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Cordarone I.V. (Amiodarone HCl)
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Pharmacology
Amiodarone is generally considered a ClassIII antiarrhythmic drug, but it possesses electrophysiologic characteristics of all4 Vaughan Williams classes. Like Class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like ClassII drugs, it exerts antisympathetic activity. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a ClassIII effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of Class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness (ClassIII effect). The antisympathetic action and block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node.
Additionally, amiodarone has vasodilatory action that can decrease cardiac workload and consequently myocardial oxygen consumption.
At higher doses (>10mg/kg) of amiodaronei.v., prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and i.v. administration suggest that the initial acute effects of amiodaronei.v. may be predominantly focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to calcium channel blockade (ClassIV activity) and b-adrenoreceptor antagonism (ClassII activity).
Pharmacodynamics: Amiodarone has been reported to produce negative inotropic and vasodilating effects in animals and humans. After long-term treatment with oral amiodarone in a dose range of 200to 600mg/day, patients with decreased left ventricular ejection fraction (LVEF) show no significant change in mean LVEF. Hypotension is uncommon (<1%) during chronic oral amiodarone therapy. In clinical studies of patients with refractory ventricular fibrillation(VF) or hemodynamically unstable ventricular tachycardia (VT), drug-related hypotension occurred in 15.6% of 1836 patients treated with amiodarone i.v. No correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of amiodarone i.v.
Clinical Trials: I.V.: A placebo-controlled study of i.v. amiodarone in patients with supraventricular arrhythmias and 2- to 3-consecutive beat ventricular arrhythmias, and a pharmacokinetic/pharmacodynamic study evaluating rapid i.v. loading in patients with recurrent, refractory VT/VF have shown rapid onset of antiarrhythmic activity well before significant blood levels of desethylamiodarone (DEA) were present; approximately 1500mg/day of i.v. amiodarone were administered using 2-and 3-stage infusion regimens. In the patients with complex ventricular arrhythmias, including sustained and nonsustained VT, amiodarone therapy reduced episodes of VT by 85%.
The acute effectiveness of amiodaronei.v. in suppressing recurrent VF or hemodynamically unstable VT is supported by 2randomized, parallel, dose-response studies of approximately 300patients each. In these studies, patients with at least 2episodes of VF or hemodynamically unstable VT in the preceding 24hours were randomly assigned to receive doses of approximately 125 or 1000mg over the first 24hours, an 8-fold difference. In one study, a middle dose of approximately 500mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional supplemental infusions of 150mg were given for “breakthrough” VT/VF more frequently to the 125-mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the 2studies.
The prospectively defined primary efficacy end point was theof VT/VF episodes/hour. For both studies, the median rate was 0.02episodes/hour in patients receiving the high dose and 0.07episodes/hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes/day (p=0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including amiodaronei.v.) was deemed necessary.
Pharmacokinetics: The absorption of oral amiodarone is slow and variable, with peak serum amiodarone concentrations being attained at 3to 12hours after administration. Absorption may continue for up to 15hours after oral ingestion. There is extensive intersubject variation: mean oral bioavailability is approximately 50% (mean range, 33% to 65%). First-pass metabolism in the gut wall and liver appears to be an important factor in determining the systemic availability of the drug. The mean terminal half-life after steady-state administration is approximately 53 days and has been found in one study (n=8) to range from 26 to 107days. Since at least 3to 4half-lives are needed to approach steady-state concentrations, loading doses must be administered at the onset of oral amiodarone therapy. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.
Food increases the rate and extent of absorption of amiodarone. The effects of food upon the bioavailability of amiodarone have been studied in 30healthy subjects who received a single 600mg dose both immediately after consuming a meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increase by as much as 2.4 and 3.8 times, respectively, in the presence of food. Food also increased the rate of absorption, decreasing the time to peak plasma concentration (Tmax) by 37%.
Amiodarone has a very high apparent volume of distribution (approximately 5000L) with an extensive accumulation in tissues, especially adipose tissues, and in highly perfused organs such as liver, lung, spleen, heart and kidney. One major metabolite of amiodarone, desethylamiodarone, has been identified, but the pharmacological activity of this metabolite is not known in humans. During chronic treatment, the plasma ratio of metabolite to parent compound approximates1.
Amiodarone exhibits complex disposition characteristics after i.v. administration. Peak serum concentrations after single 5mg/kg 15-minute i.v. infusions in healthy subjects range between 5and 41mg/L. Peak concentrations after 150mg supplemental infusions in patients with VF or hemodynamically unstable VT range between 7and 26mg/L. Due to rapid disposition, serum concentrations decline to 10% of peak values within 30to 45minutes after the end of the infusion. In clinical trials, after 48hours of continued infusions (125, 500 or 1000mg/day) plus supplemental (150mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4mg/L were observed (n=260).
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. Desethylamiodarone (DEA) is the major active metabolite of amiodarone. At the usual amiodarone daily maintenance dose of 400mg, mean steady-state DEA/amiodarone ratios ranged from 0.61 to 0.93. High-dose oral amiodarone loading in patients yielded 24-hour DEA/amiodarone ratios of 0.083 to 0.19. High-dose i.v. loading yielded a mean 24-hour DEA/amiodarone ratio of 0.041. No data are presently available on the activity of DEA in humans, but animal studies have shown that it has significant electrophysiologic and antiarrhythmic properties. The major enzyme responsible for the N-deethylation to DEA is believed to be cytochrome P-4503A4. Large interindividual variability in CYP-4503A4 activity may explain the variable systemic availability of amiodarone. DEA is highly lipophilic and has a very large apparent volume of distribution, showing a higher concentration than amiodarone in all tissue except fat at steady state. Myocardial concentrations of DEA are approximately 3- to 4.5-fold greater than those of amiodarone during long-term oral amiodarone therapy. However, after either acute oral or acute i.v. administration, both mean serum and mean myocardial DEA concentrations are quite low compared to those of amiodarone.
There is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. Amiodarone and DEA cross the placenta and both appear in breast milk.
During chronic treatment with oral amiodarone, close monitoring may be prudent for elderly patients and those with severe left ventricular dysfunction. However, during short-term i.v. use, age, sex, renal disease and hepatic disease (cirrhosis) do not have clinically significant effects on the disposition of amiodarone and DEA. No dosage adjustment is necessary for patients in any of these populations.
There is no well-established relationship between drug concentration and therapeutic response for long-term oral or short-term i.v. use. Steady-state amiodarone concentrations of 1 to 2.5mg/L, however, have been effective with minimal toxicity following chronic oral amiodarone.
Amiodarone is generally considered a ClassIII antiarrhythmic drug, but it possesses electrophysiologic characteristics of all4 Vaughan Williams classes. Like Class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like ClassII drugs, it exerts antisympathetic activity. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a ClassIII effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of Class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness (ClassIII effect). The antisympathetic action and block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node.
Additionally, amiodarone has vasodilatory action that can decrease cardiac workload and consequently myocardial oxygen consumption.
At higher doses (>10mg/kg) of amiodaronei.v., prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and i.v. administration suggest that the initial acute effects of amiodaronei.v. may be predominantly focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to calcium channel blockade (ClassIV activity) and b-adrenoreceptor antagonism (ClassII activity).
Pharmacodynamics: Amiodarone has been reported to produce negative inotropic and vasodilating effects in animals and humans. After long-term treatment with oral amiodarone in a dose range of 200to 600mg/day, patients with decreased left ventricular ejection fraction (LVEF) show no significant change in mean LVEF. Hypotension is uncommon (<1%) during chronic oral amiodarone therapy. In clinical studies of patients with refractory ventricular fibrillation(VF) or hemodynamically unstable ventricular tachycardia (VT), drug-related hypotension occurred in 15.6% of 1836 patients treated with amiodarone i.v. No correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of amiodarone i.v.
Clinical Trials: I.V.: A placebo-controlled study of i.v. amiodarone in patients with supraventricular arrhythmias and 2- to 3-consecutive beat ventricular arrhythmias, and a pharmacokinetic/pharmacodynamic study evaluating rapid i.v. loading in patients with recurrent, refractory VT/VF have shown rapid onset of antiarrhythmic activity well before significant blood levels of desethylamiodarone (DEA) were present; approximately 1500mg/day of i.v. amiodarone were administered using 2-and 3-stage infusion regimens. In the patients with complex ventricular arrhythmias, including sustained and nonsustained VT, amiodarone therapy reduced episodes of VT by 85%.
The acute effectiveness of amiodaronei.v. in suppressing recurrent VF or hemodynamically unstable VT is supported by 2randomized, parallel, dose-response studies of approximately 300patients each. In these studies, patients with at least 2episodes of VF or hemodynamically unstable VT in the preceding 24hours were randomly assigned to receive doses of approximately 125 or 1000mg over the first 24hours, an 8-fold difference. In one study, a middle dose of approximately 500mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional supplemental infusions of 150mg were given for “breakthrough” VT/VF more frequently to the 125-mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the 2studies.
The prospectively defined primary efficacy end point was theof VT/VF episodes/hour. For both studies, the median rate was 0.02episodes/hour in patients receiving the high dose and 0.07episodes/hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes/day (p=0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including amiodaronei.v.) was deemed necessary.
Pharmacokinetics: The absorption of oral amiodarone is slow and variable, with peak serum amiodarone concentrations being attained at 3to 12hours after administration. Absorption may continue for up to 15hours after oral ingestion. There is extensive intersubject variation: mean oral bioavailability is approximately 50% (mean range, 33% to 65%). First-pass metabolism in the gut wall and liver appears to be an important factor in determining the systemic availability of the drug. The mean terminal half-life after steady-state administration is approximately 53 days and has been found in one study (n=8) to range from 26 to 107days. Since at least 3to 4half-lives are needed to approach steady-state concentrations, loading doses must be administered at the onset of oral amiodarone therapy. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.
