for less than 1 week, 1-3 weeks, or longer than 3 weeks, the initial daily oral amiodarone hydrochloride dose should be 800-1600, 600-800, or 400 mg of the drug, respectively.355 These recommendations are made on the basis of a comparable total body amount of amiodarone hydrochloride delivered by IV and oral routes, taking into consideration the drug's oral bioavailability of 50%.355 When switching from IV to oral amiodarone hydrochloride therapy, clinical monitoring is recommended, particularly for geriatric patients.355
Dosage in Renal and Hepatic Impairment
Routine reduction of amiodarone hydrochloride dosage in patients with renal impairment does not appear to be necessary,1, 35 although the risk of excessive accumulation of iodine and possible resultant thyroid effects should be considered.284, 314, 315
The effects of hepatic impairment on the elimination of amiodarone have not been evaluated.1, 2, 35 Because the drug is extensively metabolized,9, 25, 76, 80, 101 probably in the liver,9, 35, 64, 76, 81 some clinicians caution that dosage reduction is probably warranted in patients with substantial hepatic impairment.35, 283, 284 Dosage reduction or discontinuance of amiodarone may be necessary in patients who develop evidence of hepatotoxicity during therapy with the drug.1, 156, 162, 163, 164
Amiodarone is a highly toxic drug and exhibits several potentially fatal toxicities, notably pulmonary toxicity.1, 25, 35, 324, 325, 327, 333, 338, 370, 374, 385 Adverse reactions to amiodarone are common in nearly all patients receiving the drug for the treatment of ventricular arrhythmias.1, 25, 35 With relatively large dosages of amiodarone hydrochloride (400 mg or more daily), adverse reactions occur in about 75% of patients and require discontinuance of the drug in about 5-20% of patients.1, 66, 70, 75, 141, 154, 368
The most severe reactions to oral amiodarone are pulmonary toxicity,1, 3, 9, 25, 35, 72, 136, 324, 325, 326, 327, 333, 338 arrhythmogenic effects,1, 35 and rare, but potentially serious, liver injury;1, 35 however, numerous other adverse reactions to the drug also may be clinically important.1 Amiodarone-induced adverse effects are often reversible following dosage reduction and nearly always reversible following discontinuance of the drug,1, 72 although adverse effects may persist for weeks or months after discontinuance of therapy because of the drug's prolonged elimination.35 The most common adverse reactions requiring discontinuance of oral amiodarone are pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevations of serum hepatic enzyme concentrations.1 The likelihood of most adverse reactions appears to increase after the first 6 months of therapy with the drug1, 35 and then remains relatively constant beyond 1 year of therapy.1 The most common adverse effect observed with IV amiodarone therapy in clinical trials was hypotension,355 which resulted in discontinuation of therapy in less than 2% of patients.355 Additional experience with amiodarone is needed to more fully characterize the adverse effect profile of the drug, particularly in relation to duration of therapy and dosage.1
Pulmonary toxicity, which is potentially fatal, is the most severe adverse effect associated with oral amiodarone therapy with or without initial IV therapy.1, 3, 9, 25, 136, 324, 325, 326, 327, 333, 338, 370 Acute-onset (days to weeks) pulmonary toxicity has been reported during postmarketing experience; manifestations include radiographic evidence of pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, hypoxia, or adult respiratory distress syndrome (ARDS), sometimes leading to respiratory failure and/or death.1, 355
Amiodarone-induced pulmonary toxicity may result from pulmonary interstitial pneumonitis (or alveolitis) or from hypersensitivity pneumonitis (e.g., eosinophilic pneumonia).1, 325, 326, 338, 339, 345, 346 Clinically apparent interstitial pneumonitis (or alveolitis), hypersensitivity pneumonitis, and pulmonary fibrosis have occurred in up to 10-17% of patients with ventricular arrhythmias receiving amiodarone hydrochloride therapy at oral dosages of about 400 mg daily,1, 136, 328, 370 and an abnormal diffusion capacity without symptoms occurs in a much higher percentage of patients.1, 35, 138, 141, 154, 243 Only one patient in clinical trials of IV amiodarone therapy developed pulmonary fibrosis;355 in this patient, the condition was diagnosed 3 months after IV therapy, during which time the patient had begun treatment with oral amiodarone.355 Amiodarone-induced pulmonary toxicity has been fatal in about 10% of cases.1, 3, 326, 327, 338 Rarely, amiodarone has been associated with exacerbation of bronchial asthma, possibly because of its antiadrenergic effects.252, 326 Hemoptysis has been reported during postmarketing experience.1, 355, 389
Amiodarone pneumonitis is a clinical syndrome consisting of progressive dyspnea and cough accompanied by functional, radiographic, scintigraphic, and pathological data consistent with pulmonary toxicity.1, 25, 136, 139, 319, 324, 325, 326, 327, 328, 333, 336, 337, 338, 348 The clinical course of pulmonary toxicity appears to be quite variable.136, 138, 338, 339 Although a slow, progressive course is often described,136, 139, 326, 327, 338 an abrupt onset of febrile illness resembling infectious illness (e.g., pneumonia) also may occur.3, 136, 138, 326, 338, 365 Early symptoms may include dyspnea (particularly with exertion),1, 3, 9, 25, 75, 136, 138, 139, 140, 141, 142, 143, 144, 146, 147, 148, 149, 151, 272, 319, 324, 325, 326, 328, 336, 338, 348 cough (generally without sputum production),1, 3, 9, 25, 75, 136, 138, 141, 142, 144, 145, 146, 147, 148, 151, 324, 325, 326, 328, 336, 338, 348 fever or chills,25, 136, 140, 142, 144, 146, 147, 324, 325, 326, 338, 348 chest pain (generally pleuritic),3, 9, 136, 140, 141, 147, 324, 326, 338, 348 malaise,136 weakness,140, 324, 326, 338 fatigue,138, 139, 143, 146, 148, 324, 329 myalgia,136 myopathy,329 nausea,136, 324 anorexia,144, 148 and/or weight loss.140, 144, 148, 324, 326, 329, 338, 348 Bronchiolitis obliterans organizing pneumonia (that may be fatal) and pleuritis have been reported during postmarketing experience.1, 355
The overall incidence of amiodarone-induced pulmonary toxicity has generally been reported to range from about 2-7%, but some studies indicate that pulmonary toxicity may occur in about 10-17% of patients receiving the drug orally.1, 324, 325, 326, 327, 331, 336, 338 Adult respiratory distress syndrome (ARDS) and lung edema were reported in 2% and less than 2%, respectively, of patients receiving IV amiodarone therapy.355 Limited evidence suggests that the incidence may increase with duration of therapy,1, 3, 138, 306, 307, 325, 326, 338 total daily dose,1, 3, 9, 25, 56, 72, 138, 142, 146, 148, 324, 325, 326, 327, 328, 336, 338 age of the patient,324 and cumulative dose.1, 3, 306, 307, 326, 338 However, pulmonary toxicity has been reported during postmarketing experience in patients receiving low dosages.1 Although not clearly established, limited data suggest that patients with evidence of pulmonary disease prior to amiodarone therapy may have an increased risk of amiodarone-induced pulmonary toxicity,138, 308, 324, 326, 335, 336, 338 although there may be a bias toward detection in such patients.338 Some clinicians state, however, that preexisting pulmonary disease does not appear to increase the risk of amiodarone-induced pulmonary toxicity;335 however, these patients have a poorer prognosis than patients without preexisting pulmonary disease if toxicity develops.1 The syndrome is usually reversible following discontinuance of the drug (with or without corticosteroid therapy),1, 3, 75, 136, 138, 139, 140, 142, 272, 308, 327, 329, 333, 336, 337, 338, 350 but pulmonary toxicity may be fatal in some patients.1, 3, 308, 319, 324, 327, 336
Hypersensitivity pneumonitis has been reported in about one-third of patients with amiodarone-induced pulmonary toxicity,326, 330, 338, 346 and may occur earlier during amiodarone therapy than interstitial pneumonitis.1, 326 Hypersensitivity pneumonitis does not appear to be dose related325 and may be characterized by acute onset of symptoms326, 338 (e.g., fever).326, 338 Alveolar infiltrates appear to be the most common radiographic findings in patients with amiodarone-induced hypersensitivity pneumonitis;326, 338 increased suppressor/cytotoxic (CD8+, T8+) T cells and neutrophils often are found in the bronchoalveolar lavage of these patients.1, 326, 332, 338, 339, 349, 351, 352, 353 It is not known whether fatalities secondary to amiodarone-induced hypersensitivity pneumonitis occur more frequently than fatalities secondary to other pulmonary toxicity induced the drug.338 The precise mechanism of amiodarone-induced hypersensitivity pneumonitis, including the possible role of immunoglobulins, complement deposition, and cytokines in the development of pulmonary toxicity, remains to be more fully elucidated.326, 332, 339
Physical findings in patients with amiodarone interstitial pneumonitis (alveolitis) may include rales,9, 143, 146, 147, 148, 149, 151, 272, 326, 338, 348 decreased breath sounds,139 and/or a pleuritic friction rub.9, 147, 148, 326, 338 Laboratory abnormalities may include hypoxemia,9, 75, 139, 141, 143, 146, 148, 272 hypercarbia,9 leukocytosis,9, 148, 151, 326, 329, 347 and elevated erythrocyte sedimentation rate.9, 146, 148, 151, 326, 338 Diffuse interstitial infiltrates appear to be the most common radiographic finding in patients with amiodarone-induced pulmonary toxicity;25, 75, 136, 138, 139, 140, 141, 142, 143, 148, 149, 319, 325, 326, 327, 338, 348 however, airspace opacities (particularly patchy, peripheral alveolar infiltrates),136, 140, 148, 151, 333, 338 well-localized infiltrates,136, 140, 144, 148, 151, 329, 333, 338 and mixed interstitial and airspace disease136, 333, 338 patterns have also been reported.
Microscopic tissue changes in patients with amiodarone pneumonitis appear to be nonspecific but generally are consistent.136, 324 Pathologic changes may include accumulation of foamy macrophages in alveolar spaces (the presence of lamellated cytoplasmic inclusions probably causes their foamy appearance),1, 35, 136, 138, 142, 145, 148, 307, 308, 319, 325, 327, 329, 333, 334, 337, 338 hyperplasia of type II pneumocytes,25, 148, 319, 325, 327, 333, 334, 337 and thickening of the alveolar septal membrane by connective tissue.25, 136, 138, 140, 142, 148, 308, 319, 325, 327 Although lamellated cytoplasmic inclusions appear to occur predominantly in macrophages,136, 142, 148 they may also occur in epithelial cells of respiratory bronchioles,136, 142 type II pneumocytes,136, 142, 148 endothelial cells,136, 142, 148 and interstitial cells.136, 142, 148 Interstitial thickening secondary to an infiltrate of lymphocytes, histiocytes, and occasional plasma cells may also occur.136, 138, 142 Because foamy alveolar macrophages and lamellated cytoplasmic inclusions have been reported in approximately 50% of patients receiving amiodarone without clinical evidence of pulmonary toxicity,1, 136, 142, 307, 308 these pathologic changes alone should not be relied on in the diagnosis of amiodarone pneumonitis.1, 136, 142, 307, 308, 328
Pulmonary function tests most commonly reveal impairment of diffusion capacity,1, 3, 9, 10, 25, 35, 75, 136, 138, 140, 141, 145, 148, 176, 272, 308, 325, 326, 328, 336 but reductions of total lung capacity (TLC)35, 136, 138, 148, 149, 307 and forced vital capacity (FVC)136, 139, 143, 148, 307, 324, 336 may also occur. Limited data suggest that pulmonary function testing is neither sensitive nor specific enough to be the only method employed in monitoring for amiodarone-induced pulmonary toxicity.136, 138, 328, 331, 337
Patients receiving amiodarone should be carefully monitored for the development of pulmonary toxicity.1, 25, 148 If hypersensitivity pneumonitis occurs, corticosteroid therapy should be initiated and amiodarone discontinued.1, 350 Rechallenge with the drug in patients with hypersensitivity pneumonitis results in more rapid and more severe adverse effects.1 If interstitial pneumonitis (alveolitis) occurs, dosage reduction and preferably discontinuance of the drug is necessary, especially in patients in whom other acceptable antiarrhythmic therapies are available.1, 326, 327, 328, 333, 338 Following dosage reduction or discontinuance of amiodarone in patients with interstitial pneumonitis, clinical improvement usually is evident within the first week and is maximal after 2 or 3 weeks;1, 326, 338 radiographic abnormalities usually resolve within 2-4 months.1 In some patients with interstitial pneumonitis, rechallenge with a lower dosage of amiodarone has not resulted in recurrence of pulmonary toxicity;1, 25, 144, 152, 324, 327 however, in some patients (e.g., those with severe alveolar damage), pulmonary lesions have been irreversible.1 Treatment of amiodarone pneumonitis is mainly supportive and may include mechanical ventilation, if necessary.136, 140, 142 Although data from uncontrolled studies suggest that corticosteroid therapy is of some benefit,1, 25, 75, 136, 139, 140, 142, 272, 308 controlled studies are needed to fully evaluate the safety and efficacy of corticosteroids in the management of amiodarone-induced pulmonary toxicity.146, 148, 326, 333, 338 Some patients have received prednisone dosages of 40-60 mg daily, which were tapered in small decrements during several weeks, depending on the patient's condition.1, 326, 333, 338
Adult respiratory distress syndrome (ARDS) has occurred occasionally following cardiothoracic or other surgery in patients with or without preexisting amiodarone-induced pulmonary toxicity.1, 309, 334, 355 A causal relationship between ARDS and amiodarone has not been clearly established, and other factors (e.g., prolonged pump-oxygenator time, oxygen toxicity, anesthetic agents) may have contributed to the development of the syndrome.1, 309, 334 Although patients usually have responded to vigorous respiratory therapy, fatalities have occurred rarely.1, 355 Some manufacturers state that forced inspiratory oxygen (FiO2) and determinants of tissue oxygenation (e.g., arterial oxygen saturation [SaO2], arterial oxygen pressure [PaO2]) should be monitored closely.1, 355
Abnormalities of liver function test results1, 3, 9, 10, 25, 30, 75, 83, 108, 141, 153, 154, 157, 158, 159, 163, 355 have generally been reported in about 3-20% of patients receiving amiodarone,1, 75, 83, 108, 153, 159, 355 although the incidence has been as high as 40-55% in some studies.9, 10, 30, 141, 355 Nonspecific hepatic disorders have occurred in about 1-3% of patients.1
Amiodarone-induced elevations in serum AST (SGOT),1, 9, 10, 25, 70, 75, 153, 155, 156, 158, 159, 161, 162, 163, 164, 355 ALT (SGPT),1, 9, 25, 75, 141, 153, 157, 158, 159, 161, 163, 164, 355γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP),355 and alkaline phosphatase concentrations9, 70, 75, 155, 156, 157, 159, 162, 163 usually are minor,1, 25, 75 not accompanied by clinical symptoms,1, 3, 9, 10, 70, 72, 75, 153, 158, 159, 161 and generally return to normal following dosage reduction or discontinuance of the drug.9, 72, 75, 141, 154, 159 Rarely, severe hepatic injury (i.e., clinical hepatitis, cholestatic hepatitis, hepatocellular necrosis, cirrhosis), which has been fatal in some patients1, 3, 35, 155, 156, 160, 162, 341, 342, 355 (including at least one child),160 has occurred.1, 3, 25, 35, 155, 156, 158, 160, 161, 162, 163, 164, 355 Signs and symptoms of amiodarone-induced hepatotoxicity may include hepatomegaly,1, 141, 155, 156, 157, 159, 161, 162, 163, 164 ascites,155, 156, 162 abdominal pain,141, 156, 159, 164 nausea,159 vomiting,159, 160, 162 anorexia,156, 159 and weight loss.155, 156, 158, 159 Hypoalbuminemia,156, 157, 162 hyperbilirubinemia,157 and hyperammonemia160 have also been reported.
Liver biopsies performed in a limited number of patients with amiodarone-induced hepatic dysfunction have revealed histologic changes resembling alcoholic hepatitis or cirrhosis.1, 3, 25, 155, 156, 158, 162, 163, 164 Microscopic tissue changes may include Mallory bodies within hepatocytes,155, 156, 157, 158, 159, 162, 163, 164 mixed inflammatory infiltrates,157, 158, 160, 162, 163, 164 collagen deposits and/or fibrosis,155, 156, 157, 158, 159, 162, 163, 164 steatosis,9, 156, 157, 158, 159, 163, 164 hepatocyte destruction,155, 156, 158, 159, 160, 163, 164 and/or cholangitis.157 Electron microscopic studies have revealed the presence of phospholipid-laden lysosomal inclusions within hepatocytes, bile duct epithelium, Kupffer cells, and endothelial cells, even in the absence of clinically apparent hepatic disease.150, 156, 157, 158, 159, 161, 162, 163, 164 Although the exact mechanism of amiodarone-induced hepatic injury has not been determined, limited evidence suggests that the drug may form amiodarone-phospholipid complexes within lysosomes, resulting in phospholipidosis.157 Acute centrolobular confluent hepatocellular necrosis, leading to hepatic coma, acute renal failure, and death, has been associated with administration of IV amiodarone at a much higher loading dose concentration and more rapid infusion rate than recommended.355
Serum hepatic enzyme concentrations should be monitored in patients receiving amiodarone.1, 153, 157, 160, 164 Persistent elevations in enzyme concentrations or the development of hepatomegaly may necessitate dosage reduction or discontinuance of the drug.1
Like other antiarrhythmic agents, amiodarone can worsen existing arrhythmias1, 3, 9, 10, 25, 35, 75, 132, 141, 175, 287, 355 or cause new arrhythmias.1, 35, 166, 167, 168, 175, 176, 355 Arrhythmogenic effects associated with amiodarone have occurred in approximately 2-5% of patients1 and have included progression of ventricular tachycardia to ventricular fibrillation,1, 132, 355 sustained ventricular tachycardia,1, 25, 141, 175, 176, 355 increased resistance to cardioversion,1, 25, 122, 175, 304 atrial fibrillation,355 nodal arrhythmia,355 and atypical ventricular tachycardia (torsades de pointes).1, 3, 9, 25, 75, 132, 171, 173, 265, 355 Transient exacerbation of preexisting cardiac arrhythmias with subsequent control during continued therapy has also been reported.287 Prolongation of the QT interval was reported in less than 2% of patients receiving IV amiodarone.355 Acceleration of ventricular rate was reported in a patient receiving IV amiodarone for the treatment of atrial fibrillation associated with Wolff-Parkinson-White syndrome.165 In most cases, amiodarone-induced arrhythmogenic effects should be manageable in the proper clinical setting.1
Arrhythmogenic effects do not appear to occur more frequently with amiodarone than with other antiarrhythmic agents;1, 25, 35 however, such effects may be prolonged if they occur.1, 9 Concomitant use of cardiac glycosides132, 174 and/or other antiarrhythmic agents may increase the risk of arrhythmogenic effects during amiodarone therapy.1, 25, 132, 141, 166, 167, 168, 169, 174, 228, 255, 264, 265, 266 Limited data suggest that hypokalemia may increase the risk of amiodarone-induced atypical ventricular tachycardia.1, 3, 9, 25, 75, 132, 171, 173
Chronic administration of antiarrhythmic drugs (e.g., amiodarone) in patients with an implanted cardiac device (e.g., defibrillator, pacemaker) may affect pacing and/or defibrillating thresholds.1 Therefore, the manufacturer recommends that pacing and defibrillation thresholds should be assessed at the inception of and during amiodarone therapy.1
Adverse nervous system effects occur in approximately 20-40% of patients receiving oral amiodarone.1, 268 Amiodarone-induced nervous system effects may be alleviated by dosage reduction1, 10, 75, 153, 175, 180, 268 and rarely require discontinuance of the drug.1, 178
Malaise and fatigue,1 tremor and/or involuntary movements,1, 3, 9, 10, 25, 70, 75, 153, 175, 178, 180, 268 lack of coordination,1 abnormal gait and/or ataxia,1, 3, 9, 75, 154, 175, 176, 178, 180, 268 dizziness,1, 3, 10 and paresthesia1, 9, 10, 70, 75, 175, 176, 177, 178, 179 occur in about 4-9% of patients.1 Other adverse nervous system effects occurring in about 1-3% of patients receiving the drug include abnormal smell,1 insomnia,1, 75, 176 sleep disturbances,1, 25, 70, 75, 153 headache,1, 25, 70, 153, 154, 268 and decreased libido.1 Adverse nervous system effects occurring less frequently include difficulty in handwriting,3 postural instability,3 dyskinetic movements,268 decreased ability to concentrate,3 confusion,1, 176 memory loss,268 and mood lability.3 Delirium, hallucination, confusional state, disorientation, and parkinsonian symptoms (e.g., akinesia, bradykinesia) have been reported during postmarketing experience.1
Peripheral neuropathy,1, 3, 9, 25, 35, 72, 75, 162, 176, 177, 178, 179, 180, 268 demyelinating polyneuropathy,1 and proximal myopathy3, 9, 25, 75, 153, 162, 176, 177, 268 have been reported rarely in patients receiving amiodarone.1, 3, 9, 25, 35, 72, 75, 153, 162, 176, 177, 178, 179, 180, 268 Although not fully established, these adverse effects may be dose related.9, 25, 72 Amiodarone-induced peripheral neuropathy, which occurs rarely during chronic oral administration of the drug,1 is usually symmetrical9, 178, 179 and involves all four limbs;9, 179 the neurologic deficit is usually more marked in the lower limbs than in the upper limbs.179 Signs and symptoms may include distal sensory loss,177, 178, 179 sensory ataxia,9, 178 loss of vibratory sensation,179, 180 paresthesia,178, 179, 180 and/or decreased tendon reflexes.177, 180 Proximal muscle weakness also may be present.3, 9, 25, 75, 153, 162, 176, 177, 180 Nerve biopsies in patients with amiodarone-induced peripheral neuropathy have demonstrated complete loss of large myelinated fibers, marked reduction of small myelinated and unmyelinated axons, and evidence of lysosomal inclusion bodies within Schwann cells.177, 179 Nerve conduction studies have demonstrated normal177, 178 or reduced nerve conduction velocities.25, 179 Although the mechanism(s) of amiodarone-induced peripheral neuropathy has not been fully determined, the mechanism may involve formation of drug-phospholipid complexes within neurons.9, 177, 179 Peripheral neuropathy and proximal myopathy generally are slowly reversible following dosage reduction or discontinuance of the drug,1, 9, 25, 72, 162, 178, 301 although resolution of peripheral neuropathy has been incomplete.1
Amiodarone-induced tremor generally presents as a fine hand tremor that is clinically indistinguishable from essential tremor;25, 75, 153, 178, 180 the tremor may be more prominent on one side of the body than the other.180 Amiodarone has also reportedly exacerbated preexisting tremor or parkinsonian tremor in some patients.180 Although limited data suggest that cautious use of propranolol may be of some benefit in the management of amiodarone-induced tremor, further study is needed.18
Pseudotumor cerebri (with papilledema) has been reported rarely during postmarketing experience in patients receiving amiodarone.1, 181, 271, 355 Although a causal relationship has not been established, chronic anxiety reactions have also occurred during therapy with the drug.182
Thyroid nodules or thyroid cancer, sometimes accompanied by hyperthyroidism, has been reported during postmarketing experience.1, 355
Amiodarone alters thyroid function test results in many patients and thyroid function in some patients.1, 4, 9, 10, 25, 35, 83, 153, 154, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 253, 355, 374, 385 Because amiodarone appears to partially inhibit the peripheral conversion of thyroxine (T4) to triiodothyronine (T3),1, 4, 9, 25, 35, 83, 154, 231, 232, 233, 234, 235, 237, 253, 269, 355 serum T4 and reverse triiodothyronine (reverse T3, rT3) concentrations may be increased and serum T3 concentrations may be decreased.1, 4, 9, 10, 25, 35, 83, 153, 230, 231, 232, 233, 234, 235, 237, 253, 283, 355, 393 Most patients remain clinically euthyroid despite these changes in serum thyroid hormone concentrations;4, 9, 10, 25, 153, 230, 234, 237, 253, 393 however, clinical hypothyroidism or hyperthyroidism may occur,1, 3, 4, 9, 10, 25, 26, 70, 83, 153, 154, 230, 231, 233, 234, 235, 236, 237, 238, 239, 240, 253, 355, 370, 374, 393 and thyroid function should therefore be monitored in patients receiving amiodarone.1, 25, 35, 231, 234, 235, 236, 237, 253, 355 Geriatric patients1, 283, 355 and/or patients with a history of thyroid dysfunction (e.g., goiter, hypothyroidism, hyperthyroidism, thyroid nodules) may be more likely to develop adverse thyroid effects while receiving the drug.1, 4, 154, 234, 237, 238, 283, 284, 355 Because of the slow elimination of amiodarone and its metabolites from the body, increased plasma iodide concentration, alterations in thyroid function, and/or abnormal thyroid function test results may persist for several weeks or months following discontinuance of the drug.1, 283, 355
Amiodarone-induced increases in serum T4 and rT3 concentrations with normal or decreased serum T3 concentrations often occur in patients receiving amiodarone1, 4, 9, 10, 25, 35, 83, 153, 230, 231, 232, 233, 234, 235, 253 and generally are not accompanied by clinical evidence of thyroid dysfunction.4, 9, 10, 25, 153, 230, 234, 237, 253 Such changes may be referred to as “euthyroid hyperthyroxinemia”3, 230 and generally do not require specific treatment.3, 230, 235 Periodic monitoring of thyroid function tests, including serum T3, T4, and thyrotropin (thyroid-stimulating hormone, TSH) concentrations, is recommended in these patients.3, 230, 235, 284, 305
Amiodarone-induced hypothyroidism has been reported in about 2-4% of patients receiving oral drug therapy in most clinical studies,1, 25, 355 although this effect has occurred more frequently (8-10%) in some patient series.1, 230, 302, 355, 374 Although not clearly established, limited data suggest that hypothyroidism may be more likely to occur in females4 and in patients with a prior history of thyroid dysfunction.4, 234 The clinical manifestations of hypothyroidism associated with amiodarone appear to be the same as those occurring in primary idiopathic hypothyroidism.4, 153, 154 Amiodarone-induced hypothyroidism is probably best detected by monitoring for the signs and symptoms of hypothyroidism1, 283, 355 and for an elevation in serum thyrotropin concentration,1, 35, 235, 237, 302, 355 a decrease in serum T3 concentration,35 and/or a decrease or no change in free serum T4 concentration compared with baseline values.1, 35, 237, 253, 355
Hypothyroidism induced by amiodarone may be managed by reduction in amiodarone dosage1, 25, 154, 283, 355 and/or careful supplementation with thyroid agents (e.g., levothyroxine sodium) if necessary.1, 25, 72, 83, 153, 154, 230, 231, 235, 283, 355, 374 Some clinicians have recommended cautious titration of levothyroxine sodium until serum T4 concentrations, but not serum thyrotropin concentrations, are within the normal range.235, 340 Thyroid agents must be administered with extreme caution, however, in patients with angina pectoris or cardiovascular disease; if chest pain or aggravation of cardiovascular disease occurs, dosage of the thyroid agent should be reduced or the thyroid agent discontinued.230, 235 Amiodarone-induced hypothyroidism may require discontinuance of the drug in some patients1, 231, 283, 344, 355, 368, 374 and appears to regress slowly once the drug is discontinued,4, 9, 72, 283 usually over a period of 2-3 months.9, 283