Food increases the rate and extent of absorption of amiodarone. The effects of food upon the bioavailability of amiodarone have been studied in 30healthy subjects who received a single 600mg dose both immediately after consuming a meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increase by as much as 2.4 and 3.8 times, respectively, in the presence of food. Food also increased the rate of absorption, decreasing the time to peak plasma concentration (Tmax) by 37%.
Amiodarone has a very high apparent volume of distribution (approximately 5000L) with an extensive accumulation in tissues, especially adipose tissues, and in highly perfused organs such as liver, lung, spleen, heart and kidney. One major metabolite of amiodarone, desethylamiodarone, has been identified, but the pharmacological activity of this metabolite is not known in humans. During chronic treatment, the plasma ratio of metabolite to parent compound approximates1.
Amiodarone exhibits complex disposition characteristics after i.v. administration. Peak serum concentrations after single 5mg/kg 15-minute i.v. infusions in healthy subjects range between 5and 41mg/L. Peak concentrations after 150mg supplemental infusions in patients with VF or hemodynamically unstable VT range between 7and 26mg/L. Due to rapid disposition, serum concentrations decline to 10% of peak values within 30to 45minutes after the end of the infusion. In clinical trials, after 48hours of continued infusions (125, 500 or 1000mg/day) plus supplemental (150mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4mg/L were observed (n=260).
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. Desethylamiodarone (DEA) is the major active metabolite of amiodarone. At the usual amiodarone daily maintenance dose of 400mg, mean steady-state DEA/amiodarone ratios ranged from 0.61 to 0.93. High-dose oral amiodarone loading in patients yielded 24-hour DEA/amiodarone ratios of 0.083 to 0.19. High-dose i.v. loading yielded a mean 24-hour DEA/amiodarone ratio of 0.041. No data are presently available on the activity of DEA in humans, but animal studies have shown that it has significant electrophysiologic and antiarrhythmic properties. The major enzyme responsible for the N-deethylation to DEA is believed to be cytochrome P-4503A4. Large interindividual variability in CYP-4503A4 activity may explain the variable systemic availability of amiodarone. DEA is highly lipophilic and has a very large apparent volume of distribution, showing a higher concentration than amiodarone in all tissue except fat at steady state. Myocardial concentrations of DEA are approximately 3- to 4.5-fold greater than those of amiodarone during long-term oral amiodarone therapy. However, after either acute oral or acute i.v. administration, both mean serum and mean myocardial DEA concentrations are quite low compared to those of amiodarone.
There is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. Amiodarone and DEA cross the placenta and both appear in breast milk.
During chronic treatment with oral amiodarone, close monitoring may be prudent for elderly patients and those with severe left ventricular dysfunction. However, during short-term i.v. use, age, sex, renal disease and hepatic disease (cirrhosis) do not have clinically significant effects on the disposition of amiodarone and DEA. No dosage adjustment is necessary for patients in any of these populations.
There is no well-established relationship between drug concentration and therapeutic response for long-term oral or short-term i.v. use. Steady-state amiodarone concentrations of 1 to 2.5mg/L, however, have been effective with minimal toxicity following chronic oral amiodarone.
Indications
Amiodarone Is Generally Considered A ClassIII Antiarrhythmic Drug, But It Possesses Electrophysiologic Characteristics Of All4 Vaughan Williams Classes. Like Class I Drugs, Amiodarone Blocks Sodium Channels At Rapid Pacing Frequencies, And Like ClassII Drugs, It Exerts Antisympathetic Activity. One Of Its Main Effects, With Prolonged Administration, Is To Lengthen The Cardiac Action Potential, A ClassIII Effect. The Negative Chronotropic Effect Of Amiodarone In Nodal Tissues Is Similar To The Effect Of Class IV Drugs. In Addition To Blocking Sodium Channels, Amiodarone Blocks Myocardial Potassium Channels, Which Contributes To Slowing Of Conduction And Prolongation Of Refractoriness (ClassIII Effect). The Antisympathetic Action And Block Of Calcium And Potassium Channels Are Responsible For The Negative Dromotropic Effects On The Sinus Node And For The Slowing Of Conduction And Prolongation Of Refractoriness In The Atrioventricular (AV) Node.
Additionally, Amiodarone Has Vasodilatory Action That Can Decrease Cardiac Workload And Consequently Myocardial Oxygen Consumption.
At Higher Doses (>10mg/kg) Of Amiodaronei.v., Prolongation Of The ERP RV And Modest Prolongation Of The QRS Have Been Seen. These Differences Between Oral And I.v. Administration Suggest That The Initial Acute Effects Of Amiodaronei.v. May Be Predominantly Focused On The AV Node, Causing An Intranodal Conduction Delay And Increased Nodal Refractoriness Due To Calcium Channel Blockade (ClassIV Activity) And B-adrenoreceptor Antagonism (ClassII Activity).
Pharmacodynamics: Amiodarone Has Been Reported To Produce Negative Inotropic And Vasodilating Effects In Animals And Humans. After Long-term Treatment With Oral Amiodarone In A Dose Range Of 200to 600mg/day, Patients With Decreased Left Ventricular Ejection Fraction (LVEF) Show No Significant Change In Mean LVEF. Hypotension Is Uncommon (<1%) During Chronic Oral Amiodarone Therapy. In Clinical Studies Of Patients With Refractory Ventricular Fibrillation(VF) Or Hemodynamically Unstable Ventricular Tachycardia (VT), Drug-related Hypotension Occurred In 15.6% Of 1836 Patients Treated With Amiodarone I.v. No Correlations Were Seen Between The Baseline Ejection Fraction And The Occurrence Of Clinically Significant Hypotension During Infusion Of Amiodarone I.v.
Clinical Trials: I.V.: A Placebo-controlled Study Of I.v. Amiodarone In Patients With Supraventricular Arrhythmias And 2- To 3-consecutive Beat Ventricular Arrhythmias, And A Pharmacokinetic/pharmacodynamic Study Evaluating Rapid I.v. Loading In Patients With Recurrent, Refractory VT/VF Have Shown Rapid Onset Of Antiarrhythmic Activity Well Before Significant Blood Levels Of Desethylamiodarone (DEA) Were Present; Approximately 1500mg/day Of I.v. Amiodarone Were Administered Using 2-and 3-stage Infusion Regimens. In The Patients With Complex Ventricular Arrhythmias, Including Sustained And Nonsustained VT, Amiodarone Therapy Reduced Episodes Of VT By 85%.
The Acute Effectiveness Of Amiodaronei.v. In Suppressing Recurrent VF Or Hemodynamically Unstable VT Is Supported By 2randomized, Parallel, Dose-response Studies Of Approximately 300patients Each. In These Studies, Patients With At Least 2episodes Of VF Or Hemodynamically Unstable VT In The Preceding 24hours Were Randomly Assigned To Receive Doses Of Approximately 125 Or 1000mg Over The First 24hours, An 8-fold Difference. In One Study, A Middle Dose Of Approximately 500mg Was Evaluated. The Dose Regimen Consisted Of An Initial Rapid Loading Infusion, Followed By A Slower 6-hour Loading Infusion, And Then An 18-hour Maintenance Infusion. The Maintenance Infusion Was Continued Up To Hour 48. Additional Supplemental Infusions Of 150mg Were Given For “breakthrough” VT/VF More Frequently To The 125-mg Dose Group, Thereby Considerably Reducing The Planned 8-fold Differences In Total Dose To 1.8- And 2.6-fold, Respectively, In The 2studies.
The Prospectively Defined Primary Efficacy End Point Was Theof VT/VF Episodes/hour. For Both Studies, The Median Rate Was 0.02episodes/hour In Patients Receiving The High Dose And 0.07episodes/hour In Patients Receiving The Low Dose, Or Approximately 0.5 Versus 1.7 Episodes/day (p=0.07, 2-sided, In Both Studies). In One Study, The Time To First Episode Of VT/VF Was Significantly Prolonged (approximately 10 Hours In Patients Receiving The Low Dose And 14hours In Patients Receiving The High Dose). In Both Studies, Significantly Fewer Supplemental Infusions Were Given To Patients In The High-dose Group. Mortality Was Not Affected In These Studies; At The End Of Double-blind Therapy Or After 48 Hours, All Patients Were Given Open Access To Whatever Treatment (including Amiodaronei.v.) Was Deemed Necessary.
Pharmacokinetics: The Absorption Of Oral Amiodarone Is Slow And Variable, With Peak Serum Amiodarone Concentrations Being Attained At 3to 12hours After Administration. Absorption May Continue For Up To 15hours After Oral Ingestion. There Is Extensive Intersubject Variation: Mean Oral Bioavailability Is Approximately 50% (mean Range, 33% To 65%). First-pass Metabolism In The Gut Wall And Liver Appears To Be An Important Factor In Determining The Systemic Availability Of The Drug. The Mean Terminal Half-life After Steady-state Administration Is Approximately 53 Days And Has Been Found In One Study (n=8) To Range From 26 To 107days. Since At Least 3to 4half-lives Are Needed To Approach Steady-state Concentrations, Loading Doses Must Be Administered At The Onset Of Oral Amiodarone Therapy. In The Absence Of A Loading-dose Period, Steady-state Plasma Concentrations, At Constant Oral Dosing, Would Therefore Be Reached Between 130 And 535 Days, With An Average Of 265 Days. For The Metabolite, The Mean Plasma-elimination Half-life Was Approximately 61 Days. These Data Probably Reflect An Initial Elimination Of Drug From Well-perfused Tissue (the 2.5- To 10-day Half-life Phase), Followed By A Terminal Phase Representing Extremely Slow Elimination From Poorly Perfused Tissue Compartments Such As Fat.
Food Increases The Rate And Extent Of Absorption Of Amiodarone. The Effects Of Food Upon The Bioavailability Of Amiodarone Have Been Studied In 30healthy Subjects Who Received A Single 600mg Dose Both Immediately After Consuming A Meal And Following An Overnight Fast. The Area Under The Plasma Concentration-time Curve (AUC) And The Peak Plasma Concentration (Cmax) Of Amiodarone Increase By As Much As 2.4 And 3.8 Times, Respectively, In The Presence Of Food. Food Also Increased The Rate Of Absorption, Decreasing The Time To Peak Plasma Concentration (Tmax) By 37%.
Amiodarone Has A Very High Apparent Volume Of Distribution (approximately 5000L) With An Extensive Accumulation In Tissues, Especially Adipose Tissues, And In Highly Perfused Organs Such As Liver, Lung, Spleen, Heart And Kidney. One Major Metabolite Of Amiodarone, Desethylamiodarone, Has Been Identified, But The Pharmacological Activity Of This Metabolite Is Not Known In Humans. During Chronic Treatment, The Plasma Ratio Of Metabolite To Parent Compound Approximates1.
Amiodarone Exhibits Complex Disposition Characteristics After I.v. Administration. Peak Serum Concentrations After Single 5mg/kg 15-minute I.v. Infusions In Healthy Subjects Range Between 5and 41mg/L. Peak Concentrations After 150mg Supplemental Infusions In Patients With VF Or Hemodynamically Unstable VT Range Between 7and 26mg/L. Due To Rapid Disposition, Serum Concentrations Decline To 10% Of Peak Values Within 30to 45minutes After The End Of The Infusion. In Clinical Trials, After 48hours Of Continued Infusions (125, 500 Or 1000mg/day) Plus Supplemental (150mg) Infusions (for Recurrent Arrhythmias), Amiodarone Mean Serum Concentrations Between 0.7 To 1.4mg/L Were Observed (n=260).
Amiodarone Is Eliminated Primarily By Hepatic Metabolism And Biliary Excretion. Desethylamiodarone (DEA) Is The Major Active Metabolite Of Amiodarone. At The Usual Amiodarone Daily Maintenance Dose Of 400mg, Mean Steady-state DEA/amiodarone Ratios Ranged From 0.61 To 0.93. High-dose Oral Amiodarone Loading In Patients Yielded 24-hour DEA/amiodarone Ratios Of 0.083 To 0.19. High-dose I.v. Loading Yielded A Mean 24-hour DEA/amiodarone Ratio Of 0.041. No Data Are Presently Available On The Activity Of DEA In Humans, But Animal Studies Have Shown That It Has Significant Electrophysiologic And Antiarrhythmic Properties. The Major Enzyme Responsible For The N-deethylation To DEA Is Believed To Be Cytochrome P-4503A4. Large Interindividual Variability In CYP-4503A4 Activity May Explain The Variable Systemic Availability Of Amiodarone. DEA Is Highly Lipophilic And Has A Very Large Apparent Volume Of Distribution, Showing A Higher Concentration Than Amiodarone In All Tissue Except Fat At Steady State. Myocardial Concentrations Of DEA Are Approximately 3- To 4.5-fold Greater Than Those Of Amiodarone During Long-term Oral Amiodarone Therapy. However, After Either Acute Oral Or Acute I.v. Administration, Both Mean Serum And Mean Myocardial DEA Concentrations Are Quite Low Compared To Those Of Amiodarone.
There Is Negligible Excretion Of Amiodarone Or DEA In Urine. Neither Amiodarone Nor DEA Is Dialyzable. Amiodarone And DEA Cross The Placenta And Both Appear In Breast Milk.
During Chronic Treatment With Oral Amiodarone, Close Monitoring May Be Prudent For Elderly Patients And Those With Severe Left Ventricular Dysfunction. However, During Short-term I.v. Use, Age, Sex, Renal Disease And Hepatic Disease (cirrhosis) Do Not Have Clinically Significant Effects On The Disposition Of Amiodarone And DEA. No Dosage Adjustment Is Necessary For Patients In Any Of These Populations.
There Is No Well-established Relationship Between Drug Concentration And Therapeutic Response For Long-term Oral Or Short-term I.v. Use. Steady-state Amiodarone Concentrations Of 1 To 2.5mg/L, However, Have Been Effective With Minimal Toxicity Following Chronic Oral Amiodarone.
Amiodarone Is Generally Considered A ClassIII Antiarrhythmic Drug, But It Possesses Electrophysiologic Characteristics Of All4 Vaughan Williams Classes. Like Class I Drugs, Amiodarone Blocks Sodium Channels At Rapid Pacing Frequencies, And Like ClassII Drugs, It Exerts Antisympathetic Activity. One Of Its Main Effects, With Prolonged Administration, Is To Lengthen The Cardiac Action Potential, A ClassIII Effect. The Negative Chronotropic Effect Of Amiodarone In Nodal Tissues Is Similar To The Effect Of Class IV Drugs. In Addition To Blocking Sodium Channels, Amiodarone Blocks Myocardial Potassium Channels, Which Contributes To Slowing Of Conduction And Prolongation Of Refractoriness (ClassIII Effect). The Antisympathetic Action And Block Of Calcium And Potassium Channels Are Responsible For The Negative Dromotropic Effects On The Sinus Node And For The Slowing Of Conduction And Prolongation Of Refractoriness In The Atrioventricular (AV) Node.
Additionally, Amiodarone Has Vasodilatory Action That Can Decrease Cardiac Workload And Consequently Myocardial Oxygen Consumption.
At Higher Doses (>10mg/kg) Of Amiodaronei.v., Prolongation Of The ERP RV And Modest Prolongation Of The QRS Have Been Seen. These Differences Between Oral And I.v. Administration Suggest That The Initial Acute Effects Of Amiodaronei.v. May Be Predominantly Focused On The AV Node, Causing An Intranodal Conduction Delay And Increased Nodal Refractoriness Due To Calcium Channel Blockade (ClassIV Activity) And B-adrenoreceptor Antagonism (ClassII Activity).
Pharmacodynamics: Amiodarone Has Been Reported To Produce Negative Inotropic And Vasodilating Effects In Animals And Humans. After Long-term Treatment With Oral Amiodarone In A Dose Range Of 200to 600mg/day, Patients With Decreased Left Ventricular Ejection Fraction (LVEF) Show No Significant Change In Mean LVEF. Hypotension Is Uncommon (<1%) During Chronic Oral Amiodarone Therapy. In Clinical Studies Of Patients With Refractory Ventricular Fibrillation(VF) Or Hemodynamically Unstable Ventricular Tachycardia (VT), Drug-related Hypotension Occurred In 15.6% Of 1836 Patients Treated With Amiodarone I.v. No Correlations Were Seen Between The Baseline Ejection Fraction And The Occurrence Of Clinically Significant Hypotension During Infusion Of Amiodarone I.v.
Clinical Trials: I.V.: A Placebo-controlled Study Of I.v. Amiodarone In Patients With Supraventricular Arrhythmias And 2- To 3-consecutive Beat Ventricular Arrhythmias, And A Pharmacokinetic/pharmacodynamic Study Evaluating Rapid I.v. Loading In Patients With Recurrent, Refractory VT/VF Have Shown Rapid Onset Of Antiarrhythmic Activity Well Before Significant Blood Levels Of Desethylamiodarone (DEA) Were Present; Approximately 1500mg/day Of I.v. Amiodarone Were Administered Using 2-and 3-stage Infusion Regimens. In The Patients With Complex Ventricular Arrhythmias, Including Sustained And Nonsustained VT, Amiodarone Therapy Reduced Episodes Of VT By 85%.
The Acute Effectiveness Of Amiodaronei.v. In Suppressing Recurrent VF Or Hemodynamically Unstable VT Is Supported By 2randomized, Parallel, Dose-response Studies Of Approximately 300patients Each. In These Studies, Patients With At Least 2episodes Of VF Or Hemodynamically Unstable VT In The Preceding 24hours Were Randomly Assigned To Receive Doses Of Approximately 125 Or 1000mg Over The First 24hours, An 8-fold Difference. In One Study, A Middle Dose Of Approximately 500mg Was Evaluated. The Dose Regimen Consisted Of An Initial Rapid Loading Infusion, Followed By A Slower 6-hour Loading Infusion, And Then An 18-hour Maintenance Infusion. The Maintenance Infusion Was Continued Up To Hour 48. Additional Supplemental Infusions Of 150mg Were Given For “breakthrough” VT/VF More Frequently To The 125-mg Dose Group, Thereby Considerably Reducing The Planned 8-fold Differences In Total Dose To 1.8- And 2.6-fold, Respectively, In The 2studies.
The Prospectively Defined Primary Efficacy End Point Was Theof VT/VF Episodes/hour. For Both Studies, The Median Rate Was 0.02episodes/hour In Patients Receiving The High Dose And 0.07episodes/hour In Patients Receiving The Low Dose, Or Approximately 0.5 Versus 1.7 Episodes/day (p=0.07, 2-sided, In Both Studies). In One Study, The Time To First Episode Of VT/VF Was Significantly Prolonged (approximately 10 Hours In Patients Receiving The Low Dose And 14hours In Patients Receiving The High Dose). In Both Studies, Significantly Fewer Supplemental Infusions Were Given To Patients In The High-dose Group. Mortality Was Not Affected In These Studies; At The End Of Double-blind Therapy Or After 48 Hours, All Patients Were Given Open Access To Whatever Treatment (including Amiodaronei.v.) Was Deemed Necessary.
Pharmacokinetics: The Absorption Of Oral Amiodarone Is Slow And Variable, With Peak Serum Amiodarone Concentrations Being Attained At 3to 12hours After Administration. Absorption May Continue For Up To 15hours After Oral Ingestion. There Is Extensive Intersubject Variation: Mean Oral Bioavailability Is Approximately 50% (mean Range, 33% To 65%). First-pass Metabolism In The Gut Wall And Liver Appears To Be An Important Factor In Determining The Systemic Availability Of The Drug. The Mean Terminal Half-life After Steady-state Administration Is Approximately 53 Days And Has Been Found In One Study (n=8) To Range From 26 To 107days. Since At Least 3to 4half-lives Are Needed To Approach Steady-state Concentrations, Loading Doses Must Be Administered At The Onset Of Oral Amiodarone Therapy. In The Absence Of A Loading-dose Period, Steady-state Plasma Concentrations, At Constant Oral Dosing, Would Therefore Be Reached Between 130 And 535 Days, With An Average Of 265 Days. For The Metabolite, The Mean Plasma-elimination Half-life Was Approximately 61 Days. These Data Probably Reflect An Initial Elimination Of Drug From Well-perfused Tissue (the 2.5- To 10-day Half-life Phase), Followed By A Terminal Phase Representing Extremely Slow Elimination From Poorly Perfused Tissue Compartments Such As Fat.