Amiodarone-induced hyperthyroidism occurs in approximately 2% of patients receiving the drug orally1, 25, 72, 283, 355, 374 and may require dosage reduction or discontinuance of amiodarone therapy.1, 253, 355, 374 Hyperthyroidism may occur more frequently in geographic areas where iodine intake is relatively low.1, 25, 57, 237, 238, 283, 355 Hyperthyroidism may occur 3 or more months following discontinuance of amiodarone therapy.4, 240 Hyperthyroidism associated with amiodarone therapy generally is more difficult to diagnose and manage and more poorly tolerated than hypothyroidism.1, 70, 153, 230, 233, 240, 253, 283, 355 Amiodarone-associated hyperthyroidism can be fatal.1, 355 The clinical manifestations of amiodarone-induced hyperthyroidism may include weight loss, anxiety, tremor, heat intolerance, thyrotoxicosis, and breakthrough arrhythmias or exacerbation of cardiac arrhythmias.1, 230, 235, 239, 240, 355 Patients receiving the drug should contact their physician if exacerbation of angina or recurrence of cardiac arrhythmias occurs after an initial apparent response to therapy, even several months after discontinuing the drug, since these signs may suggest the presence of amiodarone-induced hyperthyroidism.4, 283 Hyperthyroidism is probably best detected by monitoring for signs and symptoms associated with hyperthyroidism1, 283, 355 and by monitoring for elevations in serum T3 concentrations,1, 35, 70, 153, 237, 253, 355 elevations in serum T4 concentrations,1, 283, 355 or subnormal serum thyrotropin concentrations.1, 355 A thyrotropin-releasing hormone (protirelin) stimulation test may be performed in patients with suspected hyperthyroidism to confirm diagnosis in equivocal cases,1, 355 although the availability of sensitive assays for serum thyrotropin concentrations has virtually eliminated the need for such a test.445 Secretion of thyrotropin, induced by exogenous administration of synthetic thyrotropin-releasing hormone (protirelin), is flat or blunted in such patients.1, 230, 283, 284, 310, 355
Because clinical manifestations of hyperthyroidism (i.e., cardiac arrhythmias) may be potentially serious in patients receiving amiodarone, aggressive therapy is indicated including dosage reduction1, 283, 355 or discontinuance of amiodarone, if necessary.1, 72, 153, 154, 230, 253, 283, 344, 355, 368, 374 Conventional antithyroid agents (e.g., methimazole, propylthiouracil) have been recommended for the management of amiodarone-induced hyperthyroidism;1, 72, 235, 283, 355 however, these agents appear to be of limited benefit when used alone, since the intrathyroidal thyroglobulin stores generally are fully iodinated in patients receiving long-term amiodarone therapy.1, 238, 239, 355, 445 High intrathyroidal iodine stores antagonize the inhibitory effects of antithyroid drugs on thyroidal iodine utilization.446 Combination therapy with methimazole and potassium perchlorate has been used with good results in a limited number of patients with hyperthyroidism and evidence of goiter.238 The use of β-adrenergic blocking agents (e.g., propranolol)9, 238, 239, 283 and/or corticosteroids9, 239, 283 may be of some benefit in the management of hyperthyroidism associated with amiodarone therapy.1, 355 Radioactive iodine therapy is contraindicated in patients with amiodarone-associated hyperthyroidism because of the low radioiodine uptake due to the high concentrations of circulating iodine from amiodarone therapy and the large intrathyroidal iodine load.1, 355, 445, 446 In patients in whom aggressive treatment of thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option.1, 355 Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited and could induce thyroid storm.1, 355 Therefore, careful surgical and anesthetic management is required.1, 355 Transient hypothyroidism occasionally may occur following resolution of amiodarone-induced hyperthyroidism.1, 283, 355 Further studies are needed to determine the optimum management of hyperthyroidism in patients receiving amiodarone.238
Adverse GI effects, principally nausea, vomiting, constipation, and anorexia, occur in about 25% of patients receiving amiodarone orally1 but only rarely necessitate discontinuance of the drug.1, 141, 344, 368, 372, 373 Amiodarone-induced GI disturbances occur most commonly during administration of relatively large oral dosages of the drug (e.g., loading doses)1, 25, 73, 75, 153, 176 and usually are alleviated by dosage reduction1, 154, 176 or administration in divided doses with meals.1, 75
Nausea1, 3, 9, 25, 70, 75, 141, 153, 154, 175, 176 and vomiting1, 3, 175 occur in about 10-33% of patients receiving oral amiodarone;1 nausea and vomiting occur in approximately 4% and less than 2% of patients receiving IV amiodarone, respectively.355 Constipation1, 9, 25, 70, 75, 141, 153, 154, 175, 176 and anorexia1, 3, 9, 25, 70, 75, 141, 153, 176 have occurred in about 4-9% of patients, and abdominal pain,1, 141 abnormal salivation,1 and abnormal taste1, 141, 154 have occurred in about 1-3% of patients.1 Epigastric burning141 or fullness175, 176 and diarrhea141 have been reported rarely in patients receiving oral amiodarone; however, a causal relationship to the drug has not been established. Diarrhea has been reported in less than 2% of patients receiving the drug IV.355 Pancreatitis has been reported during postmarketing experience.1, 355, 388
Asymptomatic corneal microdeposits are present in practically all adults who receive oral amiodarone for longer than 6 months.1, 3, 9, 25, 35, 70, 72, 75, 141, 153, 176, 185, 186, 187, 393 These corneal deposits generally are detectable only by slit-lamp ophthalmologic examination1, 9, 35, 186, 187, 188 and usually are not associated with visual disturbances;1, 9, 35, 185 however, subjective visual disturbances including halo vision (particularly at night and/or while looking at bright objects),1, 25, 70, 73, 75, 141, 153, 154, 175, 176, 184, 187, 188 blurred vision,1, 3, 10, 25, 154, 185, 188 photophobia,1, 25, 75, 176, 184, 187 and dry eyes1, 175, 176 may occur in up to 10% of patients receiving the drug.1, 25, 186
The development of amiodarone-induced corneal deposits appears to be related to both dosage and duration of therapy.9, 25, 72, 153, 183, 185, 186 Limited data suggest that more extensive deposits occur in patients receiving amiodarone hydrochloride dosages of 400-1400 mg daily than in patients receiving dosages of 100-200 mg daily.9, 183 The corneal deposits generally develop within 1-4 months184, 185, 186, 187, 188 but have occurred as soon as a few weeks186 after beginning therapy with the drug. Amiodarone keratopathy appears to occur rarely in pediatric patients,9, 184, 189 possibly because of greater lacrimal secretion and more rapid lacrimal circulation in children than in adults.9, 184
Corneal microdeposits generally occur bilaterally25, 183, 184, 185, 186 and symmetrically.25, 183, 184, 186 Slit-lamp examination during the early stage of amiodarone keratopathy usually demonstrates fine, punctate, gray to golden brown opacities in a horizontal, linear pattern in the inferior cornea;183, 184, 185, 186, 187 these deposits then progress gradually into a characteristic, whorl-like pattern with continued therapy.25, 30, 183, 184, 185, 186, 187 Although the mechanism of amiodarone-induced keratopathy is not known,25, 184 the presence of complex lipid deposits within lysosome-like intracytoplasmic inclusions suggests possible deposition of amiodarone-phospholipid complexes or lipofuscin within corneal epithelium as well as other epithelial structures of the eye.25, 183, 185, 186, 187 Corneal microdeposits and visual disturbances are reversible following dosage reduction or discontinuance of amiodarone,1, 9, 25, 56, 70, 72, 153, 154, 185, 186, 187 usually within about 3 months (range: 2-7 months).9, 25, 70, 72, 153, 154, 186, 187 Methylcellulose ophthalmic solutions have been used in patients receiving amiodarone in an attempt to decrease the severity of existing microdeposits and progression of the keratopathy,9, 25, 186 but the efficacy of such therapy has not been established.186 The presence of asymptomatic corneal microdeposits does not necessitate dosage reduction or withdrawal of amiodarone.1, 154 If severe and/or persistent visual disturbances occur, they may subside with dosage reduction if continued amiodarone therapy is considered necessary.154, 186, 187
Optic neuropathy and/or optic neuritis, which may occur at any time following initiation of amiodarone therapy and usually results in visual impairment, has been reported in patients receiving amiodarone.1, 294, 311, 355, 357 In some patients, such visual impairment has progressed to permanent blindness.1, 355, 357 Diplopia,70, 75, 268 nystagmus,268 and itching of the eyes175, 176 have been reported rarely. In addition, papilledema, corneal degeneration, scotoma, lens opacities, ocular discomfort, and macular degeneration have been reported in patients receiving amiodarone therapy.1, 357 Visual disturbances infrequently impair visual acuity to a substantial degree1, 30, 186, 187, 284 and rarely require discontinuance of the drug.1, 72, 75, 141, 175, 186, 344, 373
Local, Dermatologic, and Sensitivity Reactions
Local injection-site reactions (i.e., pain, erythema, edema, pigment changes, phlebitis, cellulitis, necrosis, skin sloughing) have been reported during postmarketing experience in patients receiving IV injection of amiodarone in recommended dosages.355
Adverse dermatologic reactions occur in about 15% of patients receiving oral amiodarone.1 The most common adverse dermatologic effect associated with amiodarone is photosensitivity, which occurs in about 10% of patients1 but usually does not require discontinuance of the drug.1, 70, 72, 153, 373 When photosensitivity occurs, it generally begins within 2 hours of exposure to sunlight, and symptoms may consist of a burning or tingling sensation followed by erythema; blistering occurs infrequently.9, 153, 190, 195 Swelling of sunlight-exposed areas has been reported rarely.25, 153 Amiodarone-induced photosensitivity reactions generally last for 1-3 days,190, 195 but may last as long as a week in severe cases.190 Photosensitivity reactions may occur up to 4 months following discontinuance of the drug.9, 140 Enhanced tanning ability has also been reported in some patients receiving the drug.75, 153, 190
Since exposure to visible light (wavelengths longer than 400 nm) and/or ultraviolet (UV) wavelengths near the visible spectrum (longer than 320 nm) has resulted in photosensitivity reactions in patients receiving amiodarone,195 both sunlight and light transmitted through window glass may potentially induce photosensitivity reactions in patients receiving the drug.190, 195 Sunscreen agents may help to at least partially prevent amiodarone-induced photosensitivity reactions, particularly opaque physical sunscreens (i.e., agents containing zinc oxide, titanium dioxide) and chemical sunscreens that absorb longer UV light wavelengths (i.e., dioxybenzone, oxybenzone).1, 25, 35, 72, 153, 190, 195, 283 Protective clothing1, 35, 190, 195 and avoidance of exposure to sunlight25, 35, 190 are also recommended to at least partially prevent photosensitivity reactions.1, 25, 35, 190, 195 Although administration of pyridoxine hydrochloride has been recommended for the prevention of photosensitivity in patients receiving amiodarone,197 in vitro data and data from clinical use suggest that pyridoxine does not prevent and possibly may worsen amiodarone-induced photosensitivity reactions.35, 194, 198 Reduction in amiodarone dosage may partially alleviate photosensitivity reactions in some patients.141, 153, 154, 195
Long-term administration of amiodarone is associated with pigment deposition resulting in a blue-gray discoloration of the skin.1, 3, 9, 25, 30, 35, 108, 153, 154, 190, 191, 192, 193, 196, 385 The manufacturer states that blue-gray skin pigmentation occurred in less than 1% of patients who had received the drug for an average of about 440 days (range: 2-1515 days);1 however, in clinical studies, blue-gray skin pigmentation was reported in approximately 2-5% of patients.3, 9, 30, 35, 108 The incidence appears to be related to both the cumulative dosage and duration of therapy.1, 25, 153, 190, 192, 193 Pigmentary changes of the skin generally are restricted to exposed areas of the body, particularly the face and hands,25, 153, 191, 192, 193 and may be mistaken for cyanosis.192 Exposure to sunlight or visible light1, 25, 30, 153, 154, 191, 192, 196 and fairness of complexion1 appear to be risk factors.1, 25, 30, 153, 154, 191, 192, 196 Although not clearly established, limited data suggest that photosensitivity reactions may predispose to the development of blue-gray pigmentation.1, 9, 35, 153, 191, 192 The mechanism(s) of amiodarone-induced blue-gray discoloration is not known; however, histologic examination in a limited number of patients has revealed lysosomal, membrane-bound bodies containing amiodarone, N -desethylamiodarone, lipids, and possibly lipofuscin.30, 191, 192, 193, 196 Blue-gray pigmentation is of cosmetic importance only.1 The pigmentation usually is slowly reversible following discontinuance of the drug,1, 191 although this may require up to a year in some cases.191 Occasionally, the pigmentation may not be completely reversible.1 Skin cancer has been reported during postmarketing experience with amiodarone.1, 355
Rash1, 75, 153, 154, 175, 176 and hair loss1, 25, 70, 75, 154 have been reported in less than 1% of patients receiving oral amiodarone.1 Toxic epidermal necrolysis (sometimes fatal)1, 199, 355 and generalized pustular psoriasis367 also have been reported in patients receiving amiodarone. Exfoliative dermatitis1, 322, 355 and erythema multiforme1, 355 also have been reported. Stevens-Johnson syndrome has been reported in less than 2% of patients receiving the drug IV355 and also has been reported during postmarketing experience with amiodarone.1, 355 Pruritus has been reported during postmarketing experience with amiodarone.1, 355
Angioedema, urticaria, eczema, or bronchospasm has been reported during postmarketing experience with amiodarone therapy;1, 355 anaphylactic/anaphylactoid reactions, including shock, also have been reported during postmarketing experience in patients receiving amiodarone.1, 355, 443
Granuloma has been reported through postmarketing experience in patients receiving amiodarone.1, 355
New or worsened heart failure1, 9, 25, 35, 70, 75, 108, 299, 355 reportedly occurs in about 3% or about 2% of patients receiving oral or IV amiodarone therapy, respectively;1, 355 however, it is often difficult to distinguish between spontaneous and amiodarone-induced depression of left ventricular function.5, 299 Congestive heart failure rarely requires discontinuance of the drug.1
Hypotension was the most frequent adverse effect observed in clinical trials of IV amiodarone, occurring in approximately 16% of patients.355 Hypotension has occurred in less than 1% of patients receiving oral amiodarone.1 Hypotension refractory to treatment and resulting in death has been reported during postmarketing experience with IV amiodarone.355 The relationship to amiodarone is not known,1, 170, 203, 216, 267, 279 but hypotension (probably resulting from decreased cardiac output and/or decreased peripheral vascular resistance) has occurred rarely during open-heart surgery (during and/or following cardiopulmonary bypass) in patients receiving the drug.1, 170, 216, 267 An interaction between amiodarone and various anesthetic agents has been suggested170, 216, 267 but not clearly established.170, 203, 216, 267, 279 Some manufacturers1, 355 and clinicians170 state that close perioperative monitoring is recommended in amiodarone-treated patients undergoing general anesthesia, since amiodarone may sensitize patients to the myocardial depressant and conduction effects of halogenated hydrocarbon general anesthetics.1, 170, 355
Flushing and edema have occurred in about 1-3% of patients receiving oral amiodarone.1 In patients receiving IV amiodarone, cardiac arrest and shock have been reported in 2.9% and less than 2% of patients, respectively;355 asystole also has been reported.355, 365 Venous thrombosis and thrombophlebitis have been reported with IV amiodarone during postmarketing experience.355
Effects on Cardiac Conduction and Sinus Node Function
Clinically important conduction disturbances, mainly AV and intraventricular block,1, 3, 4, 25, 26, 30, 35, 355 occur infrequently in patients receiving amiodarone and are reversible following discontinuance of the drug.1 Sinoatrial block has also been reported.168 Rarely, amiodarone-induced QT prolongation has been associated with arrhythmogenicity.1, 42
Amiodarone generally depresses sinus node function.1, 3, 4, 5, 6, 9, 10, 11, 14, 15, 18, 20, 21, 25, 26, 28, 29, 30, 33, 34, 35, 39, 49, 50 SA node dysfunction, including symptomatic sinus bradycardia1, 3, 4, 9, 10, 25, 26, 30, 35, 50, 75, 154, 169, 175, 355, 393 or sinus arrest1, 355 with suppression of escape foci,1, 141, 166, 167, 168, 169 has occurred in approximately 1-5% of patients.1, 355 Concomitant administration of a cardiac glycoside, β-adrenergic blocking agent, and/or calcium-channel blocking agent may increase the risk of sinus bradyarrhythmias.1, 25, 35, 75, 141, 166, 167, 168, 169, 256, 301, 355 The relationship to amiodarone is not known,170, 203, 216, 267 but atropine-resistant sinus bradycardia, sinus arrest, and/or AV block have also occurred in some amiodarone-treated patients undergoing general anesthesia, mainly for open-heart surgery.170, 216, 267 Patients with preexisting sinus bradycardia or sinus node disease may have an increased risk of amiodarone-induced sinus bradyarrhythmias.9 Sinus bradycardia induced by amiodarone generally is not fully responsive to atropine.14, 33, 169, 201 Bradycardia usually responds to dosage reduction, but administration of a β-adrenergic agonist (e.g., isoproterenol)1, 169, 201 and/or insertion of an artificial ventricular pacemaker may be necessary in patients with severe amiodarone-induced sinus bradyarrhythmias;1, 3, 25, 75, 141, 154, 166, 168, 169, 175, 201, 355 amiodarone has been discontinued in several patients because of bradycardia.344, 368, 372, 373, 374, 393
Coagulation abnormalities have occurred in about 1-3% of patients receiving oral amiodarone,1 and spontaneous ecchymosis1, 244 has occurred in less than 1% of patients receiving the drug.1 Severe thrombocytopenia, resulting in ecchymoses and petechiae, has occurred in a few patients receiving the drug.244 Following discontinuance of amiodarone and initiation of corticosteroid therapy, platelet counts gradually increased to normal values over a period of 12-16 days; subsequent administration of the drug resulted in recurrence of thrombocytopenia.244 Thrombocytopenia has been reported in less than 2% of patients receiving IV amiodarone.355 Although not clearly established, positive lymphocyte stimulation test results suggest that a delayed hypersensitivity reaction may be responsible for the thrombocytopenia.244 Hemolytic anemia, aplastic anemia, pancytopenia, agranulocytosis, and neutropenia have been reported during postmarketing experience in patients receiving amiodarone.1, 355
Noninfectious epididymitis1, 246 or epididymo-orchitis301 and/or scrotal pain94, 246 have occurred in some patients receiving high oral dosages of amiodarone and/or long-term therapy with the drug.94, 246 In patients who developed epididymitis, epididymal enlargement initially occurred unilaterally but later progressed bilaterally.246 Epididymitis subsided in some patients with reduction of amiodarone dosage but resolved in other patients despite continued therapy without dosage adjustment.246 Abnormal kidney function has been reported in less than 2% of patients receiving the drug IV.355 Renal insufficiency/impairment or acute renal failure has been reported with IV amiodarone during postmarketing experience.355 Impotence also has been reported during postmarketing experience with amiodarone therapy.1, 355
Gynecomastia, which was reversible following withdrawal of amiodarone but recurred upon rechallenge, has been reported.245 Hyperglycemia,251 symptomatic hypoglycemia,72 and vasculitis1, 355 have been reported rarely. Myopathy, rhabdomyolysis, and muscle weakness have been reported during postmarketing experience in patients receiving amiodarone.1, 355 Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported during postmarketing experience in patients receiving amiodarone therapy.1, 355
Symptomatic bradycardia, sometimes requiring pacemaker intervention, has been reported in patients receiving amiodarone concomitantly with a hepatitis C virus (HCV) treatment regimen containing sofosbuvir in conjunction with another HCV direct-acting antiviral (DAA), including ledipasvir, simeprevir, or daclatasvir.453, 454, 455, 456, 457 Fatal cardiac arrest was reported in a patient receiving amiodarone concomitantly with the fixed combination containing ledipasvir and sofosbuvir (ledipasvir/sofosbuvir).453, 454, 455, 456, 457 In most reported cases, bradycardia occurred within hours to days after HCV treatment containing sofosbuvir with another DAA was initiated in patients receiving amiodarone, but has been observed up to 2 weeks after initiation of such HCV treatment regimens in patients receiving amiodarone.454, 455, 456 Bradycardia generally resolved after the HCV treatment regimen was discontinued.454, 455, 456, 457 The mechanism for this adverse cardiovascular effect is unknown.453, 454, 455, 456, 457 Patients who may be at increased risk for symptomatic bradycardia if amiodarone is used concomitantly with an HCV treatment regimen containing sofosbuvir and another DAA include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.454, 455, 456, 457 Because of these reports of symptomatic bradycardia, concomitant use of amiodarone with an HCV treatment regimen containing sofosbuvir with another DAA (e.g., ledipasvir, simeprevir, daclatasvir) is not recommended.454, 455, 456, 457
Precautions and Contraindications
Patients should be instructed to read the medication guide provided by the manufacturer before initiating therapy with amiodarone and each time the prescription is refilled, since new information may be available.431, 452
Amiodarone is a highly toxic drug and exhibits several potentially fatal toxicities, notably pulmonary toxicity.1 Because of its pharmacokinetic properties, difficult dosing schedule, and severity of adverse effects in patients who are improperly monitored, amiodarone should be administered only by clinicians who are experienced in the management of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits associated with amiodarone therapy, and who have access to laboratory facilities necessary to adequately monitor the efficacy and adverse effects of the drug, including continuous ECG monitoring and electrophysiologic techniques for evaluating the patient in both ambulatory and hospital settings.1, 106, 355 Because of the risks of substantial toxicity, amiodarone therapy currently is reserved principally for the management of documented life-threatening ventricular arrhythmias.1 Even in patients at high risk of death from arrhythmia, in whom the risks of toxicity are acceptable, use of amiodarone poses major management difficulties that could be life-threatening in a patient population at risk of sudden death, and maximum efforts should be made to utilize alternative antiarrhythmic agents initially.1
Because of the life-threatening nature of the arrhythmias treated, lack of a predictable time course of antiarrhythmic effect, and the risks of arrhythmogenic effects and potential interactions with previous drug therapy, the loading-dose phase of oral amiodarone therapy should be performed in a hospital setting.1, 35 Close monitoring of patients during the loading-dose phase of therapy is necessary, especially until the risk of recurrent ventricular tachycardia or fibrillation has abated.1 The difficulties associated with using amiodarone effectively and safely pose substantial risks to the patient.1 Even with an oral loading-dose regimen, a response to orally administered drug generally requires at least 1 week and usually 2 or more weeks of therapy.1 Because absorption and elimination of amiodarone are variable, adjustment of maintenance dosage is difficult, it is not unusual to require dosage reduction or temporary withdrawal or discontinuance of the drug.1, 284 Patients who experience serious adverse effects during therapy with amiodarone should immediately contact their clinician or seek medical attention; in addition, patients should contact their clinician before discontinuance of the drug.431
The time at which a previously controlled life-threatening arrhythmia will recur after reduction of amiodarone dosage or discontinuance of the drug is unpredictable, ranging from weeks to months.1 During this period, the patient is at great risk and may need prolonged hospitalization1, 35 or intensive ambulatory monitoring (e.g., via telemetric ECG),284 possibly with periodic determination of plasma concentrations of the drug.35 Attempts to substitute other antiarrhythmic agents when amiodarone must be discontinued because of inefficacy or intolerance are difficult because of the gradually, but unpredictably, changing body burden of the drug, the drug's residual effects, and its potential interactions with subsequent treatment.1, 35
Because amiodarone may cause pulmonary toxicity that is potentially fatal, baseline pulmonary function tests, including diffusion capacity, should be performed prior to initiation of oral amiodarone therapy,1, 25, 325, 326, 327, 328, 335, 338 and periodic chest radiographs and clinical evaluation should be performed every 3-6 months during therapy with the drug.1, 25, 148, 325, 327, 338 Periodic pulmonary function testing also should be considered.284, 325 Preoperative pulmonary function tests are recommended for patients undergoing cardiothoracic surgery since ARDS may develop postoperatively in patients receiving the drug.309 Until further studies have been performed, some manufacturers recommend that FiO2 and tissue oxygenation (as determined by SaO2 or PaO2) be closely monitored in patients receiving amiodarone.1, 355 Amiodarone should be used with caution, if at all, in patients with preexisting pulmonary disease,35 including chronic obstructive disease,252 or reduced pulmonary diffusion capacity.35, 138, 324 Patients should inform their clinician of preexisting lung or breathing disorders prior to initiation of amiodarone therapy.431 The possibility of amiodarone-induced pulmonary toxicity should be considered in any patient developing a new respiratory symptom during therapy with the drug.1, 136, 140, 326, 327 Patients should contact their clinician if dyspnea, wheezing, coughing, chest pain, hemoptysis, or any other breathing disorders occur during therapy with amiodarone.431 Clinical and radiographic evaluation, as well as scintigraphic and pulmonary function testing (including diffusion capacity), if necessary, are recommended in such patients.1, 138, 151, 324, 326, 327, 328, 333, 336, 337, 338 Respiratory symptoms should be carefully assessed and other causes of respiratory impairment (e.g., congestive heart failure, pulmonary embolism, malignancy) should be ruled out before discontinuance of the drug.1, 136, 138, 140, 328, 338 Measurement of pulmonary capillary wedge pressure may help exclude congestive heart failure as a cause of symptoms or radiographic findings.136, 138, 139, 140 Since amiodarone-induced pulmonary toxicity may mimic infection, possible infectious causes should be excluded;1, 136, 327 bronchoalveolar lavage, transbronchial lung biopsy, and/or open lung biopsy may aid in the diagnosis, especially in patients in whom alternative antiarrhythmic therapy is not available.25, 136, 140, 141, 327, 333, 338 The manufacturer states that the presence of suppressor/cytotoxic (CD8+, T8+) T-cell lymphocytosis in bronchoalveolar lavage specimens should be considered confirmatory of hypersensitivity pneumonitis.1 If hypersensitivity pneumonitis occurs, corticosteroid therapy should be initiated and amiodarone should be discontinued.1 If evidence of interstitial pneumonitis (alveolitis) is present, dosage of amiodarone should be reduced and, preferably, therapy with the drug withdrawn in an attempt to determine whether the toxicity is reversible;1, 136, 138, 140, 326, 327, 328, 338 however, amiodarone should be discontinued with caution in patients with life-threatening arrhythmias, since sudden cardiac death is common in these patients.1
Because amiodarone can alter results of thyroid function tests and/or cause clinical hypothyroidism or hyperthyroidism, thyroid function tests should be performed prior to initiating amiodarone therapy and at periodic intervals (approximately every 3-6 months) thereafter,1, 25, 35, 231, 234, 235, 236, 237, 253, 355 particularly in geriatric patients1, 283, 355 and/or in patients with a prior history of thyroid nodules, goiter, or other thyroid dysfunction.1, 4, 234, 237, 283, 355 Patients should inform their clinician if they have thyroid dysfunction or a history of such dysfunction prior to initiation of therapy.431 In addition, patients receiving amiodarone should be instructed to report episodes of chest pain, weight loss or gain, weakness, heat or cold intolerance, hair thinning, diaphoresis, menstrual cycle changes, swelling in the neck (e.g., goiter), nervousness, irritability, restlessness, decreased concentration, depression in geriatric patients, tremor, or aggravation of cardiovascular disease to their clinician, since such manifestations may indicate amiodarone-induced thyroid dysfunction.1, 4, 431 If any new signs of cardiac arrhythmias appear, the possibility of hyperthyroidism should be considered.1, 355 The risks and benefits of amiodarone therapy in patients with thyroid dysfunction should be carefully considered because of the potential for arrhythmia breakthrough or exacerbation of arrhythmias, which may result in death, in such patients.1, 355
Because amiodarone may cause elevations in serum hepatic enzyme concentrations and may rarely cause severe, potentially fatal, hepatic injury, serum hepatic enzyme concentrations should be monitored at regular intervals in patients receiving the drug,1, 153, 157, 160, 164, 355 particularly those receiving relatively high maintenance dosages.1 Patients should inform their clinician of preexisting liver dysfunction prior to initiation of amiodarone therapy.431 Patients should contact their clinician if nausea or vomiting, dark urine, fatigue, jaundice, or stomach pain occurs during amiodarone therapy.431 In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of IV amiodarone therapy.355 If serum hepatic enzyme concentrations increase to more than 3 times normal values in patients with normal pretreatment values or twice baseline pretreatment values in patients with elevated values prior to amiodarone therapy, or if hepatomegaly or progressive hepatic injury occurs, a reduction in oral amiodarone dosage, a decrease in the infusion rate during parenteral amiodarone therapy, or discontinuance of the drug should be considered.1, 156, 162, 163, 164, 355 Because the risk of hepatic necrosis during IV amiodarone therapy may be related to the use of rapid infusion rates and excessive drug concentrations in the initial loading dose, the initial amiodarone concentration and IV infusion rate should be monitored closely and should not exceed those recommended by the manufacturer.355 Liver biopsy with ultrastructural study by electron microscopy may aid in the diagnosis of amiodarone-induced hepatic toxicity.155, 157, 158, 163, 164
Because amiodarone causes corneal microdeposits in almost all patients1, 3, 9, 25, 35, 70, 72, 75, 141, 153, 185, 186, 187 and optic neuropathy occasionally may result in visual disturbances,1, 25, 153, 154, 184, 185, 186, 187 the manufacturer and some clinicians recommend that a baseline ophthalmologic examination (e.g., a slit-lamp evaluation) be performed before initiating therapy with the drug and then possibly at periodic intervals during long-term therapy (e.g., after the first 6 months and then annually and/or as necessary).1, 25, 31, 431 Patients experiencing visual disturbances or those receiving long-term therapy should be monitored carefully.1, 186, 188 Patients experiencing visual disturbances (e.g., blurred vision, visual halos, ocular photosensitivity) should contact their clinician.431 The presence of nonprogressive,284 asymptomatic1, 154 corneal microdeposits does not necessitate dosage reduction or discontinuance of amiodarone. In addition, optic neuropathy and/or optic neuritis (usually resulting in visual impairment, which sometimes may progress to permanent blindness) has been reported in patients receiving amiodarone and although a causal relationship to the drug has not been clearly established, some manufacturers state that if visual impairment occurs (e.g., changes in visual acuity, decreases in peripheral vision), a prompt ophthalmologic examination should be performed.1, 355, 357 If optic neuropathy and/or optic neuritis has developed, amiodarone therapy should be reevaluated and the described risks and complications should be weighed against the possible benefits of antiarrhythmic therapy.1, 355 Routine ophthalmologic examinations, including slit-lamp and funduscopic tests, should performed in patients receiving amiodarone therapy.1, 355 Most manufacturers of corneal refractive laser surgery devices consider the procedure to be contraindicated in patients receiving amiodarone.1, 355
The use of sunscreen agents1, 25, 35, 72, 153, 190, 195 and protective clothing1, 35, 190, 195 and avoidance of excessive exposure to sunlight25, 35, 190 are recommended to help prevent photosensitivity reactions associated with amiodarone therapy.1, 25, 35, 72, 153, 190, 195 Patients with fair complexions1 or excessive exposure to sunlight1, 9, 25, 35, 153, 191, 193 or those who have received prolonged amiodarone therapy and/or relatively large cumulative doses appear to be more susceptible to amiodarone-induced blue-gray skin discoloration.1, 25, 153, 190, 192, 193
Hypotension has been reported during open-heart surgery (during and/or following cardiopulmonary bypass) in amiodarone-treated patients.1, 170, 216, 267 Patients should inform their clinician of blood pressure abnormalities prior to initiating amiodarone therapy.431 Atropine-resistant sinus bradycardia, sinus arrest, and/or AV block also have occurred in some amiodarone-treated patients undergoing general anesthesia for major surgery.167, 170, 216, 267 The relationship of these effects to amiodarone is not known.1, 170, 203, 216, 267, 279 An interaction between the antiarrhythmic agent and various anesthetic agents has been suggested170, 216, 267 but not clearly established.170, 203, 216, 267, 279 The hypotension may be severe in some patients and require larger than usual dosages of sympathomimetic agents and/or intra-aortic balloon counterpulsation.170, 216, 267 Sinus bradyarrhythmias and/or AV block may require insertion of an artificial pacemaker.170, 216, 267 Pending further evaluation, the anesthesiologist should be aware of potential complications in patients undergoing general anesthesia who are currently receiving amiodarone or who have previously received the drug within the past 1-2 months.170, 216, 267 In addition, close perioperative monitoring is recommended in patients undergoing general anesthesia while receiving amiodarone, since amiodarone may sensitize patients to the myocardial depressant and conduction effects of halogenated hydrocarbon general anesthetics.1, 355
Because IV amiodarone therapy is associated with bradycardia,355 patients with a known predisposition to bradycardia or AV block should be treated with IV amiodarone in a setting where a temporary pacemaker is available.355 Patients should contact their clinician if they experience heart pounding, irregular heart beat, very fast or slow heartbeat, lightheadedness, or faintness during amiodarone therapy.431 Also, because of the risk of proarrhythmia during parenteral amiodarone therapy, patients should be monitored for QTc prolongation during infusion of amiodarone.355 The need to coadminister amiodarone with other drugs that are known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits in individual patients.1, 355
Since antiarrhythmic agents, including amiodarone, may be less effective and/or more arrhythmogenic in patients with hypokalemia or hypomagnesemia,1, 171, 249, 355 the possibility of a potassium or magnesium deficiency should be evaluated and, if present, corrected prior to initiation of amiodarone therapy.1, 249, 355 Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.355
Because of the possibility of clinically important interactions when amiodarone is used concomitantly with other drugs, patients should inform their clinicians of their use of other drugs, including prescription and nonprescription drugs, or of dietary and herbal supplements such as St. John's wort.431 Grapefruit juice is known to inhibit cytochrome P-450 (CYP) 3A4-mediated metabolism of oral amiodarone, resulting in increased plasma concentrations of the drug; therefore, patients should be instructed not to consume grapefruit juice during treatment with oral amiodarone.1, 355, 431
Amiodarone is contraindicated in patients with cardiogenic shock, in patients with severe sinus node dysfunction resulting in marked sinus bradycardia, in patients with second- or third-degree AV block, and in patients with episodes of bradycardia that have caused syncope, except when used concomitantly with an artificial pacemaker.1, 355 Amiodarone also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation, including iodine; IV amiodarone is contraindicated in patients with known hypersensitivity to any components of the parenteral formulation, including iodine.1, 355, 431
Safety and efficacy of amiodarone in children† have not been established.1, 355 In a clinical trial in pediatric patients 30 days to 15 years of age, hypotension (36%), bradycardia (20%), and atrioventricular block (15%) were common dose-related adverse effects, and in some cases were severe or life-threatening.355 In this trial, injection-site reactions were observed in 5 of 20 patients receiving IV amiodarone through a peripheral vein.355 Limited data suggest that the drug may be useful in carefully selected cases for the management of refractory supraventricular or ventricular tachycardias in children,35, 40, 69, 189, 280, 281, 282 and current guidelines for pediatric advanced life support (PALS) recommend the use of amiodarone or lidocaine for the treatment of shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.502 This recommendation is based principally on extrapolation of data from adult studies as well as an observational study in pediatric patients suggesting improved return of spontaneous circulation (ROSC) with lidocaine compared with amiodarone.502
Each mL of the commercially available amiodarone hydrochloride IV injection contains 20.2 mg of benzyl alcohol as a preservative.355 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.355, 408, 409, 410, 411, 412, 413, 414 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.409, 410, 411, 412, 413, 414 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,409, 411 the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.409
In addition, the commercially available amiodarone hydrochloride IV injection has been found to leach diethylhexyl phthalate (DEHP) plasticizer from IV tubing (e.g., PVC tubing).355, 408 Leaching of DEHP is increased when IV amiodarone hydrochloride is infused at higher concentrations and slower infusion rates than those recommended by the manufacturer.355 After reviewing data from animal studies and limited experience in humans, an expert panel of the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) concluded that exposure to DEHP may adversely affect male reproductive tract development during fetal, infant, and toddler stages of development if the exposure at these stages is severalfold higher than that in adults, a situation that might be associated with intensive medical procedures such as those performed in critically ill infants.408, 415 In studies in sexually mature rats, an oral amiodarone hydrochloride dosage of 3.7-14 mg/kg daily was associated with no observable adverse effects; however, in rats at the postnatal stage, a dosage level associated with no observable adverse effects was not identified. 408 The maximum anticipated exposure to DEHP following IV administration of amiodarone hydrochloride in pediatric patients has been calculated to be about 1.9 mg/kg daily for a 3-kg infant, which provides about a 2- to 7-fold margin of safety. 408 In pediatric patients requiring therapy with IV amiodarone hydrochloride, dosing methods that may reduce potential exposure to DEHP (e.g., IV loading dose of 5 mg/kg given in 5 divided doses of 1 mg/kg, with each incremental dose infused over 5-10 minutes)416 may be considered.408
While clinical experience to date has not revealed age-related differences in response to amiodarone, clinical studies evaluating the drug have not included sufficient numbers of adults 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1, 355 The manufacturers state that dosage in general for geriatric patients should be selected carefully, usually starting at the low end of the dosage range, because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1, 355 In addition, geriatric patients may be more susceptible to bradycardia and conduction disturbances induced by the drug.301
Pregnancy, Fertility, and Lactation
Reproduction studies in pregnant rats or rabbits receiving oral amiodarone hydrochloride dosages of 25 mg/kg daily (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]) revealed no evidence of harm to the fetus.1, 283, 355 However, in pregnant rabbits receiving oral amiodarone hydrochloride dosages of 75 mg/kg daily (approximately 2.7 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]), abortions occurred in more than 90% of these rabbits.1, 283 Slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones were reported in pregnant rats receiving oral amiodarone hydrochloride dosages of 50 mg/kg daily (approximately 0.8 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]) or more.1, 283 In addition, in rats receiving oral amiodarone hydrochloride dosages of 100 mg/kg daily (approximately 1.6 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area] or more, or 200 mg/kg daily (approximately 1.6 or 3.2 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]), reduced fetal body weight or increased incidence of fetal resorptions, respectively, were observed.1, 283 Adverse effects on fetal growth and survival also were reported in 1 of 2 strains of mice receiving oral amiodarone hydrochloride dosages of 5 mg/kg daily (approximately 0.04 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]).1, 283
In a reproductive study in which amiodarone was administered IV to rabbits at dosages of 5, 10, or 25 mg/kg daily (approximately 0.1, 0.3, or 0.7 times the recommended maximum human dose on the basis of body surface area, respectively), maternal deaths occurred in all groups, including controls.355 Embryotoxicity, as manifested by fewer full-term fetuses and increased resorptions with concomitantly lower litter weights, occurred at dosages of 10 mg/kg and greater.355 No evidence of embryotoxicity was observed at the 5 mg/kg dosage and no teratogenicity was observed at any dosage level tested.355 In a teratology study in which amiodarone was administered by continuous IV infusion to rats at dosages of 25, 50, or 100 mg/kg daily (approximately 0.4, 0.7, or 1.4 times the recommended maximum human dose on the basis of body surface area, respectively), maternal toxicity (as evidenced by reduced weight gain and food consumption) and embryotoxicity (as evidenced by increased resorptions, decreased live litter size, reduced body weights, and retarded sternum and metacarpal ossification) were observed in the group receiving 100 mg/kg daily.355
Amiodarone and N -desethylamiodarone cross the placenta to a limited extent.1, 2, 78, 88, 89, 91, 355 QT prolongation88 and transient sinus bradycardia91 have been observed in neonates of a limited number of pregnant women who received the drug during the second and/or third trimester.88, 89, 91 Specific data are not available, but there are concerns that amiodarone potentially could adversely affect fetal thyroid function and overall development.25, 35, 89, 91 Congenital goiter/hypothyroidism and hyperthyroidism have been observed in a limited number of neonates born to women who received amiodarone during pregnancy.1, 330, 354, 355 Amiodarone should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1, 88, 89, 355 Women should inform their clinicians if they are or plan to become pregnant or plan to breast-feed.431 If amiodarone is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.1 Women of childbearing potential should avoid becoming pregnant during amiodarone therapy.431 The prolonged elimination of amiodarone from the body after discontinuance of the drug should be considered when a woman of childbearing potential receiving amiodarone plans to become pregnant.35, 89 It is not known whether use of amiodarone during labor and delivery could have any immediate or delayed adverse effects on the mother or fetus.1, 355 Studies in rodents have not shown any effect of the drug on duration of gestation or on parturition.1, 355
Reproduction studies in male and female rats using oral amiodarone hydrochloride dosages of 90 mg/kg daily (approximately 1.4 times the maximum recommended human maintenance dosage of 600 mg for a 50-kg patient [calculated on the basis of body surface area]) and initiated 9 weeks prior to mating, have revealed evidence of reduced fertility.1, 355 Amiodarone and N -desethylamiodarone are distributed in high concentrations into human testes10, 62, 84, 94 and semen.94 No fertility studies were conducted with IV amiodarone.355
Amiodarone and, to a lesser extent, N -desethylamiodarone are distributed into milk in concentrations substantially higher than concurrent maternal plasma concentrations.1, 2, 78, 89, 91, 355 Nursing offspring of lactating rats receiving amiodarone have been shown to be less viable and to have reduced bodyweight gains.1, 355 Because nursing may expose the infant to a substantial dose of amiodarone and its metabolite,1, 89, 91, 355 it is recommended that nursing be discontinued during amiodarone therapy.1, 91, 355 The slow elimination of amiodarone from the body after discontinuance of the drug should also be considered.
While only a limited number of drug interactions with amiodarone have been investigated, most drugs studied to date have been shown to interact with amiodarone.1, 208, 215 Few data are available on drug interactions with parenteral amiodarone therapy;355 most of the information on drug interactions with amiodarone comes from experience with oral administration of the drug.355 The possibility of interactions with any concomitantly administered drug and amiodarone should be anticipated, particularly for drugs with potentially serious toxic effects such as other antiarrhythmic agents.1, 35, 208, 215, 355 If such drugs are needed, their dosage should be carefully reassessed and adjusted as necessary, and plasma concentrations of such drugs should be measured, if appropriate.1, 215, 355
Because of the long and variable elimination half-life of amiodarone, the potential for interactions exists not only with concomitantly administered drugs but also with drugs administered after discontinuance of amiodarone therapy.1, 35, 208, 215, 355
Drugs Affecting the QT Interval
Amiodarone prolongs the QTc interval, and clinicians should consider the possibility that potentially serious cardiac arrhythmias, including torsades de pointes, could occur if amiodarone were used concomitantly with other drugs that prolong the QTc interval (e.g., cisapride [no longer commercially available in the US], halofantrine [no longer commercially available in the US], dolasetron, pimozide, disopyramide, fluoroquinolones, loratadine, macrolide antibiotics, trazodone, ziprasidone, azole antifungal agents).1, 355, 432, 433, 437, 438, 444 Use of amiodarone with any other agent known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of such combination therapy.1, 355, 443 Some manufacturers state that such combined use should be avoided or is contraindicated.366, 432, 433, 434, 435, 436, 437, 444 If dolasetron and amiodarone are used concomitantly, caution should be exercised and cardiac function should be monitored.432, 438
Drugs with P-Glycoprotein-mediated Clearance
Amiodarone inhibits the P-glycoprotein transport system, which may result in unexpectedly high plasma concentrations of drugs that are substrates for this transport system.1, 355, 432
Drugs, Foods, and Dietary or Herbal Supplements Affecting Hepatic Microsomal Enzymes
Amiodarone is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally the isoenzymes CYP3A4 and CYP2C8.1, 355 Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors, or inducers of CYP3A4 and CYP2C8.1, 355 Amiodarone also inhibits CYP2D6, CYP1A2, CYP2C9, and CYP3A4 isoenzymes.1, 355 Inhibition of these isoenzymes by amiodarone may result in unexpectedly high plasma concentrations of other drugs which are metabolized by these isoenzymes.1, 355
The use of amiodarone in conjunction with other antiarrhythmic agents generally should be reserved for patients with life-threatening arrhythmias who do not respond completely to either a single antiarrhythmic agent or amiodarone alone.1, 355 When combination therapy with amiodarone is employed, it is generally recommended that dosage of the currently administered antiarrhythmic agent(s) be reduced by 30-50% several days after initiation of amiodarone therapy, since the onset of amiodarone's antiarrhythmic effect may be delayed.1, 355 The necessity of continuing the other antiarrhythmic agent(s) should be assessed after the antiarrhythmic effect of amiodarone has been established, and discontinuance of the other antiarrhythmic agent(s) usually should be attempted.1, 355 If combination therapy with the other antiarrhythmic agent(s) is continued, patients should be monitored with particular care for possible adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias.1, 355 In patients already receiving amiodarone, the initial dosage of other antiarrhythmic agents should be reduced to approximately 50% of their usual recommended initial dosages.1, 355
Atypical ventricular tachycardia (torsades de pointes) has been reported rarely when amiodarone was administered concomitantly with various antiarrhythmic agents, including disopyramide,207, 255, 264, 265, 266 mexiletine,207, 264 propafenone,207, 264 and quinidine.207, 228, 264 Pending further accumulation of data, amiodarone should be used with caution when administered concomitantly with other antiarrhythmic agents,1, 207, 228, 255, 264, 265, 266 particularly class IA antiarrhythmic agents.207, 228, 255, 264, 265, 266
Plasma flecainide concentrations adjusted for daily dosage increased by an average of about 60% (range: 5-190%) when amiodarone therapy was initiated in a limited number of patients receiving flecainide.1, 226, 355 Although the mechanism(s) of this interaction is not known, it has been suggested that amiodarone may inhibit the hepatic metabolism and/or decrease the renal clearance of flecainide.226 Pending further accumulation of data, it is recommended that the dosage of flecainide be reduced by 30-50% several days after initiation of amiodarone therapy;1, 226, 355 subsequently, the patient and plasma flecainide concentrations should be monitored closely and flecainide dosage adjusted as necessary.1, 226, 320, 355
Concomitant use of amiodarone and procainamide may result in increased plasma procainamide and N -acetylprocainamide (NAPA) concentrations and subsequent toxicity.1, 203, 227 In a limited number of patients receiving 2-6 g of procainamide hydrochloride daily, initiation of amiodarone hydrochloride (1200 mg daily for 5-7 days and then 600 mg daily) increased plasma procainamide and NAPA concentrations by about 55 and 33%, respectively, during the first week of amiodarone therapy.1, 203, 227, 355 The exact mechanism(s) has not been elucidated, but it has been suggested that amiodarone may decrease the renal clearance of procainamide or NAPA and/or inhibit the hepatic metabolism of procainamide.203, 227 In addition to a pharmacokinetic interaction, additive electrophysiologic effects, including increased QTc and QRS intervals, occur during concomitant use; adverse electrophysiologic effects (e.g., acceleration of ventricular tachycardia) may also occur.313 Pending further accumulation of data, it is recommended that procainamide dosage be reduced by 20-33% when amiodarone therapy is initiated in patients currently receiving procainamide or that procainamide therapy be discontinued.1, 227, 313, 355
Serum quinidine concentrations may increase following initiation of amiodarone therapy in patients currently receiving quinidine, with subsequent toxicity occurring in some patients.1, 35, 227, 228, 355 Administration of amiodarone hydrochloride (1200 mg daily for 5-7 days then reduced to 600 mg daily) to a limited number of patients receiving quinidine gluconate or sulfate (average dose of about 3 g daily) resulted in an increase in serum quinidine concentrations of about 33%.1, 227, 355 Serum quinidine concentrations may begin to increase within a couple days after initiation of amiodarone therapy.1, 227, 355 The mechanism of the interaction is not fully established, but it has been suggested that amiodarone may inhibit hepatic clearance or decrease renal clearance of quinidine and/or displace quinidine from tissue- and/or protein-binding sites.227, 228 Although not clearly established, combination therapy with amiodarone and quinidine may also cause marked QT prolongation, predisposing patients to atypical ventricular tachycardia (torsades de pointes).207, 228, 264 It is generally recommended that quinidine dosage be reduced by 33-50% when amiodarone therapy is initiated in patients currently receiving quinidine or that quinidine therapy be discontinued.1, 227, 355 Serum quinidine concentrations should be monitored carefully and quinidine dosage reduced as necessary in patients receiving concomitant amiodarone and quinidine therapy; patients should be observed closely for signs of toxicity, including QT prolongation.1, 227, 228, 355
Sinus bradycardia was observed in a patient receiving oral amiodarone who was given lidocaine for local anesthesia.1, 355 Seizures associated with increased lidocaine concentrations were observed in one patient receiving concomitant IV amiodarone therapy.1, 355
HIV protease inhibitors inhibit CYP3A4 to varying degrees, which may result in a decrease in the metabolism of amiodarone.1, 355 Concomitant use of amiodarone and an HIV protease inhibitor used with low-dose ritonavir ( ritonavir-boosted ) or without low-dose ritonavir (unboosted) may result in increased plasma concentrations of amiodarone and the HIV protease inhibitor.1, 200, 355
Concomitant use of amiodarone and ritonavir-boosted saquinavir or ritonavir-boosted tipranavir is not recommended.200 If amiodarone is used concomitantly with other ritonavir-boosted HIV protease inhibitors or with unboosted HIV protease inhibitors, some experts recommend caution and state that the patient should be monitored for amiodarone toxicity and consideration given to monitoring ECG and amiodarone plasma concentrations.200
Histamine H2-Receptor Antagonists
Cimetidine inhibits CYP3A4 and can increase plasma amiodarone concentrations.1, 355
Histamine H1-Receptor Antagonists
Use of amiodarone with loratadine may result in a decrease in the metabolism of loratadine, a substrate of CYP3A4.1, 355 QT-interval prolongation and torsades de pointes have been reported with concomitant use of amiodarone and loratadine.1, 355
Amiodarone inhibits CYP3A4, which may result in a decrease in the metabolism of cyclosporine, a substrate of CYP3A4.1, 355 Concomitant use of amiodarone and cyclosporine has been reported to produce persistently elevated plasma concentrations of cyclosporine, resulting in elevated serum creatinine concentrations despite reduction in the dose of cyclosporine.1, 355
HMG-CoA Reductase Inhibitors (Statins)
Potent inhibitors of CYP3A4 can increase plasma concentrations of HMG-CoA reductase inhibitory activity and increase the risk of myopathy.1, 355, 371, 417, 448, 449, 450, 451 Because the risk of myopathy/rhabdomyolysis is increased following concomitant use of amiodarone with higher dosages of certain HMG-CoA reductase inhibitors (e.g., simvastatin dosages exceeding 20 mg daily),1, 355, 371, 417, 448, 449, 450, 451 the daily dosage of lovastatin417 or simvastatin371, 448 should not exceed 40 or 20 mg, respectively, during concomitant therapy with amiodarone.