Food Increases The Rate And Extent Of Absorption Of Amiodarone. The Effects Of Food Upon The Bioavailability Of Amiodarone Have Been Studied In 30healthy Subjects Who Received A Single 600mg Dose Both Immediately After Consuming A Meal And Following An Overnight Fast. The Area Under The Plasma Concentration-time Curve (AUC) And The Peak Plasma Concentration (Cmax) Of Amiodarone Increase By As Much As 2.4 And 3.8 Times, Respectively, In The Presence Of Food. Food Also Increased The Rate Of Absorption, Decreasing The Time To Peak Plasma Concentration (Tmax) By 37%.
Amiodarone Has A Very High Apparent Volume Of Distribution (approximately 5000L) With An Extensive Accumulation In Tissues, Especially Adipose Tissues, And In Highly Perfused Organs Such As Liver, Lung, Spleen, Heart And Kidney. One Major Metabolite Of Amiodarone, Desethylamiodarone, Has Been Identified, But The Pharmacological Activity Of This Metabolite Is Not Known In Humans. During Chronic Treatment, The Plasma Ratio Of Metabolite To Parent Compound Approximates1.
Amiodarone Exhibits Complex Disposition Characteristics After I.v. Administration. Peak Serum Concentrations After Single 5mg/kg 15-minute I.v. Infusions In Healthy Subjects Range Between 5and 41mg/L. Peak Concentrations After 150mg Supplemental Infusions In Patients With VF Or Hemodynamically Unstable VT Range Between 7and 26mg/L. Due To Rapid Disposition, Serum Concentrations Decline To 10% Of Peak Values Within 30to 45minutes After The End Of The Infusion. In Clinical Trials, After 48hours Of Continued Infusions (125, 500 Or 1000mg/day) Plus Supplemental (150mg) Infusions (for Recurrent Arrhythmias), Amiodarone Mean Serum Concentrations Between 0.7 To 1.4mg/L Were Observed (n=260).
Amiodarone Is Eliminated Primarily By Hepatic Metabolism And Biliary Excretion. Desethylamiodarone (DEA) Is The Major Active Metabolite Of Amiodarone. At The Usual Amiodarone Daily Maintenance Dose Of 400mg, Mean Steady-state DEA/amiodarone Ratios Ranged From 0.61 To 0.93. High-dose Oral Amiodarone Loading In Patients Yielded 24-hour DEA/amiodarone Ratios Of 0.083 To 0.19. High-dose I.v. Loading Yielded A Mean 24-hour DEA/amiodarone Ratio Of 0.041. No Data Are Presently Available On The Activity Of DEA In Humans, But Animal Studies Have Shown That It Has Significant Electrophysiologic And Antiarrhythmic Properties. The Major Enzyme Responsible For The N-deethylation To DEA Is Believed To Be Cytochrome P-4503A4. Large Interindividual Variability In CYP-4503A4 Activity May Explain The Variable Systemic Availability Of Amiodarone. DEA Is Highly Lipophilic And Has A Very Large Apparent Volume Of Distribution, Showing A Higher Concentration Than Amiodarone In All Tissue Except Fat At Steady State. Myocardial Concentrations Of DEA Are Approximately 3- To 4.5-fold Greater Than Those Of Amiodarone During Long-term Oral Amiodarone Therapy. However, After Either Acute Oral Or Acute I.v. Administration, Both Mean Serum And Mean Myocardial DEA Concentrations Are Quite Low Compared To Those Of Amiodarone.
There Is Negligible Excretion Of Amiodarone Or DEA In Urine. Neither Amiodarone Nor DEA Is Dialyzable. Amiodarone And DEA Cross The Placenta And Both Appear In Breast Milk.
During Chronic Treatment With Oral Amiodarone, Close Monitoring May Be Prudent For Elderly Patients And Those With Severe Left Ventricular Dysfunction. However, During Short-term I.v. Use, Age, Sex, Renal Disease And Hepatic Disease (cirrhosis) Do Not Have Clinically Significant Effects On The Disposition Of Amiodarone And DEA. No Dosage Adjustment Is Necessary For Patients In Any Of These Populations.
There Is No Well-established Relationship Between Drug Concentration And Therapeutic Response For Long-term Oral Or Short-term I.v. Use. Steady-state Amiodarone Concentrations Of 1 To 2.5mg/L, However, Have Been Effective With Minimal Toxicity Following Chronic Oral Amiodarone.
Contraindications
In patients with known hypersensitivity to any of the components of oral amiodarone (tablets) or amiodaronei.v., and in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block unless a functioning pacemaker is available. In addition, oral amiodarone is contraindicated in patients with evidence of acute hepatitis (see Precautions), thyroid dysfunction (see Warnings), or pulmonary interstitial abnormalities.
In patients with known hypersensitivity to any of the components of oral amiodarone (tablets) or amiodaronei.v., and in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block unless a functioning pacemaker is available. In addition, oral amiodarone is contraindicated in patients with evidence of acute hepatitis (see Precautions), thyroid dysfunction (see Warnings), or pulmonary interstitial abnormalities.
Safety Information / Warning
Oral: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in postmyocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in nonfatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine- and placebo-treatment groups only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine-treated group.
The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present, it is prudent to consider these results when using any antiarrhythmic agent.
Cordarone therapy was evaluated in 2multicentre, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200mg/day.
These data are consistent with the results of a pooled analysis of 13 smaller, controlled studies involving patients with structural heart disease (including myocardial infarction) where total mortality was reduced by only 13% (odds ratio 0.87, [95% confidence interval 0.75 to 0.99] p=0.03) based on classic fixed effects meta-analysis.
Thyroid Dysfunction: Amiodarone inhibits peripheral conversion of thyroxine (T 4) to triiodothyronine (T 3) and may cause increased thyroxine levels, decreased T 3 levels, and increased levels of inactive reverse T 3 (rT 3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Both hyper- and hypothyroidism may occur during, or soon after treatment with oral amiodarone. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone withdrawal.
Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by amiodarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone in some patients.
Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of arrhythmia breakthrough or aggravation. In fact, if any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T 3 RIA, and further elevations of serum T 4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. The institution of antithyroid drugs, beta-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Experience with thyroid surgery in this setting is extremely limited, and this form of therapy runs the theoretical risk of inducing thyroid storm. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism.
In a rat carcinogenicity study, at doses of 5, 16 and 50mg/kg/day, amiodarone produced statistically significant dose-related changes in the thyroid gland, including follicular adenomas and carcinomas. The significance of these changes for the long-term use of amiodarone in humans is unknown.
Neonatal Hypo- or Hyperthyroidism: Pregnancy: Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If amiodarone is used during pregnancy, or if the patient becomes pregnant while taking amiodarone, the patient should be apprised of the potential hazard to the fetus.
In general, amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus.
In pregnant rats and rabbits, amiodarone in doses of 25mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose*.) Adverse effects on fetal growth and survival also were noted in 1of 2strains of mice at a dose of 5mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*.)
*600mg in a 50kg patient (doses compared on a body surface area basis).
Loss of Vision: Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of amiodarone therapy. The risks and complications of antiarrhythmic therapy with amiodarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including fundoscopy and slit-lamp examination, is recommended during administration of amiodarone (see Adverse Effects).
I.V. and Oral: Pulmonary Toxicity: One of the most serious complications resulting from oral amiodarone therapy is pulmonary toxicity, characterized by pneumonitis. Clinical symptoms include cough, dyspnea, weight loss and weakness. On chest x-ray, there is a diffuse interstitial pattern of lung involvement frequently with patchy alveolar infiltrates, particularly in the upper lobe. Predicting which patient will develop pulmonary toxicity has been difficult (see Contraindications). Pulmonary toxicity can appear abruptly either early or late during therapy, and it commonly mimics viral or bacterial infection or worsening congestive heart failure. The relationship of pulmonary toxicity to duration of therapy, maintenance dose and total dose is unclear. The majority of patients have recovered with this management, although some fatalities have occurred. Therefore, when amiodarone therapy is initiated, a baseline chest x-ray and pulmonary function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam and chest x-ray every 3to 6months.
Pulmonary toxicity secondary to amiodarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis or interstitial/alveolar pneumonitis, respectively at rates as high as 10to 17% in patients with ventricular arrhythmias given doses around 400mg/day. Pulmonary toxicity has been fatal about 10% of the time.
Hypersensitivity pneumonitis usually appears earlier in the course of therapy and rechallenging these patients with amiodarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and amiodarone therapy discontinued in these patients.
Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of amiodarone-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of amiodarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably to withdrawal of the amiodarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first 2to 3weeks. Chest x-ray changes usually resolve within 2to 4months. According to some experts steroids may prove beneficial. Prednisone in doses of 40to 60mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with amiodarone at a lower dose has not resulted in return of toxicity. Recent reports suggest that the use of lower loading and maintenance doses of amiodarone are associated with a decreased incidence of amiodarone-induced pulmonary toxicity.
In a patient receiving amiodarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest x-ray and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup.
Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with lifethreatening arrhythmias, discontinuation of amiodarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy etc.) before discontinuing amiodarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available.
If a diagnosis of amiodarone-induced hypersensitivity pneumonitis is made, amiodarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of amiodarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, amiodarone discontinued or, at a minimum, reduced in dosage. Some cases of amiodarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in amiodarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible.