Concomitant administration of amiodarone and rifampin has been associated with decreases in plasma concentrations of amiodarone and desethylamiodarone because of induction of CYP3A4 by rifampin.1, 355
St. John's Wort (Hypericum perforatum)
St. John's wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin.429, 430 There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2.429, 430 Since amiodarone is a substrate for CYP3A4, concomitant use of amiodarone and St. John's wort has the potential to result in decreased plasma concentrations of amiodarone.1, 355
Other Drugs Affecting Hepatic Microsomal Enzymes
Concomitant administration of fentanyl and amiodarone may result in hypotension, bradycardia, and decreased cardiac output.1, 355 Prolonged (exceeding 2 weeks) administration of oral amiodarone impairs the metabolism of dextromethorphan, phenytoin, and methotrexate.1, 355
Use of amiodarone concurrently with trazodone may result in a decrease in the metabolism of trazodone, a substrate of CYP3A4.1, 355 QT-interval prolongation and torsades de pointes have been reported with concomitant use of amiodarone and trazodone.1, 355
Clopidogrel undergoes biotransformation through the CYP3A4 isoenzyme, and concomitant use with amiodarone may decrease the biotransformation of clopidogrel to the active form.1, 355 Ineffective inhibition of platelet aggregation has been reported during concomitant use of clopidogrel and amiodarone.1, 355
Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in intestinal mucosa, resulting in increased plasma concentrations of amiodarone.1, 355 In healthy individuals receiving grapefruit juice and oral amiodarone concurrently, the area under the plasma concentration-time curve (AUC) and peak plasma concentration of amiodarone increased by 50 and 84%, respectively, and desethylamiodarone plasma concentrations decreased to below the detection limits of the assay.1, 355 Therefore, grapefruit juice should not be consumed during treatment with oral amiodarone.1, 355, 431 This interaction should be considered when switching from IV to oral amiodarone therapy.1, 3, 355
Concomitant use of amiodarone and phenytoin has resulted in a twofold to threefold increase in steady-state serum concentrations of phenytoin and subsequent signs of phenytoin toxicity (e.g., nystagmus, ataxia, lethargy) in a limited number of patients.1, 203, 205, 206 The increase in serum phenytoin concentrations occurred within 3-4 weeks of initiating amiodarone therapy.1, 203, 205, 206, 355 Although the exact mechanism(s) has not been clearly established, amiodarone may inhibit hepatic metabolism of phenytoin.203, 205 Patients receiving phenytoin should be monitored closely for signs of phenytoin toxicity when amiodarone is administered concomitantly; serum phenytoin concentrations also should be monitored and dosage of phenytoin reduced as necessary.1, 205, 355
Phenytoin has been reported to decrease plasma amiodarone concentrations.1, 355
An increase in prothrombin time (PT) appears to occur in almost all patients treated with amiodarone and a coumarin or indandione anticoagulant concomitantly1, 203, 208, 210, 301, 316, 355, 390 and can result in serious or fatal hemorrhage.1, 203, 204, 207, 208, 209, 211, 212, 214, 316, 355 The increase in PT usually begins within 3-4 days,1, 203, 207, 355 although onset of the effect may be delayed for 1-3 weeks in some patients.203, 207, 390 Bleeding episodes generally have been reported to occur 1-4 weeks following initiation of amiodarone therapy.204, 209, 390 The magnitude of the increase in PT appears to average 100%.1, 204, 207, 209, 355 Because of amiodarone's long elimination half-life, the PT may not return to normal for 1-4 months following discontinuance of the antiarrhythmic agent.203, 204, 207, 209, 210, 316, 390 The exact mechanism is not fully established,204, 207 but amiodarone appears to decrease the hepatic clearance of warfarin.203, 204, 207, 208, 316 If amiodarone therapy is initiated in patients receiving warfarin or another coumarin or indandione anticoagulant, a reduction in anticoagulant dosage of 33-50% is recommended.1, 204, 207, 209, 214, 283, 355 In patients receiving amiodarone and an oral anticoagulant concomitantly, the PT should be determined frequently and patients should be observed closely for adverse effects; dosage of the anticoagulant should be adjusted as necessary.1, 203, 204, 207, 209, 316, 355, 390
Concomitant use of amiodarone and digoxin regularly results in increased serum digoxin concentrations, which may reach toxic levels with subsequent digoxin toxicity.1, 9, 25, 35, 203, 204, 207, 217, 218, 219, 220, 221, 222, 223, 301, 355 Serum digoxin concentrations generally increase by an average of 70-100% in adults, but substantial variability exists in the magnitude of the increase.1, 9, 217, 218, 221, 223, 355 Limited data suggest that the magnitude of the increase may be much greater in children than in adults (i.e., 70-800%).221, 222
The amiodarone-induced increase in serum digoxin concentrations usually begins within 1-7 days1, 9, 203, 207, 217, 218, 223 and progresses gradually over a period of several weeks or even months.218, 222 The exact mechanism(s) of this interaction appears to be complex and remains to be fully established,35, 218, 220 but data indicate that amiodarone may decrease the renal and/or nonrenal clearance of digoxin.25, 35, 203, 207, 218, 219, 222, 432 It has also been suggested that amiodarone may increase the oral bioavailability of digoxin220 or displace digoxin from tissue binding sites.203, 207, 220 When initiating amiodarone therapy in patients receiving digoxin, the need for continued cardiac glycoside therapy should be reassessed, and digoxin discontinued if appropriate;1, 355 if concomitant therapy is considered necessary in patients receiving digoxin, a 50% reduction in digoxin dosage is recommended when amiodarone therapy is begun.1, 25, 35, 207, 217, 223, 355 Serum digoxin concentrations should be monitored carefully and digoxin dosage reduced as necessary in patients receiving amiodarone and digoxin concomitantly;1, 9, 35, 204, 218, 219, 222, 223, 355, 432 patients should be observed closely for signs of cardiac glycoside toxicity.1, 9, 204, 218, 355 In addition, thyroid function should be monitored carefully in patients receiving concurrent amiodarone and digoxin therapy, since amiodarone-induced changes in thyroid function may increase or decrease serum digoxin concentrations or alter sensitivity to the therapeutic and toxic effects of the cardiac glycoside.218, 224, 225
Amiodarone should be used with caution in patients receiving calcium-channel blocking agents (e.g., diltiazem, verapamil)1, 35, 256, 301, 355 and/or β-adrenergic blocking agents (e.g. propranolol),1, 25, 263, 355 since possible potentiation of sinus bradycardia, sinus arrest, and AV block may occur.1, 25, 35, 256, 263, 301, 355, 432 If amiodarone therapy is considered necessary, the drug may continue to be used in patients with severe sinus bradycardia or sinus arrest following insertion of an artificial pacemaker and institution of cardiac monitoring.1, 355, 432
The effects of concomitant administration of amiodarone and anesthetic agents have not been fully evaluated.170, 203, 216, 267, 279 However, potentially serious adverse cardiovascular and cardiac effects have occurred in some amiodarone-treated patients undergoing general anesthesia,167, 170, 216, 267 suggesting the possibility of an interaction between the antiarrhythmic agent and various anesthetic agents. In addition, close perioperative monitoring is recommended in patients undergoing general anesthesia while receiving amiodarone, since amiodarone may sensitize patients to the myocardial depressant and conduction effects of halogenated hydrocarbon general anesthetics.1, 355
Concomitant use of amiodarone and a hepatitis C virus (HCV) treatment regimen containing sofosbuvir with another HCV direct-acting antiviral (DAA), including ledipasvir, simeprevir, or daclatasvir, may result in serious symptomatic bradycardia and is not recommended.453, 454, 455, 456, 457 The mechanism for this adverse cardiovascular effect is unknown;453, 454, 455, 456, 457 the effect of concomitant use of amiodarone with these HCV treatment regimens on plasma concentrations of the drugs is unknown.454, 455, 456, 457 If there are no alternative HCV treatment options and a regimen of sofosbuvir with another DAA (e.g., ledipasvir, simeprevir, daclatasvir) must be used in a patient receiving amiodarone, the patient should be advised about the risk of serious symptomatic bradycardia before HCV treatment is initiated.454, 455, 456, 457 Cardiac monitoring should be performed in an inpatient setting during the first 48 hours of concomitant use of amiodarone and a regimen containing sofosbuvir with another DAA;454, 455, 456, 457 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.454, 455, 456, 457 Similar cardiac monitoring is recommended in patients who discontinued amiodarone just prior to initiation of a regimen that includes sofosbuvir with another DAA or if an alternative antiarrhythmic agent cannot be used and amiodarone must be initiated in a patient already receiving such sofosbuvir regimens.454, 455, 456, 457 Patients receiving amiodarone concomitantly with a regimen containing sofosbuvir with another DAA should be advised about the risk of serious symptomatic bradycardia and the importance of immediately contacting a clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur.454, 455, 456, 457
Concomitant use of oral amiodarone and simeprevir is expected to result in modestly increased amiodarone concentrations due to intestinal CYP3A4 inhibition by simeprevir.456 If amiodarone is used concomitantly with a simeprevir-containing HCV treatment regimen that does not include sofosbuvir, caution is warranted and therapeutic drug monitoring of the antiarrhythmic agent, if available, is recommended.456
Concomitant use of amiodarone and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir is expected to increase plasma concentrations of amiodarone.458 If amiodarone is used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir, caution is warranted and therapeutic drug monitoring of the antiarrhythmic agent, if available, is recommended.458
Limited data indicate that administration of cholestyramine resin following a single oral dose of amiodarone may decrease the elimination half-life and plasma concentrations of amiodarone, possibly by interfering with enterohepatic circulation of the antiarrhythmic agent.1, 203, 262, 355 Further evaluation of this potential interaction is needed.203, 262
Some clinicians state that because of a theoretical risk of inhibited intracellular α-galactosidase activity with amiodarone, it should not be administered concurrently with agalsidase beta, a biosynthetic form of α-galactosidase.439
Limited information is available on the acute toxicity of amiodarone.1, 201, 202, 261 However, cases of amiodarone overdosage, sometimes fatal, have been reported.1 If an overdosage occurs, patients should contact their clinician or proceed immediately to a hospital emergency room.431
The acute lethal dose of amiodarone hydrochloride in humans is not known.1, 201 The oral LD50 of the drug in rats, mice, and dogs is greater than 3 g/kg.1, 201 Following oral administration of single large doses of amiodarone hydrochloride (up to 3 g/kg) in dogs, emesis, tremors, and hindlimb paresis were observed.201
In general, overdosage of amiodarone may be expected to produce effects that are extensions of pharmacologic effects, including sinus bradycardia and/or heart block, hypotension, and QT prolongation.201 The most likely effects of an inadvertent overdosage of IV amiodarone are hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity.355 Nausea is likely to occur with ingestions of greater than 1 g of the drug.201 Slight, asymptomatic bradycardia201, 202, 261 and QT prolongation201, 202, 261 occurred about 1-3 days following acute ingestion of 2.6-8 g of amiodarone hydrochloride in 3 patients.201, 202, 261 In an adult who reportedly intentionally ingested 8 g of amiodarone hydrochloride and an unknown amount of diazepam and lorazepam, profuse perspiration occurred within 12 hours and slight bradycardia and QT prolongation (to about 500 ms) occurred 2-3 days after ingestion.201, 202, 261 In another adult who had received 200 mg of amiodarone hydrochloride daily for 1 week and then intentionally ingested 2.6 g of the drug, no ECG changes were apparent 6 hours after ingestion, but QT prolongation, T-wave inversion, and transient disappearance of precordial R waves occurred the day following ingestion.201 No symptoms were reported, and the patient's heart rate remained normal; repolarization returned to baseline about 10 days after ingestion.201 No deaths or permanent sequelae occurred in these patients.201, 202, 261
Management of amiodarone overdosage generally involves symptomatic and supportive care, with ECG and blood pressure monitoring.1, 201 In case of hypotension or cardiogenic shock in patients receiving amiodarone IV, the infusion rate should be decreased.355 There is no specific antidote for amiodarone intoxication.1, 201
Following recent acute ingestion of amiodarone, the stomach should be emptied immediately by inducing emesis or by gastric lavage.201 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.201 Administration of activated charcoal after emesis or gastric lavage may be useful in minimizing absorption of amiodarone, although specific data are not available.201 Because the onset of toxicity may be delayed, ECG monitoring may be necessary for several days following acute ingestion of the drug.201 For bradycardia, IV administration of a β-adrenergic agonist (e.g., isoproterenol) or use of a transvenous cardiac pacemaker is recommended;1, 169, 201, 355 amiodarone-induced bradycardia generally is not fully responsive to atropine.14, 33, 169, 201 For AV block, the use of a transvenous cardiac pacemaker may be necessary.355 Administration of IV fluids and placement of the patient in Trendelenburg's position is recommended for the initial treatment of hypotension.201, 355 An inotropic agent or vasopressor (e.g., dopamine, norepinephrine)201, 355 should be given for hypotension accompanied by signs of inadequate tissue perfusion.1, 201 Hepatic enzymes also should be monitored closely in the case of IV amiodarone overdosage.355 Hemodialysis or peritoneal dialysis is not useful for enhancing elimination of amiodarone or N -desethylamiodarone in acute overdosage.1, 2, 25, 35, 78, 92, 95, 201, 355
Antiarrhythmic and Electrophysiologic Effects
The antiarrhythmic and electrophysiologic actions of amiodarone hydrochloride are complex and differ from those of other currently available antiarrhythmic agents.6, 11, 13, 18, 24, 25, 46, 49, 364 Studies in animals have shown that amiodarone is effective in preventing and/or suppressing experimentally induced arrhythmias.1, 3, 10, 13, 18, 24, 26, 31
The exact mechanism(s) of antiarrhythmic action of amiodarone has not been conclusively determined.1, 2, 4, 8 Amiodarone is considered to be predominantly a class III antiarrhythmic agent,1, 2, 4, 5, 8, 12, 17, 18, 21, 24, 25, 26, 28, 31, 38, 355 but the drug also appears to exhibit activity in each of the four Vaughn-Williams antiarrhythmic classes, including some class I (membrane-stabilizing) antiarrhythmic action.5, 7, 8, 21, 25, 32, 35, 44, 46, 355, 364 The principal effect of amiodarone on cardiac tissue is to delay repolarization by prolonging the action potential duration (APD) and effective refractory period (ERP).1, 2, 3, 4, 5, 6, 7, 12, 13, 17, 18, 19, 21, 22, 25, 26, 38, 355 The drug also appears to inhibit transmembrane influx of extracellular sodium ions via fast sodium channels, as indicated by a decrease in the maximal rate of depolarization of phase 0 of the action potential.1, 5, 13, 32, 35, 44, 355 Like class I antiarrhythmic agents,286 amiodarone is believed to combine with fast sodium channels in their inactive state and thereby inhibit recovery after repolarization in a time- and voltage-dependent manner, which is associated with subsequent dissociation of the drug from the sodium channels.21, 25, 32, 35, 44, 46 Amiodarone appears to have little affinity for activated fast sodium channels.32, 44, 1, 3, 4, 5, 6, 9, 10, 11, 13, 14, 15, 16, 19, 21, 24, 25, 34, 35, 51, 364 Amiodarone also produces a noncompetitive inhibition of α- and β-adrenergic activity that may contribute to the drug's antiarrhythmic activity.1, 21 Limited data suggest that the drug may possess some vagolytic276 and/or calcium-channel blocking activity,33, 35, 284, 317, 364 and that recovery from calcium-channel blockade may be substantially more rapid than that with diltiazem or verapamil,317 but additional study is needed. Amiodarone does not appear to have vagomimetic6, 10, 13 or local anesthetic activity.9, 10, 13, 50
Amiodarone predominantly exhibits electrophysiologic effects characteristic of class III antiarrhythmic agents (i.e., prolonged repolarization and refractoriness),1, 2, 4, 5, 8, 12, 17, 18, 21, 24, 25, 26, 28, 31, 38, 355 but the drug also appears to exhibit activity in each of the four Vaughn-Williams antiarrhythmic classes, including some electrophysiologic effects characteristic of class I5, 7, 8, 21, 25, 32, 35, 44, 46, 355, 364 (particularly class IA or IC)284, 364 antiarrhythmic agents. The drug prolongs APD in atrial and ventricular muscle, the sinus node, the atrioventricular (AV) node, and the His-Purkinje system2, 4, 5, 12, 13, 17, 18, 19, 21, 25, 26, 38 without substantially altering resting membrane potential or action potential height,1, 3, 4, 13, 18, 25, 26, 38 except in automatic cells (e.g., those in the sinus node or His-Purkinje system) in which it reduces the slope of diastolic depolarization and thereby generally reduces automaticity.1, 7, 21, 34, 46 Although several investigators have suggested that the myocardial effects observed during chronic amiodarone therapy are comparable to those associated with hypothyroidism and may be related to competitive inhibition of sodium-potassium-activated adenosine triphosphatase (Na+-K+-ATPase) activity, other data suggest that amiodarone's effects on thyroid function contribute minimally, if at all, to the overall electrophysiologic effects of the drug.115, 284, 295
Effects on Cardiac Conduction and Refractoriness
Amiodarone appears to prolong refractoriness throughout the myocardium including the atria, ventricles, His-Purkinje system, sinus node, and AV node, as well as in accessory pathways, if present.1, 2, 3, 4, 5, 6, 7, 9, 10, 17, 18, 21, 24, 25, 27, 28, 29, 30, 35, 36, 37, 38, 39, 40, 41, 43, 46, 47, 48, 49, 318, 355 The effect of amiodarone on cardiac conduction is less well defined, but the drug appears to decrease AV conduction following a single IV dose or chronic oral administration;4, 5, 6, 9, 18, 20, 24, 26, 33, 35, 38, 317 the decrease appears to be heart-rate dependent, with substantially larger reductions in AV conduction at high rates.317 Amiodarone may also partially impair conduction within the His-Purkinje system.2, 4, 5, 7, 18, 21, 24, 25, 29, 30, 32, 35, 36, 37, 43, 44, 46 When administered IV, amiodarone prolongs intranodal conduction and AV node refractoriness, but has little to no effect on sinus cycle length, refractoriness of the right atrium or right ventricle, repolarization, intraventricular conduction, or intranodal conduction.355 At higher than usual IV doses (e.g., greater than 10 mg/kg), amiodarone prolongation of right ventricular refractoriness and modest prolongation of the QRS complex have been observed.355 Differences in the effect between parenterally versus orally administered amiodarone are seen predominantly in effects on AV nodal conduction; IV amiodarone causes an intranodal conduction delay and increased nodal refractoriness secondary to slow-channel blockade (class IV activity) and noncompetitive adrenergic antagonism (class II activity).355 The effects of amiodarone on intracardiac conduction may result from its class I antiarrhythmic activity;5, 7, 21, 25, 32, 35, 44, 46 the drug's effects on slow calcium channels also may be involved.317 Further studies are needed to fully determine the effects of the drug on intracardiac conduction.5, 7, 21, 25, 32, 35, 44
The effects of amiodarone on refractoriness and intracardiac conduction are manifested by increases in PR1, 2, 3, 4, 9, 18, 25, 33, 40, 42, 49 and QT1, 2, 3, 4, 5, 6, 9, 12, 18, 23, 25, 26, 28, 35, 36, 39, 40, 42, 49, 50 intervals. Following chronic oral administration of the drug, increases in PR interval and QT interval corrected for rate (QTc) average about 10-17%1, 42 and 10-23%,1, 23, 42, 49 respectively. Limited data suggest that amiodarone-induced QT prolongation may constitute an antiarrhythmic mechanism, although additional study is necessary.2, 6, 8, 23, 42, 274 Rarely, QT prolongation induced by the drug is associated with arrhythmogenicity.1, 3, 9, 25, 75, 132, 171, 173, 265 QRS intervals may be unchanged4, 39, 42, 49, 50 or increased.3, 4, 18, 25, 36, 45 Amiodarone generally increases the AH interval4, 5, 9, 18, 24, 25, 30, 38, 48, 49, 317 but has a variable effect on the HV interval, which may be unchanged4, 9, 38, 49 or prolonged2, 4, 5, 9, 18, 21, 24, 25, 29, 43 following chronic oral administration of the drug. Changes in T-wave contour,1, 25, 26, 39, 40 such as widening, bifurcation, or reduction in amplitude,25, 26, 39, 40 and the development of prominent U waves may also occur during amiodarone therapy.1, 18, 25, 26, 39, 40, 284
The antiarrhythmic and electrophysiologic effects of amiodarone following single IV doses appear to differ substantially from those observed during chronic oral administration of the drug.2, 4, 5, 6, 7, 18, 23, 24, 29 Following a single IV dose, the major effect of the drug is on the AV node with lengthening of ERP and prolongation of intranodal conduction time,4, 5, 7, 17, 25, 29 whereas during chronic oral therapy, prolongation of APD and ERP in the atria, ventricles, and AV nodal tissue occurs.4, 5, 7, 13, 17, 18, 29 At a constant oral dosage, the electrophysiologic effects of amiodarone, including increases in APD and refractoriness, appear to develop as a function of time.5, 6, 22
Amiodarone generally depresses sinus node function.1, 3, 4, 5, 6, 9, 10, 11, 14, 15, 18, 20, 21, 25, 26, 28, 29, 30, 33, 34, 35, 39, 49, 50 Following chronic oral administration of amiodarone, sinus rate is reduced by about 10-20%;1, 6, 49, 50 however, changes in sinus rate following single IV doses of the drug do not appear to be substantial.6, 7 Marked sinus bradycardia or sinus arrest and heart block may occur in some patients.1, 168 Amiodarone appears to depress sinus node automaticity.1, 5, 6, 9, 25 Data are conflicting,7, 18 but amiodarone may in part reduce automaticity by increasing the APD and depressing the slope of diastolic depolarization in the sinus node.9, 10, 18, 21, 25, 33, 34 Administration of propranolol or atropine does not appear to substantially influence these changes, but a low calcium concentration enhances the drug's negative chronotropic effect.5, 6, 9, 14, 15, 25, 33 Following chronic administration of amiodarone, spontaneous cycle lengths are increased.7, 25, 30 The effects of amiodarone on sinus node recovery time (SNRT) and sinoatrial conduction time (SACT) have not been fully established;6 however, prolongation of both SNRT and SACT has occurred in some patients receiving long-term therapy with the drug.9, 18, 25
Effects on His-Purkinje System
In addition to prolonging repolarization and refractoriness, amiodarone reduces the maximum rate of phase 0 depolarization in Purkinje fibers in a use-dependent manner (i.e., the magnitude of depression of the maximum rate of phase 0 depolarization increases at faster stimulation rates).21, 25, 32, 35, 46 Clinical experience indicates that chronic oral therapy with the drug may result in prolongation of intraventricular conduction as manifested by lengthening of the HV interval.2, 4, 5, 7, 18, 21, 24, 25, 29, 30, 37, 43 However, amiodarone's effect on the HV interval appears to be variable; data from clinical studies indicate that the HV interval may either be unchanged4, 9, 38, 49 or prolonged by up to about 15-30%2, 4, 5, 9, 18, 21, 24, 25, 29, 43 during chronic administration of the drug. In addition, amiodarone therapy reportedly has exacerbated preexisting His-Purkinje delay in some patients.18, 26, 30, 32
Effects on Accessory AV Pathways and Reentry Mechanisms
The electrophysiologic effects of amiodarone on accessory pathways, the AV node, the His-Purkinje system, and/or atrial and ventricular myocardium may contribute to the drug's efficacy in terminating and preventing paroxysmal reentrant supraventricular tachycardias.4, 5, 7, 8, 17, 18, 25, 26, 27, 28, 29, 36, 37, 38, 39, 40, 41, 317, 318 In patients with Wolff-Parkinson-White syndrome or concealed accessory AV pathways, amiodarone generally increases refractoriness of the anterograde and retrograde accessory pathways,4, 7, 8, 17, 18, 21, 25, 26, 27, 28, 29, 37, 38, 39, 40, 284, 318 but the effect on refractoriness of the retrograde accessory pathway appears to be somewhat more variable and less pronounced.4, 8, 18, 25, 37, 284 Limited data indicate that the effects of amiodarone may be greater on anterograde accessory pathways that have relatively long pretreatment refractory periods.5, 25, 41, 284 In addition to its effects on accessory pathways, amiodarone may increase refractoriness in atrial and ventricular tissue, the AV node, and the His-Purkinje system, resulting in possible prevention or interruption of reentrant tachyarrhythmias.4, 5, 7, 8, 17, 18, 25, 28, 29, 36, 37, 38, 39, 40, 41 Amiodarone may also decrease the occurrence of atrial premature complexes (APCs) and ventricular premature complexes (VPCs) responsible for initiation of reentrant tachyarrhythmias.5, 25, 39, 41
Amiodarone noncompetitively inhibits α- and β-adrenergic responses to sympathetic stimulation and catecholamine administration.1, 3, 4, 5, 6, 9, 10, 11, 13, 14, 15, 16, 19, 21, 24, 25, 34, 35, 51 In vitro and in vivo data indicate that the drug noncompetitively antagonizes cardiovascular effects (e.g., tachycardia, hypertension, increase in myocardial oxygen consumption) induced by epinephrine, norepinephrine, and/or isoproterenol.5, 6, 11, 14, 15, 16, 19, 25, 34, 51 The precise mechanism of adrenergic inhibition is unclear.11, 24, 35, 51 Some data suggest that amiodarone does not bind directly to the catecholamine-recognition site on β-adrenergic receptors11, 35, 51 but instead may reduce β-adrenergic activity by decreasing the number of β-adrenergic receptors.11, 24, 51, 277 Although conflicting results have been reported,33 limited data suggest that amiodarone may also inhibit the release of neurotransmitter from presynaptic adrenergic neurons.5, 6, 25 Although not clearly established, the antiadrenergic activity of amiodarone may contribute to its antiarrhythmic and antianginal efficacy.6, 14, 19, 24, 34, 35, 51, 284
Like other antiarrhythmic agents, amiodarone can worsen existing arrhythmias1, 3, 9, 10, 25, 35, 75, 132, 141, 175, 287, 296, 355 or cause new arrhythmias.1, 35, 166, 167, 168, 175, 176, 296, 355 The arrhythmogenic effects of the drug have included ventricular fibrillation,1, 132, 355 sustained ventricular tachycardia,1, 25, 141, 175, 176 increased resistance to cardioversion,1, 25, 122, 175, 304 and atypical ventricular tachycardia (torsades de pointes).1, 3, 9, 25, 75, 132, 171, 173, 265, 355
Amiodarone generally exhibits minimal cardiovascular effects following oral administration.1, 4, 9, 35, 73 The cardiovascular effects of the drug appear to be more pronounced following IV than oral administration,9, 17, 54 but evaluations have been more extensive following IV administration.9, 17, 54 In addition, some cardiovascular effects observed following IV administration may be related to the solvent, polysorbate (Tween®) 80, used in the parenteral dosage form of the drug.53, 275
Long-term oral administration of amiodarone generally depresses sinus node function,1, 3, 4, 5, 9, 10, 11, 14, 15, 18, 20, 21, 25, 26, 28, 29, 30, 33, 34, 35, 39, 49, 50 and heart rate is reduced by an average of about 10-20%.1, 6, 49, 50 Following a single IV dose of amiodarone, heart rate may be increased, decreased, or unchanged;4, 53, 229 however, changes in heart rate after IV administration, if present, generally are minimal and transient.6, 7 Amiodarone generally does not appear to have a substantial negative inotropic effect following long-term oral administration,1, 9, 26, 42, 54 even in patients with depressed left ventricular ejection fraction (LVEF);1, 9, 54, 229 however, a mild negative inotropic effect (possibly related to the rate of injection)53, 284 may occur following IV administration of the drug.1, 14, 53, 54, 355
Amiodarone generally relaxes cardiac and vascular smooth muscle, thereby dilating both systemic and coronary arteries.1, 3, 4, 9, 10, 13, 14, 17, 35, 53, 54 Following IV administration of 5 mg/kg of amiodarone hydrochloride, systemic blood pressure, systemic vascular resistance, coronary vascular resistance, and left ventricular end-diastolic pressure (LVEDP) are generally decreased, while coronary sinus flow may increase transiently and cardiac index may increase slightly.1, 4, 9, 17, 25, 53 Studies in humans and animals indicate that IV amiodarone may produce a transient, dose-related increase in coronary artery blood flow,3, 4, 10, 14, 17, 53, 54 mainly as a result of a direct relaxant effect on coronary arteries, but reductions in contractility and LVEF may also be involved.4, 14, 17 Although not clearly established, limited data suggest that the transient reduction in coronary and systemic vascular resistance observed following IV administration may at least partially result from the vasodilatory effects of polysorbate 80 present as a solvent in the injection.53, 275, 365 Studies in humans and animals also suggest that amiodarone reduces myocardial oxygen consumption, resulting in a protective effect on ischemic myocardium.9, 52, 53, 54, 229 Although not clearly established, decreased myocardial oxygen consumption appears to result from a reduction in heart rate, systemic vascular resistance, and possibly myocardial contractility.9, 13, 35, 52, 53, 54, 229
Long-term oral administration of amiodarone generally does not appear to produce substantial changes in LVEF,1, 25, 54, 75 even in patients with left ventricular dysfunction.1, 54 The drug, however, has been associated with new or worsened heart failure in some patients receiving chronic oral therapy.1, 9, 25, 35, 70, 75, 108, 299 (See Cautions: Cardiovascular Effects.) IV administration of amiodarone may transiently depress left ventricular function, probably as a result of the drug's negative inotropic effect,1, 9, 53, 54 particularly in patients with preexisting left ventricular dysfunction9, 25, 53, 54 or at high doses.4, 9 Although decreases in left ventricular function following IV administration of the drug are generally transient and well tolerated, severe hypotension has occurred rarely in patients with severe heart failure.9, 25, 53, 54
Amiodarone has variable and complex effects on thyroid function.1, 4, 9, 10, 25, 35, 83, 153, 230, 231, 232, 233, 234, 235, 253, 297, 355 The drug's principal effect appears to be inhibition of extrathyroidal deiodinases,231, 237, 269 resulting in decreased peripheral conversion of thyroxine (T4) to triiodothyronine (T3)1, 4, 9, 25, 35, 83, 154, 231, 232, 233, 234, 235, 237, 253, 269, 298, 355 and a subsequent increase in serum T4 and inactive reverse triiodothyronine (reverse T3, rT3) concentrations and decrease in serum T3 concentrations.1, 4, 9, 10, 25, 35, 83, 153, 230, 231, 232, 233, 234, 235, 253, 355 Serum concentrations of thyrotropin (thyroid-stimulating hormone, TSH) usually increase initially but return to baseline or slightly below baseline values within a few months to a year despite continued therapy.35, 232, 234, 235, 236, 237, 253 In addition, the thyrotropin response to protirelin initially may be accentuated in patients receiving amiodarone;232, 234, 237, 253 normal or depressed responses may occur during long-term therapy.253
Despite the changes in serum thyroid hormone concentrations, most patients receiving amiodarone remain clinically euthyroid;1, 4, 9, 10, 25, 153, 230, 234, 237, 253 however, clinical hypothyroidism or hyperthyroidism may occur.1, 3, 4, 9, 10, 25, 26, 70, 83, 153, 154, 230, 231, 233, 234, 235, 236, 237, 238, 239, 240, 253, 298, 355 The mechanism(s) of amiodarone-induced hypothyroidism or hyperthyroidism has not been fully elucidated,1, 9, 35, 230, 231, 232, 233, 234, 235, 236, 237, 240, 253, 297, 355 but may be related to the iodine content of amiodarone1, 4, 9, 83, 154, 230, 231, 232, 235, 236, 237, 253, 298, 355, 445, 446 and/or involve a direct effect of the drug or its major metabolite on thyroid function.1, 9, 83, 232, 253, 297 It has also been proposed that amiodarone may alter the sensitivity of the pituitary gland and peripheral organs to the actions of thyroid hormones; however, additional study is needed.234
Amiodarone inhibits phospholipase (including phospholipase A1, A2, and C)150, 270 activity in vitro.35, 150, 157, 270, 326, 339 In patients receiving the drug, histologic examination has revealed the presence of phospholipid-laden lysosomal inclusions within pulmonary cells,35, 150, 326, 329, 339 liver cells,150, 156, 157, 158, 159, 161, 162, 163, 164 Schwann cells,177, 179 leukocytes,150, 196, 270 epithelial cells in skin,30, 191, 192, 193, 196 and possibly within epithelial cells in the eye.25, 183, 185, 186, 187 The exact mechanism(s) of amiodarone-induced injury to various body organs remains to be clearly established;35, 150 however, the production of amiodarone-phospholipid complexes within certain organs may play a role in the development of many of the adverse effects associated with the drug.9, 25, 35, 150, 156, 157, 158, 159, 161, 162, 163, 164, 177, 179, 183, 185, 186, 187, 191, 192, 193, 196, 270 It also has been suggested that accumulation of phospholipids within pulmonary cells also may result from increased phospholipid synthesis.326, 338, 339 In addition, amiodarone-induced pulmonary toxicity may be related to surfactant ingestion by macrophages,326, 339 release of free oxygen radicals,1, 326, 339 increased iodide content,326, 339 and/or altered cellular function secondary to the amphophilic nature of the drug.326, 327, 339 Although pulmonary toxicity appears to result from a hypersensitivity reaction in some patients,1, 325, 326, 339, 345, 346 and there was evidence of an IgG-mediated immune response initiated against an amiodarone/native pulmonary protein complex (hapten-protein complex) in at least one patient,319 the mechanism of amiodarone-induced hypersensitivity, including the possible role of immunoglobulins, complement deposition, and cytokines in this reaction remains to be more fully elucidated.326, 332, 339 In patients developing amiodarone-induced hypersensitivity pneumonitis, suppressor/cytotoxic (CD8+, T8+) T-cell lymphocytosis often is present in bronchoalveolar lavage specimens.1, 326, 332, 338, 339, 349, 351, 352, 353
Amiodarone theoretically can inhibit intracellular α-galactosidase activity.439 (See Drug Interactions: Agalsidase Beta.)
The effects of amiodarone on serum lipid concentrations have not been clearly established.235, 247, 248, 251, 300 Serum cholesterol and triglyceride concentrations in patients receiving the drug have variably been reported to be increased or decreased.235, 247, 251
Amiodarone hydrochloride is slowly1, 2, 10, 25, 35, 40, 49, 55, 58, 59, 61, 62, 65, 78, 79, 80, 81, 99 and variably absorbed from the GI tract following oral administration.1, 2, 5, 25, 26, 35, 49, 55, 56, 58, 59, 60, 61, 62, 65, 70, 76, 77, 78, 79, 80, 81, 99 The absolute bioavailability of commercially available amiodarone hydrochloride tablets averages approximately 50%,1, 25, 55, 58, 59, 60, 61, 78, 79, 80, 355 but varies considerably, ranging from 22-86%.2, 3, 25, 55, 58, 59, 60, 78, 99 The sometimes low and often variable bioavailability of amiodarone may possibly result from N -dealkylation or other metabolism in the intestinal lumen and/or GI mucosa,3, 4, 35, 59, 61, 76, 78, 81, 99 from first-pass metabolism in the liver,2, 4, 59, 60, 61, 76, 78, 81, 99 and/or from poor dissolution characteristics of the drug.2, 55, 78, 79 Food increases the rate and extent of absorption of amiodarone.1, 283 Results of a study in healthy adults indicate that administration of a single 600-mg oral dose of amiodarone hydrochloride after a high-fat meal increases the area under the plasma concentration-time curve (AUC) and the peak plasma concentration of amiodarone by 2.3 (range: 1.7-3.6) and 3.8 (range: 2.7-4.4) times, respectively, compared with administration in the fasting state.1, 283 Food also increases the rate of absorption of amiodarone; when administered with food, the time to achieve peak plasma concentration of unchanged drug is decreased by about 37% to 4.5 hours.1, 283 The mean AUC and mean peak plasma concentrations of N -desethylamiodarone (the major metabolite) increase by about 55 and 32%, respectively; however, the time to peak plasma concentration of this metabolite remains unchanged in the presence of food.1 Limited data suggest that the drug may undergo enterohepatic circulation.1, 2, 35, 55, 59, 76, 262, 288, 355
Following oral administration, peak plasma amiodarone concentrations usually occur within 3-7 hours1, 2, 10, 25, 35, 55, 58, 59, 60, 61, 62, 64, 65, 73, 78, 79, 80, 81, 99 (range: 2-12 hours).2, 10, 58, 59, 60, 62, 73, 78, 80, 99 Following oral administration of a single 400-mg dose of amiodarone hydrochloride in fasting, healthy adults, peak plasma amiodarone concentrations of approximately 0.15-0.7 mcg/mL are attained.58, 99 Within the oral dosage range of 100-600 mg daily, steady-state plasma concentrations of the drug are approximately proportional to dosage,1, 2, 5, 55, 56, 57, 62, 63, 64, 75, 77, 79, 97 increasing by an average of 0.5 mcg/mL per 100-mg increment in dosa 1 however, there is considerable interindividual variation in plasma concentrations attained with a given dosage.1, 5, 56, 60, 70, 75 Following continuous oral administration of the drug in the absence of an initial loading-dose regimen, steady-state plasma amiodarone concentrations would not be attained for at least 1 month2, 4, 78 and generally not for up to 5 months or longer.1, 23, 25, 55, 66, 77, 79 Following chronic oral administration of amiodarone, plasma concentrations of N -desethylamiodarone, the major metabolite of the drug, are approximately 0.5-2 times those of unchanged drug.35, 55, 56, 63, 65, 73, 75, 77, 78, 81, 86, 95, 96, 99, 101, 103
In a study of single-dose IV amiodarone hydrochloride (5 mg/kg over 15 minutes) in healthy individuals, peak drug concentration ranged from 5-41mcg/mL.355 Following 10-minute IV infusions of amiodarone hydrochloride at a dose of 150 mg in patients with ventricular fibrillation or hemodynamically unstable ventricular tachycardia, peak drug concentration ranged from 7-26 mcg/mL.355 Because of a rapid distribution phase, the concentration of amiodarone declines to 10% of peak values within 30-45 minutes after the end of the infusion.355 In clinical trials after 48 hours of continuous IV infusions (125, 500, or 1000 mg daily) plus supplemental infusions (150 mg) as needed for recurrent arrhythmias, mean plasma concentrations of amiodarone ranged from 0.7-1.4 mcg/mL.355 Following administration of a single IV dose of amiodarone in patients with cirrhosis, lower peak and mean plasma concentrations of N -desethylamiodarone are observed; mean amiodarone concentration remains unchanged.355
Following oral administration of amiodarone, the onset of antiarrhythmic activity is highly variable.1, 2, 3, 23, 25, 42, 59, 64, 68, 72 A therapeutic response may begin within 2-3 days in some patients1, 2, 3, 25, 64, 81 but generally is not evident until 1-3 weeks after beginning therapy with the drug, even when loading doses are administered.1, 2, 3, 5, 23, 25, 42, 59, 64, 68, 72 Limited data suggest that the onset of action occurs earlier in patients receiving loading doses of the drug1, 2, 4, 5, 35, 55, 58, 64, 68, 73 and in pediatric patients.2, 5, 35, 40, 69 Although not clearly established,18 the time of maximal antiarrhythmic effect usually occurs within 1-5 months after initiating oral amiodarone therapy.2, 5, 23, 25, 30, 42, 55, 72 Antiarrhythmic effects generally persist for 10-150 days following withdrawal of long-term amiodarone therapy;1, 2, 3, 4, 5, 23, 24, 26, 49, 56, 59, 67, 72, 79 however, duration of antiarrhythmic activity is variable and unpredictable1 and appears to depend on the length of therapy2, 26 as well as the type of cardiac arrhythmia being treated.5, 23 In general, when amiodarone therapy is resumed after prior discontinuance of the drug and subsequent recurrence of the arrhythmia, control of the arrhythmia occurs relatively rapidly compared to the initial response, presumably because tissues are not fully depleted of the drug at the time therapy is resumed.1, 23
There is considerable interindividual variation in the relationship between plasma amiodarone concentrations and antiarrhythmic effects.1, 2, 5, 9, 35, 49, 70 Limited data suggest that prolongation of the QTc interval is correlated with plasma amiodarone concentrations.2, 82 Based on suppression of arrhythmias, plasma amiodarone concentrations of approximately 1-2.5 mcg/mL are usually necessary for optimum therapeutic effect,1, 3, 25, 62, 63, 64, 70, 75, 289, 355 although therapeutic response may be apparent at lower concentrations in some patients;2, 9, 10, 35, 59, 62 plasma concentrations higher than 2.5 mcg/mL are generally not necessary.1 There is no established relationship between drug concentration and therapeutic response for short-term IV amiodarone therapy.355 Although considerable overlap exists between therapeutic and toxic plasma concentrations,71 certain adverse reactions including adverse hepatic,2, 75, 83 ocular,57, 75 and neuromuscular effects62, 70, 75 appear to occur more frequently when plasma amiodarone concentrations exceed 2.5 mcg/mL.2, 3, 5, 62, 63, 70, 71, 75, 81
Distribution of amiodarone into human body tissues and fluids has not been fully characterized.2, 55, 84 Following IV administration in rats, amiodarone is distributed extensively into many tissues, including adipose tissue, liver, kidneys, heart, and, to a lesser extent, the CNS.85 Following chronic oral administration of the drug in humans, amiodarone and N -desethylamiodarone are distributed extensively into many body tissues and fluids, including adipose tissue,1, 2, 10, 25, 35, 55, 56, 62, 78, 81, 84, 98, 99 liver,1, 2, 10, 25, 35, 55, 56, 62, 78, 81, 84, 98, 99, 290 lung,1, 2, 10, 25, 35, 55, 56, 62, 81, 84, 98, 99 spleen,1, 10, 25, 62, 78, 84 skeletal muscle,2, 25, 55, 84, 98 bone marrow,10, 62, 81 adrenal glands,10, 62, 84 kidneys,2, 10, 98, 99 pancreas,2, 10, 62, 98 testes,10, 62, 84, 94 semen,94 saliva,62 lymph nodes,55, 84 myocardium,2, 10, 55, 62, 78, 86, 98, 99 thyroid gland,2, 10, 55, 62, 84, 98, 99 skin,55, 62, 84 and brain.55, 62, 84 Amiodarone is also distributed into bile.1, 2, 3, 59, 78, 84, 98 Limited data indicate that peak biliary concentrations of the drug may be approximately 50 times greater than peak plasma concentrations.59 Tissue concentrations of amiodarone generally exceed concurrent plasma concentrations of the drug.2, 10, 35, 55, 62, 78, 82, 84, 85 N -Desethylamiodarone appears to accumulate in the same body tissues as amiodarone;2, 10, 81, 84 however, after long-term therapy, concentrations of the metabolite are usually substantially higher than concentrations of unchanged drug in almost all tissues, except adipose tissue, which mainly contains amiodarone.2, 5, 35, 55, 78, 81, 82, 84, 86, 99 N -Desethylamiodarone and, to a lesser extent, amiodarone also distribute into erythrocytes.2, 55, 56 Ratios of erythrocyte-to-plasma concentrations of amiodarone and N -desethylamiodarone were 0.33 and 0.67, respectively, after a single oral dose of amiodarone254 and 0.38-0.48 and 1.3-1.76, respectively, after long-term oral therapy with the drug.56 Following a single IV dose, the mean blood-to-plasma ratio for amiodarone is 0.73.55
Following IV administration, amiodarone is rapidly and widely distributed.2, 9, 10, 25, 55, 58, 59, 60, 78, 81, 85 The apparent volume of distribution of the drug or its major metabolite, N -desethylamiodarone, in healthy adults reportedly averages 65.8 L/kg (range: 18.3-147.7 L/kg) or ranges from 68-168 L/kg, respectively, following a single IV dose.55, 355
In vitro, amiodarone is approximately 96% bound to plasma proteins,1, 2, 87, 90, 355 mainly to albumin and, to a lesser extent, a high-density lipoprotein that is probably β-lipoprotein.87, 90
Amiodarone and N -desethylamiodarone cross the placenta to a limited extent.1, 2, 78, 88, 89, 91, 355 In pregnant women receiving amiodarone, ratios of umbilical venous to maternal venous plasma concentrations of amiodarone and N -desethylamiodarone were 0.1-0.28 and 0.25-0.55, respectively.2, 88, 89, 91 Amiodarone and its major metabolite are distributed into milk1, 2, 78, 89, 91, 355 in concentrations substantially higher than concurrent maternal plasma concentrations.89, 91 Limited data in a lactating woman indicate amiodarone and N -desethylamiodarone milk-to-plasma ratios ranging from 2.3-9.1 and 0.8-3.8, respectively.91
Plasma concentrations of amiodarone appear to decline in at least a biphasic manner,1, 2, 25, 35, 55, 58, 60, 81, 93 although more complex, multicompartmental pharmacokinetics have been described.250, 284, 291 Following a single IV dose in healthy adults, the half-life of the drug in the terminal elimination phase (t½β) has been reported to average 25 days (range: 9-47 days).2, 5, 55, 355 The elimination half-life of the major metabolite, N -desethylamiodarone, is equal to or longer than that of the parent drug.355 Following single-dose administration of amiodarone in a limited number of healthy individuals, amiodarone exhibits multicompartmental pharmacokinetics; the mean apparent terminal plasma elimination half-life of amiodarone and N -desethylamiodarone were 58 (range: 15-142) and 36 (range: 14-75) days, respectively.1 The half-life of amiodarone appears to be substantially more prolonged following multiple rather than single doses.2, 4, 9, 26, 55, 58, 59, 64, 65, 78, 81, 99, 291 It has been suggested that differences in reported elimination half-lives may result in part from misinterpretation of slow distribution phases as elimination phases following IV administration of the drug.250, 291 Following chronic oral administration of amiodarone hydrochloride in patients with cardiac arrhythmias (200-600 mg daily for 2-52 months), the drug appears to be eliminated in a biphasic manner with an initial elimination half-life of about 2.5-10 days, which is followed by a terminal elimination half-life averaging 53 days (range: 26-107 days), with most patients exhibiting a terminal elimination half-life in the range of 40-55 days.1, 55 The elimination half-life of the major metabolite, N -desethylamiodarone, averages 57-61 days (range: 20-118 days) following long-term oral administration of amiodarone.1, 25, 55, 93, 97, 99, 101 The elimination profile of amiodarone probably reflects an initial elimination of the drug from well-perfused tissues followed by prolonged elimination from poorly perfused tissues such as adipose tissue.1, 55, 64
In a study of single-dose amiodarone hydrochloride (5 mg/kg over 15 minutes) in healthy individuals, clearance of the drug and its major active metabolite, N -desethylamiodarone, ranged from 90-158 and 197-290 mL/hour per kg, respectively.355 In clinical studies lasting 2-7 days, clearance of IV amiodarone in patients with ventricular fibrillation or ventricular tachycardia ranged from 220-440 mL/hour per kg.355 Clearance of the drug in healthy geriatric individuals (i.e., older than 65 years of age) was decreased to approximately 100 mL/hour per kg, as compared with clearance of approximately 150 mL/hour per kg in younger individuals;355 in addition, the elimination half-life of the drug was increased in these geriatric individuals to 47 days, as compared with 20 days in younger individuals.355
The exact metabolic fate of amiodarone has not been fully elucidated,2, 81, 101 but the drug appears to be extensively metabolized,9, 25, 76, 80, 101 probably in the liver9, 35, 64, 76, 81 and possibly in the intestinal lumen and/or GI mucosa,35, 64, 76 to at least one major metabolite.1, 2, 25, 35, 76, 77, 78, 81, 96, 101 The major metabolite, N -desethylamiodarone, is formed by N -deethylation.1, 2, 25, 35, 76, 77, 78, 81, 96, 101, 273, 355 Although not clearly established,1, 24, 25, 35, 62, 81, 99, 100, 101, 355 limited data in animals indicate that the desethyl metabolite possesses substantial electrophysiologic and antiarrhythmic activity similar to amiodarone's.1, 86, 99, 100, 101, 273, 285, 355 Following IV administration of a single dose of N -desethylamiodarone in animals, the metabolite prolonged atrial and ventricular refractoriness and decreased conduction within the AV node; however, further studies are needed to determine the effects of the desethyl metabolite following chronic administration.285 The precise role of N -desethylamiodarone in the antiarrhythmic activity of amiodarone has not been clearly established.1, 355 The development of maximal ventricular class III antiarrhythmic effects after oral amiodarone administration in humans correlates more closely with N -desethylamiodarone accumulation over time than with amiodarone accumulation.1, 355 A minor metabolite of amiodarone, di- N -desethylamiodarone, has been identified in animals following chronic administration of the drug.2, 35, 101, 103 Amiodarone and N -desethylamiodarone may undergo deiodination to form deiodoamiodarone and deiodo- N -desethylamiodarone, respectively; iodine (in the form of iodide); and possibly other iodine-containing metabolites.2, 4, 23, 50, 57, 59, 60, 77, 78, 80, 96, 101, 103, 104 It is not known whether deiodinated metabolites are pharmacologically active.57, 77, 101
The excretory patterns of amiodarone and its metabolite have not been well characterized.2 Following oral or IV administration, amiodarone appears to be excreted almost completely in feces as unchanged drug and N -desethylamiodarone, presumably via biliary elimination.1, 3, 9, 25, 35, 59, 77, 78, 80, 95, 98, 355 Although not clearly established, limited data suggest that amiodarone may undergo enterohepatic circulation.1, 2, 35, 55, 59, 76, 262, 355 Renal excretion of amiodarone and N -desethylamiodarone appears to be negligible.1, 2, 5, 9, 25, 55, 58, 59, 60, 62, 77, 78, 80, 81, 95, 99, 355
Following IV administration of amiodarone in healthy individuals, total plasma clearance of the drug averages approximately 1.9 mL/minute per kg (range: 1.4-2.5 mL/minute per kg).2, 5, 55 Although not clearly established, total apparent plasma clearance of the drug appears to decrease with time.5, 55, 64 Clinical experience suggests that clearance of amiodarone may be more rapid in pediatric patients;2, 9, 40, 69 however, further studies are needed to fully determine the effects of age on clearance of the drug.9, 69 Factors of age, gender, or renal or hepatic disease appear to have no effect on the disposition of amiodarone or its major metabolite, N -desethylamiodarone.355
In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered;355 however, the terminal elimination half-life of N -desethylamiodarone is prolonged in these patients.355
Amiodarone and N -desethylamiodarone are not appreciably removed by hemodialysis1, 2, 25, 35, 78, 92, 95 or peritoneal dialysis.1, 25, 78, 95
Amiodarone hydrochloride is an iodinated benzofuran-derivative antiarrhythmic agent.1, 2, 3, 4, 5, 6, 13, 25, 355 The drug differs structurally and pharmacologically from other currently available antiarrhythmic agents.1, 2, 3, 4, 5, 6, 13, 25
Amiodarone hydrochloride occurs as a white to cream-colored, crystalline powder1, 355 and has solubilities of approximately 0.72 mg/mL in water and 12.8 mg/mL in alcohol at 25°C.241 The drug is highly lipophilic.241 Amiodarone hydrochloride contains 37.3% iodine; each 200-mg tablet of the drug or each mL of the commercially available injection contains approximately 75 or 18.7 mg of iodine, respectively.1, 2, 13, 355, 445, 446 The commercially available injection contains benzyl alcohol as a preservative.355 Amiodarone has a pKa of approximately 6.6.2, 241, 283
Amiodarone hydrochloride tablets should be protected from light1, 242, 443 and stored in tight containers1, 283, 443 at 20-25°C.1, 443 The manufacturer of one commercially available amiodarone hydrochloride tablet preparation (Pacerone®) states that the tablets may be exposed to temperatures ranging from 15-30°C.443 Commercially available amiodarone tablets have an expiration date of 3 years following the date of manufacture.283
Commercially available amiodarone hydrochloride injection concentrate should be stored at 20-25°C and protected from light and excessive heat.355 Ampuls containing the injection concentrate should be stored in the carton to protect the solution from light until used.355 Diluted solutions of amiodarone hydrochloride injection do not need to be protected from light during administration.355
Although amiodarone hydrochloride adsorbs to polyvinyl chloride (PVC) tubing, the parenteral drug doses and administration schedule studied in clinical trials were designed to take this fact into account.355 Therefore, the manufacturer recommends using PVC tubing and closely following the suggested infusion regimen when administering amiodarone hydrochloride by IV infusion.355 Leaching of diethylhexyl phthalate (DEHP) from IV tubing may occur.355
Following dilution of amiodarone hydrochloride injection concentrate to a concentration of 1-6 mg/mL in 5% dextrose in a PVC container, there is physical compatibility, with a loss of less than 10% of drug at 2 hours at room temperature.355 Following dilution of amiodarone hydrochloride injection concentrate to a concentration of 1-6 mg/mL in 5% dextrose in a glass or polyolefin container, there is physical compatibility, with no loss of drug at 24 hours at room temperature.355 Therefore, the manufacturer states that amiodarone hydrochloride infusions exceeding 2 hours should be administered in 5% dextrose in a glass or polyolefin containers.355 However, evacuated glass containers should not be used since incompatibility with a buffer in the container may cause precipitation.355
When admixed in 5% dextrose, amiodarone hydrochloride injection is incompatible with aminophylline, cefamandole nafate, cefazolin sodium, mezlocillin sodium, heparin sodium, or sodium bicarbonate.355 Specialized references should be consulted for specific compatibility information.
Clinicians should provide information to patients regarding proper techniques for storage and disposal of out-of-date amiodarone tablets.431
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 100 mg | ||
200 mg* | ||||
Cordarone® (scored) | ||||
Pacerone® (scored) | Upsher-Smith | |||
400 mg* | Amiodarone Hydrochloride Tablets | |||
Pacerone® (scored) | Upsher-Smith | |||
Parenteral | Concentrate for injection, for IV infusion | 50 mg/mL* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Wyeth Pharmaceuticals Inc. Cordarone® (amiodarone hydrochloride) tablets prescribing information. Philadelphia, PA; 2009 Aug.
2. Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet . 1984; 9:136-56. [PubMed 6370540]
3. Anon. Amiodarone. Med Lett Drugs Ther . 1986; 28:49-50. [PubMed 3702807]
4. Marcus FI, Fontaine GH, Frank R et al. Clinical pharmacology and therapeutic applications of the antiarrhythmic agent, amiodarone. Am Heart J . 1981; 101:480-93. [PubMed 7010975]
5. Zipes DP, Prystowsky EN, Heger JJ. Amiodarone: electrophysiologic actions, pharmacokinetics and clinical effects. J Am Coll Cardiol . 1984; 3:1059-71. [PubMed 6368644]
6. Singh BN. Amiodarone: historical development and pharmacologic profile. Am Heart J . 1983; 106(4 Part 2):788-97. [PubMed 6351575]
7. Ikeda N, Nademanee K, Kannan R et al. Electrophysiologic effects of amiodarone: experimental and clinical observation relative to serum and tissue drug concentrations. Am Heart J . 1984; 108(4 Part 1):890-8. [PubMed 6485999]
8. Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol . 1984; 24:129-47. [PubMed 6144698]
9. Sloskey GE. Amiodarone: a unique antiarrhythmic agent. Clin Pharm . 1983; 2:330-40. [PubMed 6349912]
10. Canada AT, Lesko LJ, Haffajee CI et al. Amiodarone for tachyarrhythmias: pharmacology, kinetics, and efficacy. Drug Intell Clin Pharm . 1983; 17:100-4. [PubMed 6337802]
11. Gagnol JP, Devos C, Clinet M et al. Amiodarone: biochemical aspects and haemodynamic effects. Drugs . 1985; 29(Suppl 3):1-10. [PubMed 2986937]
12. Olsson SB, Brorson L, Varnauskas E. Class 3 antiarrhythmic action in man: observations from monophasic action potential recordings and amiodarone treatment. Br Heart J . 1973; 35:1255-9. [PubMed 4586372]
13. Singh BN, Vaughan Williams EM. The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol . 1970; 39:657-67. [PubMed 5485142]
14. Charlier R, Deltour G, Baudine A et al. Pharmacology of amiodarone, an anti-anginal drug with a new biological profile. Arzneimittelforschung . 1968; 18:1408-17. [PubMed 5755904]
15. Charlier R. Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoreceptors. Br J Pharmacol . 1970; 39:668-74. [PubMed 5485143]
16. Polster P, Broekhuysen J. The adrenergic antagonism of amiodarone. Biochem Pharmacol . 1976; 25:131-4. [PubMed 1259774]
17. Coté P, Bourassa MG, Delaye J et al. Effects of amiodarone on cardiac and coronary hemodynamics and on myocardial metabolism in patients with coronary artery disease. Circulation . 1979; 59:1165-72. [PubMed 436209]
18. Finerman WB Jr, Hamer A, Peter T et al. Electrophysiologic effects of chronic amiodarone therapy in patients with ventricular arrhythmias. Am Heart J . 1982; 104(5 Part 1):987-96. [PubMed 7137016]
19. Bauthier J, Broekhuysen J, Charlier R et al. Nature of the inhibition by amiodarone of isoproterenol-induced tachycardia in the dog. Arch Int Pharmacodyn Ther . 1976; 219:45-51. [PubMed 1267541]
20. Touboul P, Atallah G, Gressard A et al. Effects of amiodarone on sinus node in man. Br Heart J . 1979; 42:573-8. [PubMed 518781]
21. Rosen MR, Wit AL. Electropharmacology of antiarrhythmic drugs. Am Heart J . 1983; 106(4 Part 2):829-39. [PubMed 6412533]
22. Venkatesh N, Somani P, Bersohn M et al. Electropharmacology of amiodarone: absence of relationship to serum, myocardial, and cardiac sarcolemmal drug concentrations. Am Heart J . 1986; 112:916-22. [PubMed 3776818]
23. Nademanee K, Singh BN, Hendrickson JA et al. Pharmacokinetic significance of serum reverse T3 levels during amiodarone treatment: a potential method for monitoring chronic drug therapy. Circulation . 1982; 66:202-11. [PubMed 7083508]
24. Bigger JT Jr, Hoffman BF. Antiarrhythmic drugs. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: The Macmillan Company; 1985:748-83.
25. Naccarelli GV, Rinkenberger RL, Dougherty AH et al. Amiodarone: pharmacology and antiarrhythmic and adverse effects. Pharmacotherapy . 1985; 5:298-313. [PubMed 2934688]
26. Rosenbaum MB, Chiale PA, Halpern MS et al. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol . 1976; 38:934-44. [PubMed 793369]
27. Rowland E, Krikler DM. Electrophysiological assessment of amiodarone in treatment of resistant supraventricular arrhythmias. Br Heart J . 1980; 44:82-90. [PubMed 7426165]
28. Rasmussen V, Berning J. Effect of amiodarone in the Wolff-Parkinson-White snydrome. Acta Med Scand . 1979; 205:31-7. [PubMed 367085]
29. Wellens HJJ, Brugada P, Abdollah H et al. A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient. Circulation . 1984; 69:120-4. [PubMed 6689635]
30. Heger JJ, Prystowsky EN, Jackman WM et al. Amiodarone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med . 1981; 305:539-45. [PubMed 6789201]
31. Schwartz PJ, Vanoli E. An experimental approach to the choice of antiarrhythmic therapy. Eur Heart J . 1986; 7(Suppl A):135-44. [PubMed 3720768]
32. Mason JW, Hondeghem LM, Katzung BG. Amiodarone blocks inactivated cardiac sodium channels. Pfluegers Arch . 1983; 396:79-81.
33. Gloor HO, Urthaler F, James TN. Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region. J Clin Invest . 1983; 71:1457-66. [PubMed 6853721]
34. Goupil N, Lenfant J. The effects of amiodarone on the sinus node activity of the rabbit heart. Eur J Pharmacol . 1976; 39:23-31. [PubMed 964302]
35. Mason JW. Amiodarone. N Engl J Med . 1987; 316:455-666. [PubMed 3543680]
36. Morady F, DiCarlo LA Jr, Krol RB et al. Acute and chronic effects of amiodarone on ventricular refractoriness, intraventricular conduction and ventricular tachycardia induction. J Am Coll Cardiol . 1986; 7:148-57. [PubMed 3941203]
37. Wellens HJJ, Lie KI, Bar FW et al. Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol . 1976; 38:189-94. [PubMed 952262]
38. Waleffe A, Bruninx P, Kulbertus HE. Effects of amiodarone studied by programmed electrical stimulation of the heart in patients with paroxysmal re-entrant supraventricular tachycardia. J Electrocardiol . 1978; 11:253-60. [PubMed 308527]
39. Rosenbaum MB, Chiale PA, Ryba D et al. Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol . 1974; 34:215-23. [PubMed 4843156]
40. Shahar E, Barzilay Z, Frand M et al. Amiodarone in control of sustained tachyarrhythmias in children with Wolff-Parkinson-White syndrome. Pediatrics . 1983; 72:813-6. [PubMed 6646922]
41. Wellens HJJ, Brugada P, Abdollah H. Effect of amiodarone in paroxysmal supraventricular tachycardia with or without Wolff-Parkinson-White syndrome. Am Heart J . 1983; 106(4 Part 2):876-80. [PubMed 6613833]
42. Nademanee K, Hendrickson JA, Cannom DS et al. Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone. Am Heart J . 1981; 101:759-68. [PubMed 7234654]
43. Shenasa M, Denker S. Mahmud R et al. Effect of amiodarone on conduction and refractoriness of the His-Purkinje system in the human heart. J Am Coll Cardiol . 1984; 4:105-10. [PubMed 6736436]
44. Mason JW, Hondeghem LM, Katzung BG. Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone. Circ Res . 1984; 55:277-85.
45. Morady F, DiCarlo LA Jr, Baerman JM et al. Rate-dependent effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction. J Am Coll Cardiol . 1985; 6:179-85. [PubMed 4008772]
46. Yabek SM, Kato R, Singh BN. Acute effects of amiodarone on the electrophysiologic properties of isolated neonatal and adult cardiac fibers. J Am Coll Cardiol . 1985; 5:1109-15. [PubMed 3989122]
47. Wellens HJJ, Bar FW, Dassen WRM et al. Effect of drugs in the Wolff-Parkinson-White syndrome: importance of initial length of effective refractory period of the accessory pathway. Am J Cardiol . 1980; 46:665-9. [PubMed 7416026]
48. Alboni P, Shantha N, Pirani R et al. Effects of amiodarone on supraventricular tachycardia involving bypass tracts. Am J Cardiol . 1984; 53:93-8. [PubMed 6691283]
49. Nademanee K, Hendrickson J, Kannan R et al. Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythmias: potent suppression of spontaneously occurring tachyarrhythmias versus inconsistent abolition of induced ventricular tachycardia. Am Heart J . 1982; 103:950-9. [PubMed 7081035]
50. Pritchard DA, Singh BN, Hurley PJ. Effects of amiodarone on thyroid function in patients with ischaemic heart disease. Br Heart J . 1975; 37:856-60. [PubMed 1191447]
51. Nokin P, Clinet M, Schoenfeld P. Cardiac β-adrenoceptor modulation by amiodarone. Biochem Pharmacol . 1983; 32:2473-7. [PubMed 6311220]
52. DeBoer LWV, Nosta JJ, Kloner RA et al. Studies of amiodarone during experimental myocardial infarction: beneficial effects on hemodynamics and infarct size. Circulation . 1982; 65:508-12. [PubMed 7055872]
53. Remme WJ, van Hoogenhuyze DCA, Kruyssen DACM et al. Amiodarone: haemodynamic profile during intravenous administration and effect on pacing-induced ischaemia in man. Drugs . 1985; 29(Suppl 3):11-22. [PubMed 3996243]
54. Schwartz A, Shen E, Morady F et al. Hemodynamic effects of intravenous amiodarone in patients with depressed left ventricular function and recurrent ventricular tachycardia. Am Heart J . 1983; 106(4 Part 2):848-56. [PubMed 6613831]
55. Holt DW, Tucker GT, Jackson PR et al. Amiodarone pharmacokinetics. Am Heart J . 1983; 106(4 Part 2):840-7. [PubMed 6613830]
56. Heger JJ, Prystowsky EN, Zipes DP. Relationships between amiodarone dosage, drug concentrations, and adverse side effects. Am Heart J . 1983; 106(4 Part 2):931-5. [PubMed 6613839]
57. Staubli M, Bircher J, Galeazzi RL et al. Serum concentrations of amiodarone during long term therapy: relation to dose, efficacy, and toxicity. Eur J Clin Pharmacol . 1983; 24:485-94. [PubMed 6861863]
58. Riva E, Gerna M, Latini R et al. Pharmacokinetics of amiodarone in man. J Cardiovasc Pharmacol . 1982; 4:264-9. [PubMed 6175810]
59. Andreasen F, Agerbaek H, Bjerregaard P et al. Pharmacokinetics of amiodarone after intravenous and oral administration. Eur J Clin Pharmacol . 1981; 19:293-9. [PubMed 7286032]
60. Anatasiou-Nana M, Levis GM, Moulopoulos S. Pharmacokinetics of amiodarone after intravenous and oral administration. Int J Clin Pharmacol Ther Toxicol . 1982; 20:524-9. [PubMed 7174155]
61. Pourbaix S, Berger Y, Desager JP et al. Absolute bioavailability of amiodarone in normal subjects. Clin Pharmacol Ther . 1985; 37:118-23. [PubMed 3967454]
62. Haffajee CI, Love JC, Canada AT et al. Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation . 1983; 67:1347-55. [PubMed 6851030]
63. Boppana VK, Greenspan A, Swanson BN et al. Clinical efficacy and serum concentrations of amiodarone. Clin Pharmacol Ther . 1983; 33:209.
64. Siddoway LA, McAllister CB, Wilkinson GR et al. Amiodarone dosing: a proposal based on its pharmacokinetics. Am Heart J . 1983; 106(4 Part 2):951-6. [PubMed 6613842]
65. Kannan R, Nademanee K, Hendrickson JA et al. Amiodarone kinetics after oral doses. Clin Pharmacol Ther . 1982; 31:438-44. [PubMed 7060325]
66. Ward DE, Camm AJ, Spurrell RAJ. Clinical antiarrhythmic effects of amiodarone in patients with resistant paroxysmal tachycardias. Br Heart J . 1980; 44:91-5. [PubMed 7426166]
67. Kaski JC, Girotti LA, Messuti H et al. Long-term management of sustained, recurrent, symptomatic ventricular tachycardia with amiodarone. Circulation . 1981; 64:273-9. [PubMed 6788399]
68. Rakita L, Sobol SM. Amiodarone in the treatment of refractory ventricular arrhythmias. JAMA . 1983; 250:1293-5. [PubMed 6348310]
69. Coumel P, Lucet V, Do Ngoc D. The use of amiodarone in children. PACE . 1983; 6:930-9. [PubMed 6195613]
70. Haffajee CI, Love JC, Alpert JS et al. Efficacy and safety of long-term amiodarone in treatment of cardiac arrhythmias: dosage experience. Am Heart J . 1983; 106(4 Part 2):935-43. [PubMed 6613840]
71. Graboys TB, Podrid PJ, Lown B. Efficacy of amiodarone for refractory supraventricular tachyarrhythmias. Am Heart J . 1983; 106(4 Part 2):870-6. [PubMed 6613832]
72. Rosenbaum MB, Chiale PA, Haedo A et al. Ten years of experience with amiodarone. Am Heart J . 1983; 106(4 Part 2):957-64. [PubMed 6613843]
73. Mostow ND, Vrobel TR, Noon D et al. Rapid suppression of complex ventricular arrhythmias with high-dose oral amiodarone. Circulation . 1986; 73:1231-8. [PubMed 3698254]
74. Nademanee K, Singh BN, Hendrickson J et al. Amiodarone in refractory life-threatening ventricular arrhythmias. Ann Intern Med . 1983; 98(5 Part 1):577-84. [PubMed 6846970]
75. Rotmensch HH, Belhassen B, Swanson BN et al. Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity. Ann Intern Med . 1984; 101:462-9. [PubMed 6476633]
76. Berdeaux A, Roche A, Labaille T et al. Tissue extraction of amiodarone and N -desethylamiodarone in man after a single oral dose. Br J Clin Pharmacol . 1984; 18:759-63. [PubMed 6508984]
77. Staubli M, Troendle A, Schmid B et al. Pharmacokinetics of amiodarone, desethylamiodarone and other iodine-containing amiodarone metabolites. Eur J Clin Pharmacol . 1985; 29:417-23. [PubMed 4092724]
78. Paton DM, Webster DR, Neutze JM. A review of the clinical pharmacokinetics of amiodarone. Methods Find Exp Clin Pharmacol . 1984; 6:41-9. [PubMed 6371407]
79. Canada AT, Lesko LJ, Haffajee CI. Disposition of amiodarone in patients with tachyarrhythmias. Curr Ther Res . 1981; 30:968-74.
80. Broekhuysen J, Laruel R, Sion R. Recherches dans la série des benzofurannes XXXVII: étude comparée du transit et du métabolisme de l'amiodarone chez diverses espèces animales et chez l'homme. (French; with English abstract.) Arch Int Pharmacodyn Ther . 1969; 177:340-59.
81. Rotmensch HH, Swanson BN, Greenspon AJ et al. Amiodarone: individualizing dosage with serum concentrations. PACE . 1983; 6:1327-35. [PubMed 6196742]
82. Debbas NMG, Bexton RS, du Cailar C et al. Relation between myocardial amiodarone concentration and QT interval. Br Heart J . 1983; 49:297.
83. Harris L, McKenna WJ, Rowland E et al. Side effects of long-term amiodarone therapy. Circulation . 1983; 67:45-51. [PubMed 6291807]
84. Adams PC, Holt DW, Storey GCA et al. Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy. Circulation . 1985; 72:1064-75. [PubMed 3930086]
85. Riva E, Gerna M, Neyroz P et al. Pharmacokinetics of amiodarone in rats. J Cardiovasc Pharmacol . 1982; 4:270-5. [PubMed 6175811]
86. Barbieri E, Conti F, Zampieri P et al. Amiodarone and desethylamiodarone distribution in the atrium and adipose tissue of patients undergoing short- and long-term treatment with amiodarone. J Am Coll Cardiol . 1986; 8:210-3. [PubMed 3711518]
87. Neyroz P, Bonati M. In vitro amiodarone protein binding and its interaction with warfarin. Experientia . 1985; 41:361-3. [PubMed 3972082]
88. Candelpergher G, Buchberger R, Suzzi GL et al. Passagio trans-placentare dell'amiodarone: evidenza elettrocardiografica e documentazione farmacologica in un neonato. (Italian; with English abstract.) G Ital Cardiol . 1982; 12:79-82.
89. Pitcher D, Leather HM, Storey GCA et al. Amiodarone in pregnancy. Lancet . 1983; 1:597-8. [PubMed 6131292]
90. Lalloz MRA, Byfield PGH, Greenwood RM et al. Binding of amiodarone by serum proteins and the effects of drugs, hormones and other interacting ligands. J Pharm Pharmacol . 1984; 36:366-72. [PubMed 6146666]
91. McKenna WJ, Harris L, Rowland E et al. Amiodarone therapy during pregnancy. Am J Cardiol . 1983; 51:1231-3. [PubMed 6837469]
92. Bonati M, Galletti F, Volpi A et al. Amiodarone in patients on long-term dialysis. N Engl J Med . 1983; 308:906. [PubMed 6835293]
93. Wilkinson PR, Rees JR, Storey GCA et al. Amiodarone: prolonged elimination following cessation of chronic therapy. Am Heart J . 1984; 107:787-8. [PubMed 6322563]
94. Adams PC, Holt P, Holt DW. Amiodarone in testis and semen. Lancet . 1985; 1:341. [PubMed 2857390]
95. Harris L, McKenna WJ, Krikler SJ et al. Renal elimination of amiodarone and its desethyl metabolite. Postgrad Med J . 1983; 59:440-2. [PubMed 6622326]
96. Flanagan RJ, Storey GCA, Holt DW et al. Identification and measurement of desethylamiodarone in blood plasma specimens from amiodarone-treated patients. J Pharm Pharmacol . 1982; 34:638-43. [PubMed 6128385]
97. Harris L, McKenna WJ, Rowland E et al. Plasma amiodarone and desethyl amiodarone levels in chronic oral therapy. Circulation . 1981; 64(Suppl IV):A263.
98. Maggioni AP, Maggi A, Volpi A et al. Amiodarone distribution in human tissues after sudden death during Holter recording. Am J Cardiol . 1983; 52:217-8. [PubMed 6858920]
99. Plomp TA, van Rossum JM, Robles de Medina EO et al. Pharmacokinetics and body distribution of amiodarone in man. Arzneimittelforschung . 1984; 34:513-20. [PubMed 6540111]
100. Woosley RL, Echt DS, Roden DM. Effects of congestive heart failure on the pharmacokinetics and pharmacodynamics of antiarrhythmic agents. Am J Cardiol . 1986; 57:25-33B.
101. Kates RE. Metabolites of cardiac antiarrhythmic drugs: their clinical role. Ann N Y Acad Sci . 1984; 432:75-89. [PubMed 6441496]
102. Latini R, Reginato R, Burlingame AL et al. High-performance liquid chromatographic isolation and fast atom bombardment mass spectrometric identification of di- N -desethylamiodarone, a new metabolite of amiodarone in the dog. Biomed Mass Spectrom . 1984; 11:466-71. [PubMed 6509156]
103. Holt DW, Tucker GT, Jackson PR et al. Amiodarone pharmacokinetics. Br J Clin Pract . 1986; 44(Suppl):109-14.
104. Rao RH, McCready VR, Spathis GS. Iodine kinetic studies during amiodarone treatment. J Clin Endocrinol Metab . 1986; 62:563-8. [PubMed 3944239]
105. Cruzan SM. Orphan drugs 1985 records. FDA Talk Paper T86-11. Rockville, MD: Food and Drug Administration; 1986 Feb 13.
106. Woosley RL. Risk/benefit considerations in antiarrhythmic therapy. JAMA . 1986; 256:82-4. [PubMed 3712719]
107. Solares G, Ramos F, Martin-Duran R et al. Is amiodarone an alternative to beta-blockers to treat supraventricular tachycardias in pheochromocytoma? Arch Intern Med . 1986; 146:2085. Letter.
108. Waxman HL, Groh WC, Marchlinski FE et al. Amiodarone for control of sustained ventricular tachyarrhythmia: clinical and electrophysiologic effects in 51 patients. Am J Cardiol . 1982; 50:1066-74. [PubMed 6291368]
109. Leak D, Eydt JN. Amiodarone for refractory cardiac arrhythmias: 10-year study. CMAJ . 1986; 134:495-501. [PubMed 3948063]
110. Wheeler PJ, Puritz R, Ingram DV et al. Amiodarone in the treatment of refractory supraventricular and ventricular arrhythmias. Postgrad Med J . 1979; 55:1-9. [PubMed 432163]
111. Best JF, Rinkenberger R, Lynch L et al. Amiodarone: an effective alternative for recalcitrant supraventricular and ventricular tachycardias. Clin Cardiol . 1986; 9:268-71. [PubMed 2424656]
112. Swan JH, Chisholm AW. Control of recurrent supraventricular tachycardia with amiodarone hydrochloride. Can Med Assoc J . 1976; 114:43-4. [PubMed 943223]
113. Podrid PJ, Lown B. Amiodarone therapy in symptomatic, sustained refractory atrial and ventricular tachyarrhythmias. Am Heart J . 1981; 101:374-9. [PubMed 7211665]
114. Blandford RL, Crampton J, Kudlac H. Intravenous amiodarone in atrial fibrillation complicating myocardial infarction. BMJ . 1982; 284:16-7. [PubMed 6797619]
115. Staubli M, Studer H. The effects of amiodarone on the electrocardiogram of the guineau pig are not explained by interaction with thyroid hormone metabolism alone. Br J Pharmacol . 1986; 88:405-10. [PubMed 3730700]
116. Vitolo E, Tronci M, Larovere MT et al. Amiodarone versus quinidine in the prophylaxis of atrial fibrillation. Acta Cardiol . 1981; 36:431-4. [PubMed 7039195]
117. Faniel R, Schoenfeld P. Efficacy of i.v. amiodarone in converting rapid atrial fibrillation and flutter to sinus rhythm in intensive care patients. Eur Heart J . 1983; 4:180-5. [PubMed 6861767]
118. Santos AL, Aleixo AM, Landeiro J et al. Conversion of atrial fibrillation to sinus rhythm with amiodarone. Acta Med Port . 1979; 1:15-23. [PubMed 549456]
119. Gold RL, Haffajee CI, Charos G et al. Amiodarone for refractory atrial fibrillation. Am J Cardiol . 1986; 57:124-7. [PubMed 3942054]
120. Horowitz LN, Spielman SR, Greenspan AM et al. Use of amiodarone in the treatment of persistent and paroxysmal atrial fibrillation resistant to quinidine therapy. J Am Coll Cardiol . 1985; 6:1402-7. [PubMed 4067122]
121. Solares G, Ramos F, Martin-Duran R et al. Amiodarone, phaeochromocytoma and cardiomyopathy. Anaesthesia . 1986; 41:186-90. [PubMed 3953991]
122. Lubbe WF, Mercer CJ, Roche AHG et al. Amiodarone in long term management of refractory cardiac tachyarrhythmias. N Z Med J . 1981; 93:31-5. [PubMed 6940024]
123. Cowan JC, Gardiner P, Reid DS et al. A comparison of amiodarone and digoxin in the treatment of atrial fibrillation complicating suspected acute myocardial infarction. J Cardiovasc Pharmacol . 1986; 8:252-6. [PubMed 2422461]
124. Varma MPS, Geddes JS, Pantridge JF. D.C. conversion in patients on amiodarone. Eur J Cardiol . 1981; 12:271-4. [PubMed 7250169]
125. Coumel P, Chouty F, Slama R. Logic and empiricism in the selection of antiarrhythmic agents: the role of drug combinations. Drugs . 1985; 29(Suppl 4):68-76. [PubMed 4006782]
126. Brodsky M, Allen B, Ferguson C et al. Amiodarone plus type 1A anti-arrhythmic drugs for the treatment of refractory atrial fibrillation. J Am Coll Cardiol . 1985; 5:480.