Only 1 of more than 1000 patients treated with amiodaronei.v. in clinical studies developed pulmonary fibrosis. For that patient, the condition was diagnosed 3months after treatment with amiodaronei.v., during which time she had received oral amiodarone. Amiodaronei.v. therapy should be discontinued if a diagnosis of pulmonary fibrosis is made.
During clinical studies of amiodaronei.v., 2% of patients were reported to have adult respiratory distress syndrome (ARDS). ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. It is not possible to determine what role, if any, amiodarone i.v. played in causing or exacerbating the pulmonary disorder in those patients.
Liver Enzyme Elevations: In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone therapy. However, patients receiving oral or i.v. amiodarone should be monitored carefully for evidence of progressive hepatic injury.
Elevations of blood hepatic enzyme values--ALT, AST and GGT--are seen commonly in patients with immediately lifethreatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients with recent myocardial infarction, congestive heart failure, and in those who have received multiple electrical defibrillations.
Asymptomatic elevations of liver enzymes (AST and ALT) are frequently associated with the use of oral amiodarone. The mechanism whereby this hepatic effect occurs has not been defined. Phospholipidosis and fibrosis of the liver resembling alcoholic hepatitis or cirrhosis, accompanied by only a mild elevation of hepatic enzymes, have been reported in association with the use of oral amiodarone. Rises in hepatic enzymes, especially when associated with clinical signs and symptoms of hepatitis, or with asymptomatic hepatomegaly, may indicate a liver scan and, if needed, a liver biopsy with ultrastructural study. If serum enzyme levels increase significantly, or persist over time, consideration should be given to discontinuation or reducing the dose of amiodarone. Hepatic failure has been a rare cause of death in patients treated with oral amiodarone.
Approximately 54% of patients receiving amiodarone i.v. in clinical studies had baseline elevations in liver enzyme values, and 13% had clinically significant elevations. In 81% of patients with baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.
Two cases of fatal hepatocellular necrosis after treatment with amiodarone i.v. have been reported. The patients, one 28 years of age and the other 60years of age, were treated for atrial arrhythmias with an initial infusion of 1500 mg over 5 hours, a rate much higher than recommended. Both patients developed hepatic and renal failure within 24 hours after the start of amiodarone i.v. treatment and died on day 14 and day 4, respectively. Because these episodes of hepatic necrosis may have been due to the rapid rate of infusion and hypotension is related to the rate of infusion, the initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.
Proarrhythmia/QT Interval Prolongation: Amiodarone may cause a worsening of the existing arrhythmias or precipitate a new arrhythmia. Amiodarone causes prolongation of the QT interval. Proarrhythmia, primarily torsades de pointes, has been associated with prolongation of the QTc interval to 500ms or greater. Proarrhythmia has been reported (2to 5%) with oral amiodarone, especially in the presence of concomitant antiarrhythmic therapy and has included new-onset VF, incessant VT, increased resistance to cardioversion, and paroxysmal polymorphic VT associated with QT prolongation (torsades de pointes). Although QTc prolongation occurred frequently in patients receiving amiodaronei.v., torsades de pointes or new-onset VF occurred infrequently (less than 2% of all patients treated with amiodaronei.v. in controlled clinical trials). Patients should be monitored carefully for QTc prolongation during amiodarone therapy.
Even in patients at high risk of arrhythmic death, in whom the toxicity of amiodarone is an acceptable risk, amiodarone poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.
The difficulty of using amiodarone effectively and safely poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of amiodarone is given, and a response generally requires at least 1week, usually 2or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
Bradycardia and AV Block: In patients treated with oral amiodarone, symptomatic bradycardia or sinus arrest with suppression of escape foci occurred in approximately 2to 4% of patients. Bradycardia was reported as an adverse drug reaction in 4.9% of patients receiving amiodaronei.v. for life-threatening VT/VF in clinical trials. AV block was reported as an adverse drug reaction in 1.4% of patients receiving amiodaronei.v. There was no dose-related increase in bradycardia or AV block in these studies.
In patients who develop symptomatic bradycardia while taking oral amiodarone, dose reduction or discontinuation, and possibly pacing, may be considered. Due to the large body load of amiodarone that accumulates with chronic dose administration, and the long half-life of the drug, serum concentrations decline slowly after dose reduction or discontinuation.
During amiodaronei.v. therapy, bradycardia should be treated by slowing the infusion rate or discontinuing therapy. In some patients inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1(<1%) patient during controlled clinical trials. Patients with a known predisposition to bradycardia or AV block should be treated with amiodaronei.v. in a setting where a temporary pacemaker is available.
I.V.: Hypotension: Hypotension is the most common adverse event seen with amiodaronei.v. therapy: it is uncommon (<1%) during oral amiodarone therapy. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse event in 288 (16%) of 1836patients treated with amiodaronei.v. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating temporary discontinuation of amiodaronei.v. therapy was reported in 3% of the 814patients, with permanent discontinuation required in an additional 2% of the 814patients. Hypotension should be treated initially by slowing the infusion: additionally standard therapy may be needed including vasopressor drugs, positive inotropic agents and volume expansion. The initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.
Oral: Mortality: The results of the Cardiac Arrhythmia Suppression Trial (CAST) in postmyocardial infarction patients with asymptomatic ventricular arrhythmias showed a significant increase in mortality and in nonfatal cardiac arrest rate in patients treated with encainide or flecainide compared with a matched placebo-treated group. CAST was continued using a revised protocol with the moricizine- and placebo-treatment groups only. The trial was prematurely terminated because of a trend towards an increase in mortality in the moricizine-treated group.
The applicability of these results to other populations or other antiarrhythmic agents is uncertain, but at present, it is prudent to consider these results when using any antiarrhythmic agent.
Cordarone therapy was evaluated in 2multicentre, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 to 400mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200mg/day.
These data are consistent with the results of a pooled analysis of 13 smaller, controlled studies involving patients with structural heart disease (including myocardial infarction) where total mortality was reduced by only 13% (odds ratio 0.87, [95% confidence interval 0.75 to 0.99] p=0.03) based on classic fixed effects meta-analysis.
Thyroid Dysfunction: Amiodarone inhibits peripheral conversion of thyroxine (T 4) to triiodothyronine (T 3) and may cause increased thyroxine levels, decreased T 3 levels, and increased levels of inactive reverse T 3 (rT 3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Both hyper- and hypothyroidism may occur during, or soon after treatment with oral amiodarone. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone withdrawal.
Hypothyroidism has been reported in 2 to 4% of patients in most series, but in 8 to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Hypothyroidism is best managed by amiodarone dose reduction and/or thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue amiodarone in some patients.
Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of arrhythmia breakthrough or aggravation. In fact, if any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered. Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T 3 RIA, and further elevations of serum T 4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. The institution of antithyroid drugs, beta-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Experience with thyroid surgery in this setting is extremely limited, and this form of therapy runs the theoretical risk of inducing thyroid storm. Amiodarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism.
In a rat carcinogenicity study, at doses of 5, 16 and 50mg/kg/day, amiodarone produced statistically significant dose-related changes in the thyroid gland, including follicular adenomas and carcinomas. The significance of these changes for the long-term use of amiodarone in humans is unknown.
Neonatal Hypo- or Hyperthyroidism: Pregnancy: Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If amiodarone is used during pregnancy, or if the patient becomes pregnant while taking amiodarone, the patient should be apprised of the potential hazard to the fetus.
In general, amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus.
In pregnant rats and rabbits, amiodarone in doses of 25mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose*.) Adverse effects on fetal growth and survival also were noted in 1of 2strains of mice at a dose of 5mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*.)
*600mg in a 50kg patient (doses compared on a body surface area basis).
Loss of Vision: Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of amiodarone therapy. The risks and complications of antiarrhythmic therapy with amiodarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including fundoscopy and slit-lamp examination, is recommended during administration of amiodarone (see Adverse Effects).
I.V. and Oral: Pulmonary Toxicity: One of the most serious complications resulting from oral amiodarone therapy is pulmonary toxicity, characterized by pneumonitis. Clinical symptoms include cough, dyspnea, weight loss and weakness. On chest x-ray, there is a diffuse interstitial pattern of lung involvement frequently with patchy alveolar infiltrates, particularly in the upper lobe. Predicting which patient will develop pulmonary toxicity has been difficult (see Contraindications). Pulmonary toxicity can appear abruptly either early or late during therapy, and it commonly mimics viral or bacterial infection or worsening congestive heart failure. The relationship of pulmonary toxicity to duration of therapy, maintenance dose and total dose is unclear. The majority of patients have recovered with this management, although some fatalities have occurred. Therefore, when amiodarone therapy is initiated, a baseline chest x-ray and pulmonary function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam and chest x-ray every 3to 6months.
Pulmonary toxicity secondary to amiodarone seems to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis or interstitial/alveolar pneumonitis, respectively at rates as high as 10to 17% in patients with ventricular arrhythmias given doses around 400mg/day. Pulmonary toxicity has been fatal about 10% of the time.
Hypersensitivity pneumonitis usually appears earlier in the course of therapy and rechallenging these patients with amiodarone results in a more rapid recurrence of greater severity. Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and amiodarone therapy discontinued in these patients.
Interstitial/alveolar pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of amiodarone-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of amiodarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably to withdrawal of the amiodarone to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first 2to 3weeks. Chest x-ray changes usually resolve within 2to 4months. According to some experts steroids may prove beneficial. Prednisone in doses of 40to 60mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with amiodarone at a lower dose has not resulted in return of toxicity. Recent reports suggest that the use of lower loading and maintenance doses of amiodarone are associated with a decreased incidence of amiodarone-induced pulmonary toxicity.
In a patient receiving amiodarone, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest x-ray and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup.
Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with lifethreatening arrhythmias, discontinuation of amiodarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy etc.) before discontinuing amiodarone in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available.
If a diagnosis of amiodarone-induced hypersensitivity pneumonitis is made, amiodarone should be discontinued, and treatment with steroids should be instituted. If a diagnosis of amiodarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, amiodarone discontinued or, at a minimum, reduced in dosage. Some cases of amiodarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in amiodarone dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible.