127. Kappenberger LJ, Fromer MA, Steinbrunn W et al. Efficacy of amiodarone in the Wolff-Parkinson-White syndrome with rapid ventricular response via accessory pathway during atrial fibrillation. Am J Cardiol . 1984; 54:330-5. [PubMed 6465013]
128. Leak D, Eydt JN. Control of refractory cardiac arrhythmia with amiodarone. Arch Intern Med . 1979; 139:425-8. [PubMed 434996]
129. Brown AK, Primhak RA, Newton P. Use of amiodarone in bradycardia-tachycardia syndrome. Br Heart J . 1978; 40:1149-52. [PubMed 708517]
130. Posse RA, Zuelgaray JTG. Use of amiodarone in bradycardia-tachycardia syndrome. Br Heart J . 1979; 42:369. [PubMed 508465]
131. Brown AK. Use of amiodarone in bradycardia-tachycardia syndrome. Br Heart J . 1979; 42:369. [PubMed 508465]
132. McComb JM, Logan KR, Khan MM et al. Amiodarone-induced ventricular fibrillation. Eur J Cardiol . 1980; 11:381-5. [PubMed 7398728]
133. Lesbre JP, Eloy JP. An open comparison of amiodarone with diltiazem and glyceryl trinitrate in patients with stable exertional angina. Drugs . 1985; 29(Suppl 3):31-6. [PubMed 3922733]
134. Rutilzsky B, Girotti AL, Rosenbaum MB. Efficacy of chronic amiodarone therapy in patients with variant angina and inhibition of ergonovine coronary constriction. Am Heart J . 1982; 103:38-43. [PubMed 6459732]
135. Maheswaran R, Bramble MG, Hardisty CA. Massive digoxin overdose: successful treatment with intravenous amiodarone. BMJ . 1983; 287:392-3. [PubMed 6409318]
136. Kennedy JI, Myers JL, Plumb VJ et al. Amiodarone pulmonary toxicity: clinical, radiologic, and pathologic correlations. Arch Intern Med . 1987; 147:50-5. [PubMed 3800529]
137. Heger JJ, Prystowsky EN, Zipes DP. Clinical efficacy of amiodarone in treatment of recurrent ventricular tachycardia and ventricular fibrillation. Am Heart J . 1983; 106(4 Part 2):887-94. [PubMed 6613835]
138. Kudenchuk PJ, Pierson DJ, Greene HL et al. Prospective evaluation of amiodarone pulmonary toxicity. Chest . 1984; 86:541-8. [PubMed 6478892]
139. Rotmensch HH, Liron M, Tupilski M et al. Possible association of pneumonitis with amiodarone therapy. Am Heart J . 1980; 100:412-3. [PubMed 7405817]
140. Sobol SM, Rakita L. Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: a possible complication of a new antiarrhythmic drug. Circulation . 1982; 65:819-24. [PubMed 7060263]
141. McGovern B, Garan H, Kelly E et al. Adverse reactions during treatment with amiodarone hydrochloride. BMJ . 1983; 287:175-80. [PubMed 6409240]
142. Colgan T, Simon GT, Kay JM et al. Amiodarone pulmonary toxicity. Ultrastruct Pathol . 1984; 6:199-207. [PubMed 6087525]
143. Wright AJ, Brackenridge RG. Pulmonary infiltration and bone marrow depression complicating treatment with amiodarone. BMJ . 1982; 284:1303. [PubMed 6803952]
144. Zaher C, Hamer A, Peter T et al. Low-dose steroid therapy for prophylaxis of amiodarone-induced pulmonary infiltrates. N Engl J Med . 1983; 308:779. [PubMed 6828130]
145. Dake MD, Golden JA. Amiodarone and pulmonary effects. Ann Intern Med . 1983; 98:1028. [PubMed 6859696]
146. Dan M, Greif J. Amiodarone and pneumonitis. Ann Intern Med . 1983; 99:732. [PubMed 6638735]
147. Pollak PT, Sami M. Acute necrotizing pneumonitis and hyperglycemia after amiodarone therapy: case report and review of amiodarone-associated pulmonary disease. Am J Med . 1984; 76:935-9. [PubMed 6720733]
148. Marchlinski FE, Gansler TS, Waxman HL et al. Amiodarone pulmonary toxicity. Ann Intern Med . 1982; 97:839-45. [PubMed 7149492]
149. Riley SA, Williams SE, Cooke NJ. Alveolitis after treatment with amiodarone. BMJ . 1982; 284:161-2. [PubMed 6799079]
150. Hostetler KY, Reasor MJ, Walker ER et al. Role of phospholipase A inhibition in amiodarone pulmonary toxicity in rats. Biochim Biophys Acta . 1986; 875:400-5. [PubMed 3942773]
151. Gibb P, Melendez LJ. Segmental pulmonary consolidation due to amiodarone. CMAJ . 1986; 134:611-3. [PubMed 3948074]
152. Rakita L, Sobol SM, Mostow N et al. Amiodarone pulmonary toxicity. Am Heart J . 1983; 106(4 Part 2):906-16. [PubMed 6310979]
153. Harris L, McKenna WJ, Rowland E et al. Side effects and possible contraindications of amiodarone use. Am Heart J . 1983; 106(4 Part 2):916-23. [PubMed 6613838]
154. Raeder EA, Podrid PJ, Lown B. Side effects and complications of amiodarone therapy. Am Heart J . 1985; 109(5 Part 1):975-83. [PubMed 3158188]
155. Rinder HM, Love JC, Wexler R et al. Amiodarone hepatotoxicity. N Engl J Med . 1986; 314:318-9. [PubMed 3941726]
156. Tordjman K, Katz I, Bursztyn M et al. Amiodarone and the liver. Ann Intern Med . 1985; 102:411-2. [PubMed 3970484]
157. Poucell S, Ireton J, Valencia-Mayoral P et al. Amiodarone-associated phospholipidosis and fibrosis of the liver. Gastroenterology . 1984; 86:926-36. [PubMed 6706074]
158. Simon JB, Manley PN, Brien JF et al. Amiodarone hepatotoxicity simulating alcoholic liver disease. N Engl J Med . 1984; 311:167-72. [PubMed 6738602]
159. Rigas B, Rosenfeld LE, Barwick KW et al. Amiodarone hepatotoxicity: a clinicopathologic study of five patients. Ann Intern Med . 1986; 104:348-51. [PubMed 3946978]
160. Yagupsky P, Gazala E, Sofer S et al. Fatal hepatic failure and encephalopathy associated with amiodarone therapy. J Pediatr . 1985; 107:967-70. [PubMed 4067758]
161. Varma RR, Troup PJ, Komorowski RA et al. Clinical and morphologic effects of amiodarone on the liver. Gastroenterology . 1985; 88:1091-2. [PubMed 3972228]
162. Lim PK, Trewby PN, Storey GCA et al. Neuropathy and fatal hepatitis in a patient receiving amiodarone. BMJ . 1984; 288:1638-9. [PubMed 6326931]
163. Babany G, Mallat A, Zafrani ES et al. Chronic liver disease after low daily doses of amiodarone: report of three cases. J Hepatol . 1986; 3:228-32. [PubMed 3794303]
164. Elving LD, Hoefnagels WHL, Van Haelst UJGM et al. Amiodarone hepatotoxicity. Neth J Med . 1986; 29:303-7. [PubMed 3796766]
165. Sheinman BD, Evans T. Acceleration of ventricular rate by amiodarone in atrial fibrillation associated with the Wolff-Parkinson-White syndrome. BMJ . 1982; 285:999-1000. [PubMed 6812745]
166. McGovern B, Garan H, Ruskin JN. Sinus arrest during treatment with amiodarone. BMJ . 1982; 284:160-1. [PubMed 6799078]
167. McGovern B, Garan H, Ruskin JN. Sinus arrest during treatment with amiodarone. BMJ . 1982; 284:1120. [PubMed 6802437]
168. Veltri EP, Reid PR. Sinus arrest with intravenous amiodarone. Am J Cardiol . 1986; 58:1110-1. [PubMed 3776867]
169. Navalgund AA, Alifimoff JK, Jakymec AJ et al. Amiodarone-induced sinus arrest successfully treated with ephedrine and isoproterenol. Anesth Analg . 1986; 65:414-6. [PubMed 3954116]
170. Liberman BA, Teasdale SJ. Anaesthesia and amiodarone. Can Anaesth Soc J . 1985; 32:629-38. [PubMed 4075214]
171. Moro C, Romero J, Corres Peiretti MA. Amiodarone and hypokalemia: a dangerous combination. Int J Cardiol . 1986; 13:365-8. [PubMed 3793289]
172. Chiale PA, Halpern S, Nau GJ et al. Efficacy of amiodarone during long-term treatment of malignant ventricular arrhythmias in patients with chronic chagasic myocarditis. Am Heart J . 1984; 107:656-65. [PubMed 6702559]
173. Westveer DC, Gadowski GA, Gordon S et al. Amiodarone-induced ventricular tachycardia. Ann Intern Med . 1982; 97:561-2. [PubMed 7125414]
174. Nademanee K, Singh BN. Amiodarone and ventricular tachycardia. Ann Intern Med . 1983; 98:110-1. [PubMed 6848028]
175. Fogoros RN, Anderson KP, Winkle RA et al. Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias. Circulation . 1983; 68:88-94. [PubMed 6851057]
176. Anastasiou-Nana MI, Anderson JL, Nanas JN et al. High incidence of clinical and subclinical toxicity associated with amiodarone treatment of refractory tachyarrhythmias. Can J Cardiol . 1986; 2:138-45. [PubMed 2941121]
177. Meier C, Kauer B, Müller U et al. Neuromyopathy during chronic amiodarone treatment: a case report: J Neurol . 1979; 220:231-9. (IDIS 211459)
178. Lustman F, Monseu G. Amiodarone and neurological side-effects. Lancet . 1974; 1:568. [PubMed 4132014]
179. Lemaire JF, Autret A, Biziere K et al. Amiodaron neuropathy: further arguments for human drug-induced neurolipidosis. Eur Neurol . 1982; 21:65-8. [PubMed 7094952]
180. Charness ME, Morady F, Scheinman MM. Frequent neurologic toxicity associated with amiodarone therapy. Neurology . 1984; 34:669-71. [PubMed 6538658]
181. Van Zandijcke M, Dewachter A. Pseudotumor cerebri with amiodarone. J Neurol Neurosurg Psych . 1986; 49:1463-4.
182. Alves LE, Rose EP, Klingele TG et al. Adverse effects of amiodarone. JAMA . 1982; 248:1448. [PubMed 7109162]
183. Kaplan LJ, Cappaert WE. Amiodarone keratopathy: correlation to dosage and duration. Arch Ophthalmol . 1982; 100:601-2. [PubMed 7073573]
184. Feiler-Ofry V, Lazar M, Solomon A et al. Amiodarone keratopathy. Ophthalmologica . 1980; 180:257-61. [PubMed 7207963]
185. D'Amico DJ, Kenyon KR, Ruskin JN. Amiodarone keratopathy: drug-induced lipid storage disease. Arch Ophthalmol . 1981; 99:257-61. [PubMed 6258544]
186. Ingram DV. Ocular effects in long-term amiodarone therapy. Am Heart J . 1983; 106(4 Part 2):902-5. [PubMed 6613837]
187. Ingram DV, Jaggarao NSV, Chamberlain DA. Ocular changes resulting from therapy with amiodarone. Br J Ophthalmol . 1982; 66:676-9. [PubMed 7115651]
188. Klingele TG, Alves LE, Rose EP. Amiodarone for ventricular arrhythmias. N Engl J Med . 1981; 305:1587-8. [PubMed 7312002]
189. Coumel P, Fidelle J. Amiodarone in the treatment of cardiac arrhythmias in children: one hundred thirty-five cases. Am Heart J . 1980; 100(6 Part 2):1063-9. [PubMed 7446409]
190. Chalmers RJG, Muston HL, Srinivas V et al. High incidence of amiodarone-induced photosensitivity in north-west England. BMJ . 1982; 285:341. [PubMed 6212095]
191. Delage C, Lagacé R, Huard J. Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study. Can Med Assoc J . 1975; 112:1205-8. [PubMed 47784]
192. Vos AK, van Ramshorst AGS, Grosfeld JCM et al. A peculiar cutaneous pigmentation from Cordarone. Dermatologica . 1972; 145:297-303. [PubMed 4654409]
193. Matheis H. Amiodarone-Pigmentierung. (German; with English abstract). Dermatologica . 1972; 145:304-18. [PubMed 4654410]
194. Mulrow JP, Mulrow CD, McKenna WJ. Pyridoxine and amiodarone-induced photosensitivity. Ann Intern Med . 1985; 103:68-9. [PubMed 3890657]
195. Ferguson J, de Vane PJ, Wirth M. Prevention of amiodarone-induced photosensitivity. Lancet . 1984; 2:414. [PubMed 6147496]
196. Rappersberger K, Konrad K, Wieser E et al. Morphological changes in peripheral blood cells and skin in amiodarone-treated patients. Br J Dermatol . 1986; 114:189-96. [PubMed 3947537]
197. Kaufmann G. Pyridoxine against amiodarone-induced photosensitivity. Lancet . 1984; 1:51-2. [PubMed 6140378]
198. Guerciolini R, Del Favero A, Cannistraro S. Amiodarone-induced photosensitivity and pyridoxine. Lancet . 1984; 1:962. [PubMed 6143893]
199. Bencini PL, Crosti C, Sala F et al. Toxic epidermal necrolysis and amiodarone treatment. Arch Dermatol . 1985; 121:838. [PubMed 4015131]
200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 8, 2015). Updates may be available at HIV.gov website. [Web]
201. Rumack BH, ed. Poisindex: Amiodarone. Micromedex, Inc; 1987 May.
202. Bonati M, D'Aranno V, Galletti F et al. Acute overdosage of amiodarone in a suicide attempt. J Toxicol Clin Toxicol . 1983; 20:181-6. [PubMed 6887311]
203. Hansten PD, Horn JR, eds. Amiodarone drug interactions. Drug Interact Newsl . 1987; 7:13-6.
204. Hansten PD. Amiodarone drug interactions. Drug Interact Newsl . 1983; 3:23-6.
205. McGovern B, Geer VR, LaRaia PJ et al. Possible interaction between amiodarone and phenytoin. Ann Intern Med . 1984; 101:650-1. [PubMed 6486598]
206. Gore JM, Haffajee CI, Alpert JS. Interaction of amiodarone and diphenylhydantoin. Am J Cardiol . 1984; 54:1145. [PubMed 6496340]
207. Marcus FI. Drug interactions with amiodarone. Am Heart J . 1983; 106(4 Part 2):924-30. [PubMed 6137140]
208. Watt AH, Stephens MR, Buss DC et al. Amiodarone reduces plasma warfarin clearance in man. Br J Clin Pharmacol . 1985; 20:707-9. [PubMed 4092002]
209. Martinowitz U, Rabinovici J, Goldfarb D et al. Interaction between warfarin sodium and amiodarone. N Engl J Med . 1981; 304:671-2. [PubMed 7453749]
210. Almog S, Shafran N, Halkin H et al. Mechanism of warfarin potentiation by amiodarone: dose- and concentration-dependent inhibition of warfarin elimination. Eur J Clin Pharmacol . 1985; 28:257-61. [PubMed 4007030]
211. Rees A, Dalal JJ, Reid PG et al. Dangers of amiodarone and anticoagulant treatment. BMJ . 1981; 282:1756-7. [PubMed 6786610]
212. Serlin MJ, Sibeon RG, Green GJ. Dangers of amiodarone and anticoagulant treatment. BMJ . 1981; 283:58. [PubMed 6788267]
213. Richard C, Riou B, Fournier C et al. Depression of vitamin K-dependent coagulation by amiodarone. Circulation . 1983; 68(Suppl III):III-278.
214. Hamer A, Peter T, Mandel WJ et al. The potentiation of warfarin anticoagulation by amiodarone. Circulation . 1982; 65:1025-9. [PubMed 7074739]
215. Staiger C, Jauernig R, De Vries J et al. Influence of amiodarone on antipyrine pharmacokinetics in three patients with ventricular tachycardia. Br J Clin Pharmacol . 1984; 18:263-4. [PubMed 6487468]
216. Gallagher JD, Lieberman RW, Meranze J et al. Amiodarone-induced complications during coronary artery surgery. Anesthesiology . 1981; 55:186-8. [PubMed 6973297]
217. Moysey JO, Jaggarao NSV, Grundy EN et al. Amiodarone increases plasma digoxin concentrations. BMJ . 1981; 282:272. [PubMed 6779981]
218. Nademanee K, Kannan R, Hendrickson J et al. Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications. J Am Coll Cardiol . 1984; 4:111-6. [PubMed 6736437]
219. Fenster PE, White NW, Hanson CD. Pharmacokinetic evaluation of the digoxin-amiodarone interaction. J Am Coll Cardiol . 1985; 5:108-12. [PubMed 3964797]
220. Maragno I, Santastasi G, Gaion RM et al. Influence of amiodarone on oral digoxin bioavailability in healthy volunteers. Int J Clin Pharm Res . 1984; 4:149-53.
221. Hooymans PM, Merkus FWHM. Current status of cardiac glycoside drug interactions. Clin Pharm . 1985; 4:404-13. [PubMed 2412751]
222. Koren G, Hesslein PS, MacLeod SM. Digoxin toxicity associated with amiodarone therapy in children. J Pediatr . 1984; 104:467-70. [PubMed 6707801]
223. Oetgen WJ, Sobol SM, Tri TB et al. Amiodarone-digoxin interaction: clinical and experimental observations. Chest . 1984; 86:75-9. [PubMed 6734297]
224. Ben-Chetrit E, Ackerman Z, Eliakim M. Case report: amiodarone-associated hypothyroidism—a possible cause of digoxin intoxication. Am J Med Sci . 1985; 289:114-6. [PubMed 3976714]
225. Marcus FI. Commentary: digoxin-amiodarone-hypothyroidism interaction. Am J Med Sci . 1985; 289:117-8. [PubMed 3976715]
226. Shea P, Lal R, Kim SS et al. Flecainide and amiodarone interaction. J Am Coll Cardiol . 1986; 7:127-30.
227. Saal AK, Werner JA, Greene HL et al. Effect of amiodarone on serum quinidine and procainamide levels. Am J Cardiol . 1984; 53:1264-7. [PubMed 6711425]
228. Tartini R, Kappenberger L, Steinbrunn W et al. Dangerous interaction between amiodarone and quinidine. Lancet . 1982; 1:1327-9. [PubMed 6123639]
229. Pfisterer M, Burkart F. Effect of short and long term administration of amiodarone on ischaemia-induced left ventricular dysfunction: implications for combined antianginal drug therapy. Drugs . 1985; 29(Suppl 3):23-9. [PubMed 3922732]
230. Borowski GD, Garofano CD, Rose LI et al. Effect of long-term amiodarone therapy on thyroid hormone levels and thyroid function. Am J Med . 1985; 78:443-50. [PubMed 3976702]
231. Mazonson PD, Williams ML, Cantley LK et al. Myxedema coma during long-term amiodarone therapy. Am J Med . 1984; 77:751-4. [PubMed 6486153]
232. Burger A, Dinichert D, Nicod P et al. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin: a drug influencing peripheral metabolism of thyroid hormones. J Clin Invest . 1976; 58:255-9. [PubMed 783194]
233. Jonckheer MH, Blockx P, Broeckaert I et al. “Low T3 syndrome” in patients chronically treated with an iodine-containing drug, amiodarone. Clin Endocrinol . 1978; 9:27-35.
234. Amico JA, Richardson V, Alpert B et al. Clinical and chemical assessment of thyroid function during therapy with amiodarone. Arch Intern Med . 1984; 144:487-90. [PubMed 6703817]
235. Albert SG, Alves LE, Rose EP. Thyroid dysfunction during chronic amiodarone therapy. J Am Coll Cardiol . 1987; 9:175-83. [PubMed 3794094]
236. Hawthorne GC, Campbell NPS, Geddes JS et al. Amiodarone-induced hypothyroidism. A common complication of prolonged therapy: a report of eight cases. Arch Intern Med . 1985; 145:1016-9. [PubMed 2988473]
237. Martino E, Safran M, Aghini-Lombardi F et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med . 1984; 101:28-34. [PubMed 6428291]
238. Martino E, Aghini-Lombardi F, Mariotti S et al. Treatment of amiodarone associated thyrotoxicosis by simultaneous administration of potassium perchlorate and methimazole. J Endocrinol Invest . 1986; 9:201-7. [PubMed 3020113]
239. Wimpfheimer C, Staubli M, Schadelin J et al. Prednisone in amiodarone-induced thyrotoxicosis. BMJ . 1982; 284:1835-6. [PubMed 6805719]
240. Jonckheer MH, Blockx P, Kaivers R et al. Hyperthyroidism as a possible complication of the treatment of ischemic heart disease with amiodarone. Acta Cardiol . 1973; 238:192-200.
241. Bonati M, Gaspari F, D'Aranno V et al. Physicochemical and analytical characteristics of amiodarone. J Pharm Sci . 1984; 73:829-31. [PubMed 6737273]
242. USP DI: drug information for the health care provider. Johnson KW, ed. 20th ed. Englewood, CO: Micromedex, Inc; 2000:89-94.
243. Greene HL, Graham EL, Werner JA et al. Toxic and therapeutic effects of amiodarone in the treatment of cardiac arrhythmias. J Am Coll Cardiol . 1983; 2:1114-28. [PubMed 6685151]
244. Weinberger I, Rotenberg Z, Fuchs J et al. Amiodarone-induced thrombocytopenia. Arch Intern Med . 1987; 147:735-6. [PubMed 3827461]
245. Antonelli D, Luboshitzky R, Gelbendorf A et al. Amiodarone-induced gynecomastia. N Engl J Med . 1986; 315:1553. [PubMed 3785317]
246. Gasparich JP, Mason JT, Greene HL et al. Non-infectious epididymitis associated with amiodarone therapy. Lancet . 1984; 2:1211-2. [PubMed 6150253]
247. Sonnenblick M, Gottlieb S, Goldstein R et al. Effect of amiodarone on blood lipids. Cardiology . 1986; 73:147-50. [PubMed 3719600]
248. Kannan R, Pollak A, Singh BN. Elevation of serum lipids after chronic administration of amiodarone in rabbits. Atherosclerosis . 1982; 44:19-26. [PubMed 7115477]
249. Santinelli V, Chiariello M, Condorelli M. Chronic amiodarone therapy and hypokalemia. Eur Heart J . 1985; 5:92.
250. Mostow ND, Rakita L, Vrobel TR et al. Amiodarone: intravenous loading for rapid suppression of complex ventricular arrhythmias. J Am Coll Cardiol . 1984; 4:97-104. [PubMed 6736461]
251. Politi A, Poggio G, Margiotta A. Can amiodarone induce hyperglycaemia and hypertriglyceridaemia? Br Med J . 1984; 288:285. (IDIS 181694)
252. Hunt D, Kertes P, Venables S et al. Exacerbation of bronchial asthma following treatment with amiodarone: demonstration of an antiadrenergic effect in vitro . Chest . 1984; 86:492-4. [PubMed 6088179]
253. Rumolo R, Vitolo E, Tronci M et al. Alterations in thyroid function induced by chronic administration of amiodarone. Drugs Exp Clin Res . 1987; 13:29-35. [PubMed 3595442]
254. Escoubet B, Jaillon P, Berger Y et al. Amiodarone and N-desethylamiodarone in plasma, red blood cells, and myocardium after a single oral dose: relation to hemodynamic effects in surgical patients. Am Heart J . 1986; 111:280-5. [PubMed 3946169]
255. Tzivoni D, Keren A, Stern S et al. Disopyramide-induced torsade de pointes . Arch Intern Med . 1981; 141:946-7. [PubMed 7235820]
256. Lee TH, Friedman PL, Goldman L et al. Sinus arrest and hypotension with combined amiodarone-diltiazem therapy. Am Heart J . 1985; 109:163-4. [PubMed 3966317]
257. Nicholls DP, Murtagh JG, Holt DW. Use of amiodarone and digoxin specific Fab antibodies in digoxin overdosage. Br Heart J . 1985; 53:462-4. [PubMed 3986060]
258. Maron BJ, Bonow RO, Cannon RO III et al. Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy (second of two parts). N Engl J Med . 1987; 316:844-52. [PubMed 3547135]
259. McKenna WJ, Harris L, Perez G et al. Arrhythmia in hypertrophic cardiomyopathy. II: comparison of amiodarone and verapamil in treatment. Br Heart J . 1981; 46:173-8. [PubMed 7196769]
260. Neri R, Mestroni L, Salvi A et al. Ventricular arrhythmias in dilated cardiomyopathy: efficacy of amiodarone. Am Heart J . 1987; 113:707-15. [PubMed 3825860]
261. Fortunati MT, Morandi F, Santarone M et al. Farmacocinetica dell'amiodarone in un caso di intossicazione acuta (8 grammi per os). (Italian; with English abstract.) G Ital Cardiol . 1983; 13:385-8.
262. Nitsch J, Lüderitz B. Beschleunigte Elimination von Amiodaron durch Colestyramin. (German; with English abstract.) Deutsche Med Wochenschr . 1986; 111:1241-4.
263. Derrida JP, Ollagnier J, Benaim R et al. Amiodarone et propranolol: une association dangereuse? Nouv Presse Med . 1979; 8:1429. Letter.
264. Tartini R, Kappenberger L, Steinbrunn W et al. Gefahrliche Interaktionen zwischen Amiodaron und Antiarrhythmika der Klasse I. (German; with English abstract.) Schweiz Med Wochenschr . 1982; 112:1585-7.
265. Raehl CL, Patel AK, LeRoy M. Drug-induced torsade de pointes. Clin Pharm . 1985; 4:675-90. [PubMed 2416504]
266. Keren A, Tzivoni D, Gavish D et al. Etiology, warning signs and therapy of torsade de pointes. Circulation . 1981; 64:1167-74. [PubMed 7296791]
267. Meulendyk J. Anesthetic considerations with amiodarone: report of a case. J Am Osteopath Assoc . 1984; 83:585-8. [PubMed 6609913]
268. Palakurthy PR, Iyer V, Meckler RJ. Unusual neurotoxicity associated with amiodarone therapy. Arch Intern Med . 1987; 147:881-4. [PubMed 3034178]
269. Aanderud S, Sundsfjord J, Aarbakke J. Amiodarone inhibits the conversion of thyroxine to triiodothyronine in isolated rat hepacytes. Endocrinology . 1984; 115:1605-8. [PubMed 6479103]
270. Downar E, Shaikh N, Butany J. Amiodarone—a potent phospholipase inhibitor. J Am Coll Cardiol . 1984; 3:604.
271. Fikkers BG, Bogousslavsky J, Regli F et al. Pseudotumor cerebri with amiodarone. J Neurol Neurosurg Psych . 1986; 49:606.
272. Veltri EP, Reid PR. Amiodarone pulmonary toxicity: early changes in pulmonary function tests during amiodarone rechallenge. J Am Coll Cardiol . 1985; 6:802-5. [PubMed 4031295]
273. Nattel S. The pharmacodynamics of amiodarone and desethylamiodarone. J Am Coll Cardiol . 1985; 5:466.
274. Torres V, Tepper D, Flowers D et al. QT prolongation and the antiarrhythmic efficacy of amiodarone. J Am Coll Cardiol . 1986; 7:142-7. [PubMed 3941202]
275. Gough WB, Zeiler RH, Barreca P et al. Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs. J Cardiovasc Pharmacol . 1982; 4:375-80. [PubMed 6177932]
276. Cohen-Armon M, Schreiber G, Sokolovsky M. Interaction of the antiarrhythmic drug amiodarone with the muscarinic receptor in rat heart and brain. J Cardiovasc Pharmacol . 1984; 6:1148-55. [PubMed 6084773]
277. Sharma AD, Corr PB. Modulation by amiodarone of cardiac adrenergic receptors and their electrophysiologic responsivity to catecholamines. Circulation . 1983; 68(Suppl III):III-99. [PubMed 6305533]
278. Leon MB, Rosing DR, Maron BJ et al. Amiodarone in patients with hypertrophic cardiomyopathy and refractory cardiac symptoms: an alternative to current medical therapy. Circulation . 1984; 70(4 Part II):II-18.
279. Elliott PL, Schauble JF, Rogers MC et al. Risk of decompensation during anesthesia in presence of amiodarone. Circulation . 1983; 68(4 Part II):III-280.
280. Keeton BR, Bucknall CA, Curry PVL et al. Use of amiodarone in childhood. Br J Clin Pract . 1984; 40(Suppl 44):115-20.
281. Garson A Jr, Gillette PC, McVey P et al. Amiodarone treatment of critical arrhythmias in children and young adults. J Am Coll Cardiol . 1984; 4:749-55. [PubMed 6384328]
282. Bucknall CA, Keeton BR, Curry PVL et al. Intravenous and oral amiodarone for arrhythmias in children. Br Heart J . 1986; 56:278-84. [PubMed 3756044]
283. Wyeth-Ayerst Laboratories Inc, Philadelphia, PA: Personal communication.
284. Reviewers' comments (personal observations); 1987 Aug.
285. Talajic M, DeRoode MR, Nattel S. Comparative electrophysiologic effects of intravenous amiodarone and desethylamiodarone in dogs: evidence for clinically relevant activity of the metabolite. Circulation . 1987; 75:265-71. [PubMed 3791608]
286. Campbell TJ. Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res . 1983; 17:344-52. [PubMed 6883410]
287. Mostow ND, Vrobel TR, Rakita L. Transient exacerbation followed by control of ventricular tachycardia with amiodarone. Am Heart J . 1986; 111:178-80. [PubMed 3946146]
288. Nitsch J, Lüderitz B. Amiodarone. N Engl J Med . 1987; 317:452.
289. Mostow ND, Rakita L, Vrobel TR et al. Amiodarone: correlation of serum concentration with suppression of complex ventricular ectopic activity. Am J Cardiol . 1984; 54:569-74. [PubMed 6475775]
290. Shenasa M, Vaisman U, Wojciechowski M et al. Abnormal abdominal computerized tomography with amiodarone therapy and clinical significance. Am Heart J . 1984; 107:929-33. [PubMed 6720524]
291. Mostow ND, Vrobel TR, Noon D et al. Intravenous amiodarone: hemodynamics, pharmacokinetics, electrophysiology, and clinical utility. Clin Prog Electrophysiol Pacing . 1986; 4:342-57.
292. McKenna WJ, Oakley CM, Krikler DM et al. Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Br Heart J . 1985; 53:412-6. [PubMed 4039188]
293. Naccarelli GV, Fineberg NS, Zipes DP et al. Amiodarone: risk factors for recurrence of symptomatic ventricular tachycardia identified at electrophysiologic study. J Am Coll Cardiol . 1985; 6:814-21. [PubMed 3928727]
294. Wood DL, Kazmier FJ, Osborn MJ et al. Ischemic optic neuritis as a manifest reaction of amiodarone. Circulation . 1986; 74(Suppl II):II-226.