Only 1 of more than 1000 patients treated with amiodaronei.v. in clinical studies developed pulmonary fibrosis. For that patient, the condition was diagnosed 3months after treatment with amiodaronei.v., during which time she had received oral amiodarone. Amiodaronei.v. therapy should be discontinued if a diagnosis of pulmonary fibrosis is made.
During clinical studies of amiodaronei.v., 2% of patients were reported to have adult respiratory distress syndrome (ARDS). ARDS is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. The clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. It is not possible to determine what role, if any, amiodarone i.v. played in causing or exacerbating the pulmonary disorder in those patients.
Liver Enzyme Elevations: In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone therapy. However, patients receiving oral or i.v. amiodarone should be monitored carefully for evidence of progressive hepatic injury.
Elevations of blood hepatic enzyme values--ALT, AST and GGT--are seen commonly in patients with immediately lifethreatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients with recent myocardial infarction, congestive heart failure, and in those who have received multiple electrical defibrillations.
Asymptomatic elevations of liver enzymes (AST and ALT) are frequently associated with the use of oral amiodarone. The mechanism whereby this hepatic effect occurs has not been defined. Phospholipidosis and fibrosis of the liver resembling alcoholic hepatitis or cirrhosis, accompanied by only a mild elevation of hepatic enzymes, have been reported in association with the use of oral amiodarone. Rises in hepatic enzymes, especially when associated with clinical signs and symptoms of hepatitis, or with asymptomatic hepatomegaly, may indicate a liver scan and, if needed, a liver biopsy with ultrastructural study. If serum enzyme levels increase significantly, or persist over time, consideration should be given to discontinuation or reducing the dose of amiodarone. Hepatic failure has been a rare cause of death in patients treated with oral amiodarone.
Approximately 54% of patients receiving amiodarone i.v. in clinical studies had baseline elevations in liver enzyme values, and 13% had clinically significant elevations. In 81% of patients with baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment.
Two cases of fatal hepatocellular necrosis after treatment with amiodarone i.v. have been reported. The patients, one 28 years of age and the other 60years of age, were treated for atrial arrhythmias with an initial infusion of 1500 mg over 5 hours, a rate much higher than recommended. Both patients developed hepatic and renal failure within 24 hours after the start of amiodarone i.v. treatment and died on day 14 and day 4, respectively. Because these episodes of hepatic necrosis may have been due to the rapid rate of infusion and hypotension is related to the rate of infusion, the initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.
Proarrhythmia/QT Interval Prolongation: Amiodarone may cause a worsening of the existing arrhythmias or precipitate a new arrhythmia. Amiodarone causes prolongation of the QT interval. Proarrhythmia, primarily torsades de pointes, has been associated with prolongation of the QTc interval to 500ms or greater. Proarrhythmia has been reported (2to 5%) with oral amiodarone, especially in the presence of concomitant antiarrhythmic therapy and has included new-onset VF, incessant VT, increased resistance to cardioversion, and paroxysmal polymorphic VT associated with QT prolongation (torsades de pointes). Although QTc prolongation occurred frequently in patients receiving amiodaronei.v., torsades de pointes or new-onset VF occurred infrequently (less than 2% of all patients treated with amiodaronei.v. in controlled clinical trials). Patients should be monitored carefully for QTc prolongation during amiodarone therapy.
Even in patients at high risk of arrhythmic death, in whom the toxicity of amiodarone is an acceptable risk, amiodarone poses major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.
The difficulty of using amiodarone effectively and safely poses a significant risk to patients. Patients with the indicated arrhythmias must be hospitalized while the loading dose of amiodarone is given, and a response generally requires at least 1week, usually 2or more. Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment. In a retrospective survey of 192patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions. The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months. The patient is obviously at great risk during this time and may need prolonged hospitalization. Attempts to substitute other antiarrhythmic agents when amiodarone must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden. A similar problem exists when amiodarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.
Bradycardia and AV Block: In patients treated with oral amiodarone, symptomatic bradycardia or sinus arrest with suppression of escape foci occurred in approximately 2to 4% of patients. Bradycardia was reported as an adverse drug reaction in 4.9% of patients receiving amiodaronei.v. for life-threatening VT/VF in clinical trials. AV block was reported as an adverse drug reaction in 1.4% of patients receiving amiodaronei.v. There was no dose-related increase in bradycardia or AV block in these studies.
In patients who develop symptomatic bradycardia while taking oral amiodarone, dose reduction or discontinuation, and possibly pacing, may be considered. Due to the large body load of amiodarone that accumulates with chronic dose administration, and the long half-life of the drug, serum concentrations decline slowly after dose reduction or discontinuation.
During amiodaronei.v. therapy, bradycardia should be treated by slowing the infusion rate or discontinuing therapy. In some patients inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1(<1%) patient during controlled clinical trials. Patients with a known predisposition to bradycardia or AV block should be treated with amiodaronei.v. in a setting where a temporary pacemaker is available.
I.V.: Hypotension: Hypotension is the most common adverse event seen with amiodaronei.v. therapy: it is uncommon (<1%) during oral amiodarone therapy. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse event in 288 (16%) of 1836patients treated with amiodaronei.v. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating temporary discontinuation of amiodaronei.v. therapy was reported in 3% of the 814patients, with permanent discontinuation required in an additional 2% of the 814patients. Hypotension should be treated initially by slowing the infusion: additionally standard therapy may be needed including vasopressor drugs, positive inotropic agents and volume expansion. The initial rate of infusion should be monitored closely and should not exceed that recommended in the Dosage section.
Precautions
General: Patients with life-threatening arrhythmias may experience serious adverse events during their treatment and therefore should be properly monitored. Amiodarone should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and adverse events of treatment (see Indications).
Loading Phase: The higher doses of oral amiodarone used in the loading phase may sometimes be associated with adverse effects such as nausea or tremor. The nausea may respond to dividing the total dose into 2or 3fractions taken with meals, or by decreasing the total daily dose. The tremor may respond to dose reduction as well.
Oral: Cardiac Disorders: Oral amiodarone should be used with caution in patients with latent or manifest heart failure because this condition may be worsened by its administration. In these cases, oral amiodarone should be given with appropriate concurrent therapy.
Oral amiodarone therapy may be considered in the treatment of patients with Wolff-Parkinson-White (WPW) syndrome, atrial flutter, or atrial fibrillation, when these conditions are complicated by life-threatening ventricular tachyarrhythmias. In such cases, care is required since the effect of oral amiodarone in these conditions does not appear to be uniform. Electrophysiologic studies may be of value in the selection of these patients who may respond to oral amiodarone, particularly in WPW syndrome.
Nervous System Disorders: Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.
Dermatologic Disorders: Oral amiodarone may induce photosensitization in about 10% of patients. Sunscreen preparations or protective clothing may afford some protection to individual patients experiencing photosensitization. Blue-grey discoloration of exposed skin has been reported during long-term treatment. With discontinuation of therapy, the pigmentation regresses slowly over a period of up to several years. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.
Ocular Abnormalities: Microdeposits appear in the cornea in the majority of patients treated with oral amiodarone. The deposits are usually discernible only by slit-lamp examination and occasionally give rise to symptoms such as visual halos, which are experienced in as many as 10% of patients. Corneal microdeposits are reversible with reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce or discontinue treatment (see Adverse Effects).
Cases of optical neuropathy and optical neuritis have been reported.
Postsurgical Disorders: Occurrences of adult respiratory syndrome (ARDS) and low cardiac output syndrome have been reported postoperatively in patients receiving oral amiodarone therapy who have undergone either cardiac or noncardiac surgery. An intra-aortic balloon pump augmentation has been required in some patients with the low cardiac output syndrome at discontinuation of cardiopulmonary bypass. In the case of ARDS, although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. A number of patients who developed ARDS were subjected to a high concentration of oxygen in the inspired air; this could have been a factor in the respiratory complications. Until further studies have been performed, it is recommended that FiO 2 and the determinants of oxygen delivery to the tissues (e.g., SaO 2, PaO 2) be closely monitored in patients on amiodarone. Caution should also be exercised in considering amiodarone patients for surgery in the presence of preoperative pulmonary dysfunction. However, as amiodarone has a very long half-life, withdrawal before surgery implies delaying operations by several weeks and putting patients at increased risk of malignant dysrhythmias. The ARDS in these cases has rarely been fatal. Caution should be used in considering amiodarone patients for surgery in the presence of preoperative pulmonary dysfunction.
Hypotension independent of, or associated with, discontinuation of cardiopulmonary bypass following open-heart surgery has been reported. Blood vessels may respond poorly to adrenoreceptor agonists. Atropine-resistant bradycardia and complete heart block have also been reported in patients being weaned from cardiopulmonary bypass.
Urogenital System Disorders: Oral amiodarone-induced epididymitis has been observed in some patients. This form of epididymitis is rare, benign, self-limited and requires no treatment. Physicians should be aware of it to protect their patients from unnecessary invasive urologic examinations and antibiotic therapy.
Oral and I.V.: Electrolyte Disturbances: Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone, since these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea in patients receiving concomitant diuretics.
Children: The safety and efficacy of amiodarone in children have not been established; therefore, its use in children is not recommended. Experience with the use of oral amiodarone in children is very limited. The following information is provided in order to help the physician who considers that critical and treatment-resistant disease in a pediatric patient makes the use of amiodarone necessary. In a study of 26patients aged 6weeks to 29years (mean 13years), an amiodarone dose of 5mg/kg/day, b.i.d. (10mg/kg/day) was administered for 10days; the subsequent mean maintenance dose of oral amiodarone was 7.5mg/kg/day (range 2.5 to 21.5mg/kg/day).
Pregnancy: Amiodarone has been shown to be embryotoxic in some animal species. In 3different human case reports, both the parent drug and its DEA metabolite have been shown to pass through the placenta, quantitatively ranging between 10 and 50% of human maternal serum concentrations. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. Therefore, amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.
Labor and Delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.
Lactation: Amiodarone and its DEA metabolite are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.
Drug Interactions : Amiodarone can inhibit the metabolism mediated by cytochrome P-450 enzymes, probably accounting for the significant effects of oral amiodarone (and presumably amiodaronei.v.) on the pharmacokinetics of various therapeutic agents including digoxin, quinidine, procainamide, warfarin, dextromethorphan and cyclosporine. Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem and verapamil. Conversely, agents producing a significant effect on amiodarone pharmacokinetics include phenytoin, cimetidine and cholestyramine. The potential for drug interactions may persist long after discontinuation of amiodarone administration because of its long half-life. Few data are available on drug interactions with amiodaronei.v. Except as noted, TablesIV and V summarize the key interactions between oral amiodarone and other therapeutic agents.
Beta-blockers: Since amiodarone has weak beta-blocking activity, use with beta-blocking agents could increase risk of hypotension and bradycardia.
Calcium Channel Blockers: Amiodarone may have additive effects on atrioventricular conduction or myocardial contractility, increasing the risk of hypotension.
Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effect of halogenated inhalation anesthetics.
In addition to the interactions noted above, chronic (>2weeks) oral amiodarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.
In general, combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be very carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.
General: Patients with life-threatening arrhythmias may experience serious adverse events during their treatment and therefore should be properly monitored. Amiodarone should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and adverse events of treatment (see Indications).
Loading Phase: The higher doses of oral amiodarone used in the loading phase may sometimes be associated with adverse effects such as nausea or tremor. The nausea may respond to dividing the total dose into 2or 3fractions taken with meals, or by decreasing the total daily dose. The tremor may respond to dose reduction as well.
Oral: Cardiac Disorders: Oral amiodarone should be used with caution in patients with latent or manifest heart failure because this condition may be worsened by its administration. In these cases, oral amiodarone should be given with appropriate concurrent therapy.
Oral amiodarone therapy may be considered in the treatment of patients with Wolff-Parkinson-White (WPW) syndrome, atrial flutter, or atrial fibrillation, when these conditions are complicated by life-threatening ventricular tachyarrhythmias. In such cases, care is required since the effect of oral amiodarone in these conditions does not appear to be uniform. Electrophysiologic studies may be of value in the selection of these patients who may respond to oral amiodarone, particularly in WPW syndrome.
Nervous System Disorders: Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.
Dermatologic Disorders: Oral amiodarone may induce photosensitization in about 10% of patients. Sunscreen preparations or protective clothing may afford some protection to individual patients experiencing photosensitization. Blue-grey discoloration of exposed skin has been reported during long-term treatment. With discontinuation of therapy, the pigmentation regresses slowly over a period of up to several years. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.
Ocular Abnormalities: Microdeposits appear in the cornea in the majority of patients treated with oral amiodarone. The deposits are usually discernible only by slit-lamp examination and occasionally give rise to symptoms such as visual halos, which are experienced in as many as 10% of patients. Corneal microdeposits are reversible with reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce or discontinue treatment (see Adverse Effects).
Cases of optical neuropathy and optical neuritis have been reported.
Postsurgical Disorders: Occurrences of adult respiratory syndrome (ARDS) and low cardiac output syndrome have been reported postoperatively in patients receiving oral amiodarone therapy who have undergone either cardiac or noncardiac surgery. An intra-aortic balloon pump augmentation has been required in some patients with the low cardiac output syndrome at discontinuation of cardiopulmonary bypass. In the case of ARDS, although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. A number of patients who developed ARDS were subjected to a high concentration of oxygen in the inspired air; this could have been a factor in the respiratory complications. Until further studies have been performed, it is recommended that FiO 2 and the determinants of oxygen delivery to the tissues (e.g., SaO 2, PaO 2) be closely monitored in patients on amiodarone. Caution should also be exercised in considering amiodarone patients for surgery in the presence of preoperative pulmonary dysfunction. However, as amiodarone has a very long half-life, withdrawal before surgery implies delaying operations by several weeks and putting patients at increased risk of malignant dysrhythmias. The ARDS in these cases has rarely been fatal. Caution should be used in considering amiodarone patients for surgery in the presence of preoperative pulmonary dysfunction.
Hypotension independent of, or associated with, discontinuation of cardiopulmonary bypass following open-heart surgery has been reported. Blood vessels may respond poorly to adrenoreceptor agonists. Atropine-resistant bradycardia and complete heart block have also been reported in patients being weaned from cardiopulmonary bypass.
Urogenital System Disorders: Oral amiodarone-induced epididymitis has been observed in some patients. This form of epididymitis is rare, benign, self-limited and requires no treatment. Physicians should be aware of it to protect their patients from unnecessary invasive urologic examinations and antibiotic therapy.
Oral and I.V.: Electrolyte Disturbances: Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone, since these disorders can exaggerate the degree of QTc prolongation and increase the potential for torsades de pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea in patients receiving concomitant diuretics.
Children: The safety and efficacy of amiodarone in children have not been established; therefore, its use in children is not recommended. Experience with the use of oral amiodarone in children is very limited. The following information is provided in order to help the physician who considers that critical and treatment-resistant disease in a pediatric patient makes the use of amiodarone necessary. In a study of 26patients aged 6weeks to 29years (mean 13years), an amiodarone dose of 5mg/kg/day, b.i.d. (10mg/kg/day) was administered for 10days; the subsequent mean maintenance dose of oral amiodarone was 7.5mg/kg/day (range 2.5 to 21.5mg/kg/day).
Pregnancy: Amiodarone has been shown to be embryotoxic in some animal species. In 3different human case reports, both the parent drug and its DEA metabolite have been shown to pass through the placenta, quantitatively ranging between 10 and 50% of human maternal serum concentrations. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. Therefore, amiodarone should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.
Labor and Delivery: It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.
Lactation: Amiodarone and its DEA metabolite are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.
Drug Interactions : Amiodarone can inhibit the metabolism mediated by cytochrome P-450 enzymes, probably accounting for the significant effects of oral amiodarone (and presumably amiodaronei.v.) on the pharmacokinetics of various therapeutic agents including digoxin, quinidine, procainamide, warfarin, dextromethorphan and cyclosporine. Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem and verapamil. Conversely, agents producing a significant effect on amiodarone pharmacokinetics include phenytoin, cimetidine and cholestyramine. The potential for drug interactions may persist long after discontinuation of amiodarone administration because of its long half-life. Few data are available on drug interactions with amiodaronei.v. Except as noted, TablesIV and V summarize the key interactions between oral amiodarone and other therapeutic agents.
Beta-blockers: Since amiodarone has weak beta-blocking activity, use with beta-blocking agents could increase risk of hypotension and bradycardia.
Calcium Channel Blockers: Amiodarone may have additive effects on atrioventricular conduction or myocardial contractility, increasing the risk of hypotension.
Volatile Anesthetic Agents: Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effect of halogenated inhalation anesthetics.
In addition to the interactions noted above, chronic (>2weeks) oral amiodarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.
In general, combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be very carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.
Side Effects / Adverse Effects
Oral : Because of the extensive distribution of amiodarone in body tissues, and the prolonged time required for its elimination from the body following discontinuation of long-term therapy, the relationship between adverse reactions and dosage and duration of therapy, has not been fully established. For some adverse reactions--e.g., corneal microdeposits--a relationship to dosage and duration of therapy has been established, so that corneal deposits are reversible with dose reduction or with discontinuation of therapy. However, for other adverse reactions--e.g., fibrosing alveolitis or peripheral neuropathy--the dose relationship and the reversibility of the adverse reaction have not been established. Certain gastrointestinal reactions (e.g., nausea, vomiting, constipation and bad taste) and CNS reactions (e.g., fatigue, headaches, vertigo, nightmares and sleeplessness) occur frequently at the initiation of therapy when high doses are used. These may disappear on reduction of the dose. The time and dose relationship of adverse events are under continued study.
The most serious and potentially life-threatening adverse effects associated with the use of amiodarone are pulmonary fibrosis, the aggravation of arrhythmias and cirrhotic hepatitis.
Published data reflecting the North American experience with chronic oral amiodarone therapy suggest that amiodarone-associated adverse drug reactions are very common, having occurred in approximately 75% of patients taking 400mg or more/day; these adverse events have led to the discontinuation of amiodarone treatment in 7 to 18% of patients. The adverse reactions most frequently requiring discontinuation of amiodarone have included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure and elevation of liver enzymes. Other symptoms causing discontinuations less often have included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism and hypothyroidism.
Ophthalmological Abnormalities: Corneal microdeposits are apparent upon slit-lamp examination in virtually all adult patients who have taken amiodarone for longer than 6months. These deposits may give rise to symptoms such as visual halos or blurred vision (see Precautions). Other reported amiodarone-associated abnormalities have included corneal degeneration, papilledema, photosensitivity, eye discomfort, dry eyes, scotoma, lens opacities, macular degeneration, optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness (see Warnings).
Neurological Abnormalities: Occurring in 20 to 40% of patients, these common disorders have included ataxia, tremor, fatigue, dizziness, weakness, sleep disorders, headaches, cognitive disorders, disturbances of alertness, peripheral motor and sensory neuropathies, proximal muscle weakness, impotence (see Precautions) and pseudotumor cerebri.
Pulmonary Abnormalities: In some studies symptomatic pulmonary disease has been detected at rates as high as 10 to 15%, whereas asymptomatic abnormalities of pulmonary diffusion capacity have been demonstrated at greater than twice that incidence. Pulmonary toxicity has been fatal about 10% of the time (see Warnings).