295. Baerman JM, Annesley T, DiCarlo LA Jr et al. Interrelationships between serum levels of amiodarone, desethylamiodarone, reverse T3 and the QT interval during long-term amiodarone treatment. Am Heart J . 1986; 111:644-8. [PubMed 3953386]
296. Kay GN, Pryor DB, Lee KL et al. Comparison of survival of amiodarone-treated patients with coronary artery disease and malignant ventricular arrhythmias with that of a control group with coronary artery disease. J Am Coll Cardiol . 1987; 9:877-81. [PubMed 3558986]
297. Latham KR, Sellitti DF, Goldstein RE. Interaction of amiodarone and desethylamiodarone with solubilized nuclear thyroid hormone receptors. J Am Coll Cardiol . 1987; 9:872-6. [PubMed 3558985]
298. Mechlis S, Lubin E, Laor J et al. Amiodarone-induced thyroid gland dysfunction. Am J Cardiol . 1987; 59:833-5. [PubMed 3825945]
299. DePaola AAV, Horowitz LN, Spielman SR et al. Development of congestive heart failure and alterations in left ventricular function in patients with sustained ventricular tachyarrhythmias treated with amiodarone. Am J Cardiol . 1987; 60:276-80. [PubMed 3303888]
300. Kasim SE, Bagchi N, Brown TR et al. Effect of amiodarone on serum lipids, lipoprotein lipase, and hepatic triglyceride lipase. Endocrinology . 1987; 120:1991-5. [PubMed 3569123]
301. Labaz Sanofi UK Ltd. Cordarone® X Intravenous (amiodarone hydrochloride) prescribing information. Manchester, England; 1986 Feb.
302. Quattromani A, Birge S, Smith P et al. Early effects of amiodarone therapy on thyroid function. Circulation . 1986; 74(Suppl 2):II-225. [PubMed 3742762]
303. Horowitz LN, Greenspan AM, Spielman SR et al. Usefulness of electrophysiologic testing in evaluation of amiodarone therapy for sustained ventricular tachyarrhythmias associated with coronary heart disease. Am J Cardiol . 1985; 55:367-71. [PubMed 3969870]
304. Fogoros RN. Amiodarone-induced refractoriness to cardioversion. Ann Intern Med . 1984; 100:699-700. [PubMed 6712033]
305. Wiersinga WM, Endert E, Trip MD et al. Immunoradiometric assay of thyrotropin in plasma: its value in predicting response to thyroliberin stimulation and assessing thyroid function in amiodarone-treated patients. Clin Chem . 1986; 32:433-6. [PubMed 3081279]
306. Mason JW, Amiodarone Toxicity Study Group. Toxicity of amiodarone. Circulation . 1985; 72(4 Part II):III-270.
307. Liu FL, Cohen RD, Downar E et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax . 1986; 41:100-5. [PubMed 3010484]
308. Adams PC, Gibson GJ, Morley AR et al. Amiodarone pulmonary toxicity: clinical and subclinical features. Quart J Med . 1986; 59:449-71. [PubMed 3763811]
309. Nalos PC, Kass RM, Gang ES et al. Life-threatening postoperative pulmonary complications in patients with previous amiodarone pulmonary toxicity undergoing cardiothoracic operations. J Thorac Cardiovasc Surg . 1987; 93:904-12. [PubMed 3573800]
310. Staubli M, Studer H. Amiodarone-treated patients with TSH test are at risk of thyrotoxicosis. Klin Wochenschr . 1985; 63:168-75. [PubMed 3920432]
311. Feiner LA, Younge BR, Kazmier FJ et al. Optic neuropathy and amiodarone therapy. Mayo Clin Proc . 1987; 62:702-17. [PubMed 3600041]
312. Oreto G, Lapresa V, Melluso C et al. Intoxication aiguë par l'amiodarone: description d'un cas. (French; with English abstract.) Arch Mal Coeur . 1980; 73:857-61.
313. Windle J, Prystowsky EN, Miles WM et al. Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide. Clin Pharmacol Ther . 1987; 41:603-10. [PubMed 3581646]
314. Enia G, Caralano C, Zoccali C et al. Amiodarone. N Engl J Med . 1987; 317:452.
315. Enia G, Costante G, Caralano C et al. Severe hypothyroidism induced by amiodarone in a dialysis patient. Nephron . 1987; 46:206-7. [PubMed 3600929]
316. O'Reilly RA, Trager WF, Rettie AE et al. Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans. Clin Pharmacol Ther . 1987; 42:290-4. [PubMed 3621782]
317. Nattel S, Talajic M, Quantz M et al. Frequency-dependent effects of amiodarone on atrioventricular nodal function and slow-channel action potentials: evidence for calcium channel-blocking activity. Circulation . 1987; 76:442-9. [PubMed 3608127]
318. Feld GK, Nademanee K, Stevenson W et al. Clinical and electrophysiologic effects of amiodarone in patients with atrial fibrillation complicating the Wolff-Parkinson-White syndrome. Am Heart J . 1988; 115(1 Part 1):102-7. [PubMed 3336964]
319. Fan K, Bell R, Eudy S et al. Amiodarone-associated pulmonary fibrosis: evidence of an immunologically mediated mechanism. Chest . 1987; 92:625-30. [PubMed 3308345]
320. Riker Laboratories Inc. Tambocor® (flecainide acetate) B.I.D. prescribing information. St. Paul, MN; 1986 Nov.
321. Moots RJ, Banerjee A. Exfoliative dermatitis after amiodarone treatment. BMJ . 1988; 296:1332-3. [PubMed 2968133]
322. Lazzara R. Amiodarone and torsade de pointes. Ann Intern Med . 1989; 111:549-51. [PubMed 2672929]
323. Mattioni TA, Zheutlin TA, Sarmiento JJ et al. Amiodarone in patients with previous drug-mediated torsade de pointes: long-term safety and efficacy. Ann Intern Med . 1989; 111:574-80. [PubMed 2774388]
324. Dusman RE, Stanton MS, Miles WM et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation . 1990; 82:51-9. [PubMed 2364524]
325. Counihan PJ, McKenna WJ. Risk-benefit assessment of amiodarone in the treatment of cardiac arrhythmias. Drug Safety . 1990; 5:285-304.
326. Wilson JS, Podrid PJ. Side effects from amiodarone. Am Heart J . 1991; 121:158-71. [PubMed 1985357]
327. Naccarelli GV, Rinkenberger RL, Dougherty AH et al. Adverse effects of amiodarone: pathogenesis, incidence and management. Med Toxicol Adverse Drug Exp . 1989; 4:246-53. [PubMed 2671595]
328. Adams GD, Kehoe R, Lesch M et al. Amiodarone-induced pneumonitis: assessment of risk factors and possible risk reduction. Chest . 1988; 93:254-62. [PubMed 3338292]
329. Arnon R, Raz I, Chajek-Shaul T et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest . 1988; 93:425-7. [PubMed 3338315]
330. De Wolf D, De Schepper J, Verhaaren H et al. Congenital hypothyroid and goiter and amiodarone. Acta Paediatr Scand . 1988; 77:616-8. [PubMed 3394521]
331. Ohar JA, Jackson F Jr, Redd RM et al. Usefulness of serial pulmonary function testing as an indicator of amiodarone toxicity. Am J Cardiol . 1989; 64:1322-6. [PubMed 2589198]
332. Akoun GM, Gauthier-Rahman S, Liote HA et al. Leukocyte migration inhibition in amiodarone-associated pneumonitis. Chest . 1988; 94:1050-3. [PubMed 3053057]
333. Manolis AS, Tordjman T, Mack KD et al. Atypical pulmonary and neurologic complications of amiodarone in the same patient: report of a case and review of the literature. Arch Intern Med . 1987; 147:1805-9. [PubMed 3310943]
334. Kay GN, Epstein AE, Kirklin JK et al. Fatal postoperative amiodarone pulmonary toxicity. Am J Cardiol . 1988; 62:490-2. [PubMed 3414530]
335. Horowitz LN. Detection of amiodarone pulmonary toxicity: to screen or not to screen, that is the question! J Am Coll Cardiol . 1988; 12:789-90. Editorial.
336. Magro SA, Lawrence EC, Wheeler SH et al. Amiodarone pulmonary toxicity: prospective evaluation of serial pulmonary function tests. J Am Coll Cardiol . 1988; 12:781-8. [PubMed 3403839]
337. Zhu YY, Botvinick E, Dae M et al. Gallium lung scintigraphy in amiodarone pulmonary toxicity. Chest . 1988; 93:1126-31. [PubMed 3371091]
338. Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity: I. Recognition and pathogenesis. Chest . 1988; 93:1067-75. [PubMed 3282816]
339. Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity: II. Recognition and pathogenesis. Chest . 1988; 93:1242-8. [PubMed 3286141]
340. Figge J, Dluhy RG. Amiodarone-induced elevation of thyroid stimulating hormone in patients receiving levothyroxine for primary hypothyroidism. Ann Intern Med . 1990; 113:553-5. [PubMed 2393210]
341. Morse RM, Valenzuela GA, Greenwald TP et al. Amiodarone-induced liver toxicity. Ann Intern Med . 1988; 109:838-40. [PubMed 3190031]
342. Robinson K, Mulrow JP, Rowland E et al. Long-term effects of amiodarone on hepatic function. Am J Cardiol . 1989; 64:95-6. [PubMed 2741820]
343. Keung EC. Antiarrhythmic treatment and myocardial infarction. J Am Coll Cardiol . 1990; 16:1719-21. [PubMed 2254559]
344. Burkart F, Pfisterer M, Kiowski W et al. Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction with asymptomatic complex ventricular arrhythmias: Basel antiarrhythmic study of infarct survival (BASIS). J Am Coll Cardiol . 1990; 16:1711-8. [PubMed 2254558]
345. Martin WJ II. Mechanisms of amiodarone pulmonary toxicity. Clin Chest Med . 1990; 11:131-8. [PubMed 2182274]
346. Haas C, Hugues FC, Le Jeunne C. Drup-induced pleural pathology (excluding antineoplastic chemotherapy). (French; with English abstract.) Ann Med Interne . (Paris) 1989; 140:589-92.
347. Olivieri D, Pesci A, Bertorelli G. Eosinophilic alveolitis in immunologic interstitial lung disorder. Lung . 1990; 168(Suppl):964-73. [PubMed 2117217]
348. Terra Filho M, Vargas FS, Cukier A et al. Pneumonitis induced by amiodarone. (Portuguese; with English abstract.) Arq Bras Cardiol . 1989; 53:201-5.
349. Akoun GM, Milleron BJ, Badaro DM et al. Pleural T-lymphocyte subsets in amiodarone-associated pleuropneumonitis. Chest . 1989; 95:596-7. [PubMed 2784094]
350. Chrysanthopoulos C, Siablis D, Kounis NG. Amiodarone-induced recurrent allergic pneumonitis. Ann Allergy . 1988; 60:111-4. [PubMed 3341613]
351. Israel-Biet D, Venet A, Caubarrere I et al. Bronchoalveolar lavage in amiodarone pneumonitis: cellular abnormalities and their relevance to pathogenesis. Chest . 1987; 91:214-21. [PubMed 3802932]
352. Caubarrere I, Bonan G, Venet A et al. Pneumopathies caused by hypersensitivity to amiodarone and associated nephropathies: study by alveolar lavage. (French; with English abstract.) Ann Med Interne . (Paris) 1985; 136:311-5.
353. Venet A, Caubarrere I, Bonan G. Five cases of immune-mediated amiodarone pneumonitis. Lancet . 1984; 1:962-3. [PubMed 6143896]
354. Laurent M, Betremieux P, Biron Y et al. Neonatal hypothyroidism after treatment by amiodarone during pregnancy. Am J Cardiol . 1987; 60:942. [PubMed 3661421]
355. Abraxis Pharmaceutical Products. Amiodarone hydrochloride injection prescribing information. Schaumburg, IL; 2006 Sep.
356. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.
357. Deitch MW. Dear doctor letter regarding appropriate use of Cordarone®. Philadelphia, PA: Wyeth-Ayerst Laboratories; undated. (received 1997 June 30.)
358. Food and Drug Administration. Enkaid and Tambocor use in non-life-threatening arrhythmias halted. FDA Talk Paper . 1989 Apr 25.
359. The Cardiac Arrhythmia Suppression Trial (CAST) investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med . 1989; 321:406-12. [PubMed 2473403]
360. Ruskin JN. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med . 1989; 321:386-8. [PubMed 2501683]
361. Pratt CM, Brater DC, Harrell FE Jr et al. Clinical and regulatory implications of the Cardiac Arrhythmia Suppression Trial. Am J Cardiol . 1990; 65:103-5. [PubMed 1688479]
362. Anon. Restrictions on use of flecainide, encainide. FDA Drug Bull . 1989; 16.
363. Nightingale SL. Flecainide and encainide not to be used in non-life-threatening arrhythmias. JAMA . 1989; 261:3368. [PubMed 2498536]
364. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).
365. Scheinman MM, Levine JH, Cannom DS et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. Circulation . 1995; 92:3264-72. [PubMed 7586313]
366. Janssen Pharmaceuticals Inc. Levaquin® (levofloxacin) tablets, oral solution, concentrate for IV use, and solution for IV use prescribing information. Titusville, NJ; 2014 May.
367. Muir AD, Wilson M. Amiodarone and psoriasis. N Z Med J . 1982; 95:711. [PubMed 6959024]
368. Cairns JA, Connolly SJ, Roberts R et al. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisation: CAMIAT. Lancet . 1997; 349:675-82. [PubMed 9078198]
369. Sim I, McDonald KM, Lavori PW et al. Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation . 1997; 96:2823-9. [PubMed 9386144]
370. Julian DG, Camm AJ, Frangin G et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet . 1997; 349:667-74. [PubMed 9078197]
371. Merck & Co, Inc. Zocor® (simvastatin) tablets prescribing information. Whitehouse Station, NJ; 2008 Jun.
372. Doval HC, Nul DR, Grancelli HO et al. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet . 1994; 344:493-8. [PubMed 7914611]
373. Garguichevich JJ, Ramos JL, Gambarte A et al. Effect of amiodarone therapy on mortality in patients with left ventricular dysfunction and asymptomatic complex ventricular arrhythmias: Argentine pilot study of sudden death and amiodarone (EPAMSA). Am Heart J . 1995; 130:494-500. [PubMed 7661066]
374. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet . 1997; 350:1417-24. [PubMed 9371164]
375. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhytmic drug therapy in acute myocardial infarction. JAMA . 1993; 270:1589-95. [PubMed 8371471]
376. Norris RM. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1767. [PubMed 9193396]
377. Cleland JGF, Erhardt L. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1767. [PubMed 9193397]
378. Malik M, Camm AJ. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1767-8. [PubMed 9193398]
379. Incalzi RA. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1768. [PubMed 9193399]
380. Pinski SL. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1768. [PubMed 9193400]
381. Julian DG, Camm AJ. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1769.
382. Cairns JA, Connolly SJ, Roberts R et al. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1769-70.
383. Gottlieb SS. Amiodarone after myocardial infarction: EMIAT and CAMIAT trials. Lancet . 1997; 349:1770. [PubMed 9193401]
384. Camm AJ, Julian D, Janse G et al. The European Myocardial Infarct (EMIAT). Am J Cardiol . 1993; 72:95-98F. [PubMed 8517437]
385. Singh SN, Fletcher RD, Fisher SG et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med . 1995; 333:77-82. [PubMed 7539890]
386. Silver MJ, Young J, Topol EJ. Amiodarone in congestive heart failure. N Engl J Med . 1995; 333:1639-40. [PubMed 7477207]
387. Breithardt G. . Amiodarone in patients with heart failure. N Engl J Med . 1995; 333:121-2. [PubMed 7777017]
388. Bosch X, Bernadich. Acute pancreatitis during treatment with amiodarone. Lancet . 1997; 350:1300. [PubMed 9357418]
389. Vizioli LD, Cho S. Amiodarone-associated hemoptysis. Chest . 1994; 105:305-6. [PubMed 8275760]
390. Cheung B, Lam FM, Kumana CR. Insidiously evolving, occult drug interaction involving warfarin and amiodarone. BMJ . 1996; 312:106-7.
391. Gottlieb SS. Dead is dead—artificial definitions are no substitute. it/Lancet. 1997; 349:662-3. (IDIS 381353) ,RT>392.Richer M, Robert S. Fatal hepatoxicity following oral administration of amiodarone. Ann Pharmacother . 1995; 29:582-6. [PubMed 7663029]
393. Ceremuzynski L, Kleczar E, Krzeminska-Pakula M et al. Effect of amiodarone on mortality after myocardial infarction: a double-bliond, placebo-controlled, pilot study. J Am Coll Cardiol . 1992; 20:1056-62. [PubMed 1401602]
394. Cairns JA, Connolly SJ, Roberts R et al. Canadian amiodarone myocardial infarction arrhythmia trial (CAMIAT): rationale and protocol. Am J Cardiol . 1993; 72:87-94F.
395. Kudenchuk PJ, Cobb LA, Copass MK et al. Amiodarone for resuscitation after out-of-hosptal cardiac arrest due to venricular fibrillation. N Engl J Med . 1999; 341:871-8. [PubMed 10486418]
396. Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med . 1997; 127:294-303. [PubMed 9265430]
397. American College of Cardiology and American Heart Association. ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations. Circulation . 1999; 100:1016-1030. [PubMed 10468535]
398. Wyeth-Ayerst Laboratories. American Home Products Corporation's Cordarone® (amiodarone HCl) improved survival to hospital by 29%: published data offers hope to patients with life-threatening condition both insode and outside hospital setting. Press release. Madison, NJ; 1999 Sep 15.
401. Lui CY, Franchina JJ. Verapamil and multifocal atrial tachycardia. Ann Intern Med . 1988; 108:485-6.
402. Roy D, Talajic M, Dorian P et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med . 2000; 342:913-20. [PubMed 10738049]
403. Arsura EL, Scher DL. Verapamil and multifocal atrial tachycardia. Ann Intern Med. 1988; 108:486. Letter.
404. Scher DL, Arsura EL. Multifocal atrial tachycardia: mechanisms, clinical correlates, and treatment. Am Heart J. 1989; 118:574-80.
405. Arsura E, Lefkin AS, Scher DL et al. A randomized, double-blind, placebo-controlled study of verapamil and metoprolol in treatment of multifocal atrial tachycardia. Am J Med. 1988; 85:519-24. [Errtum: Am J Med. 1989; 86:142.]
406. Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol . 1995; 6:920-36. [PubMed 8548113]
407. Goldschlager N, Epstein AE, Naccarelli G et al. Practical guidelines for clinicans who treat patients with amiodarone. Arch Intern Med . 2000; 160:1741-8. [PubMed 10871966]
408. de Vane PJ. Dear doctor letter regarding off-label use of Cordarone® IV in pediatric patients. Philadelphia, PA: Wyeth-Ayerst Laboratories; 2001 March 21.
409. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics . 1983; 72:356-8. [PubMed 6889041]
410. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull . 1982; 12(2):10-11. [PubMed 7188569]
411. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR Morb Mortal Wkly Rep . 1982; 31:290-1. [PubMed 6810084]
412. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med . 1982; 307:1384-8. [PubMed 7133084]
413. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol . 1984; 1:288-92. [PubMed 6440575]
414. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol . 1984; 148:344-6. [PubMed 6695984]
415. NTP-CERHR expert panel report on di(2-ethylhexyl) phthalate. From the National Toxicology Program website. 2005 Nov 21 [Web]
416. Perry JC, Fenrich AL, Hulse JE et al. Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol. J Am Coll Cardiol . 1996; 27:1246-50. [PubMed 8609351]
417. Merck & Co, Inc. Mevacor® (lovastatin) tablets prescribing information. Whitehouse Station, NJ; 2008 Sep.
418. Landers MD, Reiter MJ. General principles of antiarrhythmic therapy for ventricular tachyarrhythmias. Am J Cardiol . 1997; 80(Suppl 8A):31-44G.
419. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardica arrhythmias. N Engl J Med . 2001; 345:1473-82. [PubMed 11794197]
420. Dorian P, Cass D, Schwartz B et al. Amiodarone as Compared with Lidocaine for Shock-Resistant Ventricular Fibrillation. N Engl J Med . 2002; 346:884-890. [PubMed 11907287]
421. Bigger JT. Expanding indications for implantable cardiac defibrillators. N Engl J Med . 2002; 346:931-3. [PubMed 11907294]
422. Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med . 2002; 346:877-83. [PubMed 11907286]
423. Connolly SJ, Hallstrom AP, Cappato R et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart J . 2000; 21:2071-8. [PubMed 11102258]
424. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med . 1997; 337:1576-83. [PubMed 9411221]
425. Connolly SJ, Gent M, Roberts RS et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation . 2000; 101:1297-302. [PubMed 10725290]
426. Hallstrom AP, McAnulty JH, Wilkoff BL et al. Patients at lower risk of arrhythmia recurrence: a subgroup in whom implantable defibrillators may not offer benefit. Antiarrhythmics Versus Implantable Defibrillator (AVID) Trial Investigators. J Am Coll Cardiol . 2001; 37:1093-9. [PubMed 11263614]
427. Gregoratos G, Cheitlin MD, Conill A et al. ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Pacemaker Implantation). J Am Coll Cardiol . 1998; 31:1175-209. [PubMed 9562026]
429. Johne A, Brockmoller J, Bauer S et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther . 1999; 66:338-45. [PubMed 10546917]
430. Ruschitzka F, Meier PJ, Turina M et al. Acute heart transplant rejection due to Saint John's wort. Lancet . 2000; 355:548-9. [PubMed 10683008]
431. Wyeth Pharmaceuticals. Cordarone® (amiodarone hydrochloride) medication guide. Philadelphia, PA; 2009 Aug.
432. Yamreudeewong W, DeBisschop M, Martin LG et al. Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf . 2003; 26:421-38. [PubMed 12688833]
433. Gate Pharmaceuticals. Orap® (pimozide) tablets prescribing information. Sellersville, PA; 2004 Jun.
434. Schering-Plough. Avelox® (moxifloxacin hydrochloride) tablets and injection prescribing information. Kenilworth, NJ; 2005 Dec.
435. Bayer HealthCare Pharmaceuticals Inc. Cipro® (ciprofloxacin hydrochloride) tablets and Cipro® (ciprofloxacin) for oral suspension prescribing information. Whippany, NJ; 2015 Feb.
436. Oscient Pharmaceuticals. Factive® (gemifloxacin mesylate) tablets prescribing information. Waltham, MA; 2004 Aug.
437. Pfizer Inc. Geodon® (ziprasidone hydrochloride) capsules and injection prescribing information. New York, NY; 2005 May.
438. Aventis Pharmaceuticals Inc. Anzemet® (dolasetron mesylate) tablets prescribing information. Kansas City, MO; 2005 Jun.
439. Desnick RJ, Brady R, Barranger J et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med . 2003; 138:338-46. [PubMed 12585833]
441. Eigel B. (American Heart Association, Dallas, TX): Personal communication; 2006 Apr 13.
442. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol . 2004; 44:671-719. [PubMed 15358045]
443. Upsher-Smith Laboratories, Inc. Pacerone® (amiodarone hydrochloride) tablets prescribing information. Minneapolis, MN. 2006 Apr.
444. SmithKline Beecham Pharmaceuticals. Halfan® (halofantrine hydrochloride) tablets prescribing information. Philadelphia, PA. 2001 Oct.
445. Larsen PR, Kronenberg HM, Melmed S et al. Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders, 2003. 354, 411-2.
446. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med . 2005; 118:706-14. [PubMed 15989900]
447. Field JM, Hazinski MF, Gilmore D, eds. Handbook of emergency cardiovascular care for healthcare providers. Dallas, TX: American Heart Association; 2006:89
448. Food and Drug Administration. Information for healthcare professionals: Simvastatin (marketed as Zocor and generics), ezetimibe/simvastatin (marketed as Vytorin), niacin extended-release/simvastatin (marketed as Simcor), used with amiodarone (Cordarone, Pacerone). 2008 Aug 8. From FDA website. Accessed 2008 Aug 12. [Web]
449. Schmidt GA, Hoehns JD, Purcell JL et al. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir. J Am Board Fam Med . 2007 Jul-Aug; 20:411-6.
450. Ricaurte B, Guirguis A, Taylor HC et al. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother . 2006; 40:753-7. [PubMed 16537817]
451. Roten L, Schoenenberger RA, Krähenbühl S et al. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother . 2004; 38:978-81. [PubMed 15069169]
452. Food and Drug Administration. FDA and Wyeth notified pharmacists and physicians of a new Medication Guide for amiodarone hydrochloride tablets (Cordarone, Pacerone). The FDA regulation 21CFR 208 requires a Medication Guide to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. The Medication Guide and current Prescribing Information for amiodarone hydrochloride and its generic equivalents are also provided below. For more information visit the FDA website at: [Web] and [Web].
453. US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral. 2015 Mar 24. From FDA website. [Web]
454. Gilead Sciences, Inc. Harvoni® (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Mar.
455. Gilead Sciences, Inc. Sovaldi® (sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Mar.
456. Janssen Therapeutics. Olysio® (simeprevir) capsules prescribing information. Titusville, NJ; 2015 Apr.
457. Bristol-Myers Squibb Company. Daklinza® (daclatasvir) tablets prescribing information. Princeton, NJ; 2015 Jul.
458. AbbVie, Inc. Viekira Pak® (ombitasvir, paritaprevir, and ritonavir copackaged with dasabuvir) tablets prescribing information. North Chicago, IL; 2015 Mar.
459. Valdes SO, Donoghue AJ, Hoyme DB et al. Outcomes associated with amiodarone and lidocaine in the treatment of in-hospital pediatric cardiac arrest with pulseless ventricular tachycardia or ventricular fibrillation. Resuscitation . 2014; 85:381-6. [PubMed 24361455]
460. ASHP. Standardize 4 Safety: pediatric continuous infusion standard. Updated 2025 June. From ASHP website. Updates may be available at ASHP website. [Web]
461. ASHP. Standardize 4 Safety: adult continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
462. ASHP. Standardize 4 Safety: compounded oral liquid standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website [Web]
463. Nahata MC. Stability of amiodarone in an oral suspension stored under refrigeration and at room temperature. Ann Pharmacother. 1997 Jul-Aug;31(7-8):851-2. doi: 10.1177/106002809703100707. PMID: 9220043.
464. Nahata MC, Morosco RS, Hipple TF. Stability of amiodarone in extemporaneous oral suspensions prepared from commercially available vehicles. J Pediatr Pharm Pract. 1999; 4:186-9.
500. Link MS, Berkow LC, Kudenchuk PJ et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S444-64.
501. Neumar RW, Otto CW, Link MS et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S729-67.
502. de Caen AR, Berg MD, Chameides L et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2015; 132(18 Suppl 2):S526-42. [PubMed 26473000]
503. Kleinman ME, Chameides L, Schexnayder SM et al. Part 14: pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S876-908.
700. Page RL, Joglar JA, Caldwell MA et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2016; 67:e27-e115.
701. January CT, Wann LS, Alpert JS et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2014; 64:e1-76. [PubMed 24685669]