Cardiovascular Abnormalities: Exacerbation of arrhythmia has had a reported incidence of about 2 to 5% in most series (new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion and paroxysmal polymorphic ventricular tachycardia (torsades de pointes). In addition, symptomatic bradycardia or sinus arrest with suppression of escape foci have occurred in 2 to 4% of patients. Congestive heart failure has occurred in approximately 3% of patients. Second degree AV block and left bundle branch block (LBBB) have occurred in less than 1% of patients, vasculitis and angioedema have also been reported. Hypotension independent of--as well as associated with--discontinuation of cardiopulmonary bypass following open-heart surgery has also been reported (see Warnings and Precautions).
Gastrointestinal Abnormalities: Complaints of this nature have occurred in about 25% of patients and have included nausea, vomiting, constipation, anorexia, abnormal taste, dyspepsia, abdominal pain and diarrhea (see Precautions).
Hepatic Abnormalities: Abnormal elevations of serum levels of enzymes associated with hepatic dysfunction have occurred in approximately 15% of patients. Symptomatic hepatitis has occurred in less than 1% of patients and cholestatic hepatitis and cirrhosis have been reported (see Precautions). Overt liver disease can occur, however, and has been fatal in a few cases.
Dermatologic Abnormalities: These have occurred in approximately 15% of patients, with photosensitivity (10% of patients) being the most common. Blue-grey skin pigmentation has been reported in 2 to 3% of patients. Hair loss (alopecia) has been observed in up to 4% of patients. Other amiodarone-associated phenomena reported with less than 1% incidence have included nonspecific skin eruptions, pruritus, acquired keratoderma, hyperhidrosis, onycholysis, generalized pustular psoriasis, vasculitis and polyserositis, and toxic epidermal necrolysis (see Precautions).
Thyroid Abnormalities: Amiodarone-associated hypothyroidism has been reported in 2 to 4% of patients in most series but in 8 to 10% of patients with other series: hyperthyroidism has been reported in 1 to 3% of patients.
Oral : Because of the extensive distribution of amiodarone in body tissues, and the prolonged time required for its elimination from the body following discontinuation of long-term therapy, the relationship between adverse reactions and dosage and duration of therapy, has not been fully established. For some adverse reactions--e.g., corneal microdeposits--a relationship to dosage and duration of therapy has been established, so that corneal deposits are reversible with dose reduction or with discontinuation of therapy. However, for other adverse reactions--e.g., fibrosing alveolitis or peripheral neuropathy--the dose relationship and the reversibility of the adverse reaction have not been established. Certain gastrointestinal reactions (e.g., nausea, vomiting, constipation and bad taste) and CNS reactions (e.g., fatigue, headaches, vertigo, nightmares and sleeplessness) occur frequently at the initiation of therapy when high doses are used. These may disappear on reduction of the dose. The time and dose relationship of adverse events are under continued study.
The most serious and potentially life-threatening adverse effects associated with the use of amiodarone are pulmonary fibrosis, the aggravation of arrhythmias and cirrhotic hepatitis.
Published data reflecting the North American experience with chronic oral amiodarone therapy suggest that amiodarone-associated adverse drug reactions are very common, having occurred in approximately 75% of patients taking 400mg or more/day; these adverse events have led to the discontinuation of amiodarone treatment in 7 to 18% of patients. The adverse reactions most frequently requiring discontinuation of amiodarone have included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure and elevation of liver enzymes. Other symptoms causing discontinuations less often have included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism and hypothyroidism.
Ophthalmological Abnormalities: Corneal microdeposits are apparent upon slit-lamp examination in virtually all adult patients who have taken amiodarone for longer than 6months. These deposits may give rise to symptoms such as visual halos or blurred vision (see Precautions). Other reported amiodarone-associated abnormalities have included corneal degeneration, papilledema, photosensitivity, eye discomfort, dry eyes, scotoma, lens opacities, macular degeneration, optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness (see Warnings).
Neurological Abnormalities: Occurring in 20 to 40% of patients, these common disorders have included ataxia, tremor, fatigue, dizziness, weakness, sleep disorders, headaches, cognitive disorders, disturbances of alertness, peripheral motor and sensory neuropathies, proximal muscle weakness, impotence (see Precautions) and pseudotumor cerebri.
Pulmonary Abnormalities: In some studies symptomatic pulmonary disease has been detected at rates as high as 10 to 15%, whereas asymptomatic abnormalities of pulmonary diffusion capacity have been demonstrated at greater than twice that incidence. Pulmonary toxicity has been fatal about 10% of the time (see Warnings).
Cardiovascular Abnormalities: Exacerbation of arrhythmia has had a reported incidence of about 2 to 5% in most series (new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion and paroxysmal polymorphic ventricular tachycardia (torsades de pointes). In addition, symptomatic bradycardia or sinus arrest with suppression of escape foci have occurred in 2 to 4% of patients. Congestive heart failure has occurred in approximately 3% of patients. Second degree AV block and left bundle branch block (LBBB) have occurred in less than 1% of patients, vasculitis and angioedema have also been reported. Hypotension independent of--as well as associated with--discontinuation of cardiopulmonary bypass following open-heart surgery has also been reported (see Warnings and Precautions).
Gastrointestinal Abnormalities: Complaints of this nature have occurred in about 25% of patients and have included nausea, vomiting, constipation, anorexia, abnormal taste, dyspepsia, abdominal pain and diarrhea (see Precautions).
Hepatic Abnormalities: Abnormal elevations of serum levels of enzymes associated with hepatic dysfunction have occurred in approximately 15% of patients. Symptomatic hepatitis has occurred in less than 1% of patients and cholestatic hepatitis and cirrhosis have been reported (see Precautions). Overt liver disease can occur, however, and has been fatal in a few cases.
Dermatologic Abnormalities: These have occurred in approximately 15% of patients, with photosensitivity (10% of patients) being the most common. Blue-grey skin pigmentation has been reported in 2 to 3% of patients. Hair loss (alopecia) has been observed in up to 4% of patients. Other amiodarone-associated phenomena reported with less than 1% incidence have included nonspecific skin eruptions, pruritus, acquired keratoderma, hyperhidrosis, onycholysis, generalized pustular psoriasis, vasculitis and polyserositis, and toxic epidermal necrolysis (see Precautions).
Thyroid Abnormalities: Amiodarone-associated hypothyroidism has been reported in 2 to 4% of patients in most series but in 8 to 10% of patients with other series: hyperthyroidism has been reported in 1 to 3% of patients.
Overdose
Symptoms and Treatment: Oral: Overdose may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or patients on digitalis therapy.
One report of the acute ingestion of a single 8g dose of oral amiodarone by a healthy 20-year-old female has been reported. At first assessment, the patient was conscious and profuse perspiration and a slight tachycardia were the only abnormal findings on clinical observation. Slight bradycardia was observed during the second and third day; thereafter, QT interval and heart rate returned to normal. No clinical adverse events were documented over the subsequent 3-month monitoring period.
If an overdose should occur, gastric lavage or induced emesis should be employed to reduce absorption, in addition to general supportive measures. The patient's cardiac rhythm and blood pressure should be monitored, and if clinically significant bradycardia ensues, a temporary pacemaker should be used.
I.V.: The most likely effects of an inadvertent overdose of amiodaronei.v. are hypotension, cardiogenic shock, bradycardia, AV block and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents and volume expansion. Bradycardia and AV block may require temporary pacing. Hepatic enzyme concentrations should be monitored closely.
Neither amiodarone nor DEA is dialyzable.
Symptoms and Treatment: Oral: Overdose may lead to severe bradycardia and to conduction disturbances with the appearance of an idioventricular rhythm, particularly in elderly patients or patients on digitalis therapy.
One report of the acute ingestion of a single 8g dose of oral amiodarone by a healthy 20-year-old female has been reported. At first assessment, the patient was conscious and profuse perspiration and a slight tachycardia were the only abnormal findings on clinical observation. Slight bradycardia was observed during the second and third day; thereafter, QT interval and heart rate returned to normal. No clinical adverse events were documented over the subsequent 3-month monitoring period.
If an overdose should occur, gastric lavage or induced emesis should be employed to reduce absorption, in addition to general supportive measures. The patient's cardiac rhythm and blood pressure should be monitored, and if clinically significant bradycardia ensues, a temporary pacemaker should be used.
I.V.: The most likely effects of an inadvertent overdose of amiodaronei.v. are hypotension, cardiogenic shock, bradycardia, AV block and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents and volume expansion. Bradycardia and AV block may require temporary pacing. Hepatic enzyme concentrations should be monitored closely.
Neither amiodarone nor DEA is dialyzable.
Recommended Dosage
Oral: General Considerations: Amiodarone therapy should be initiated in hospital and continued in a monitored environment until adequate control of the arrhythmia has occurred. Patients treated with amiodarone should be under the supervision of a cardiologist or a physician with equivalent experience in cardiology. Dose administration must be individualized, particularly taking into account concomitant antiarrhythmic therapy.
The dosage schedule for amiodarone is still somewhat controversial, probably in part due to its poor absorption, unusually long elimination half-life, and huge volume of distribution. Extensive tissue stores of amiodarone must be established before the effects on the heart of oral dose administration are apparent. Intersubject variability as well as differences in dosage regimens and methods of assessment have made it difficult to precisely define the time of onset of initial and maximal antiarrhythmic effect in an individual patient. In order to ensure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of amiodarone has not been determined. Because of the food effect on the absorption of amiodarone, administration of amiodarone should be consistent with regard to meals (see Pharmacology, Pharmacokinetics). Amiodarone's antiarrhythmic effect after oral administration may be noted in as early as 3days (72hours) but more often takes 1to 3weeks.
Because of the slow rate of elimination of amiodarone, its antiarrhythmic effects may persist for weeks or months after its discontinuation, but the time of arrhythmia recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established more rapidly relative to the initial response, possibly because tissue stores were not wholly depleted at the time of recurrence.
The combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening arrhythmias who are unresponsive to adequate doses of a single agent (see Precautions, Drug Interactions).
Adults: Ventricular Arrhythmias: Loading Dose: Loading doses of 800to 1600mg/day are required for 1to 3weeks (occasionally longer) until therapeutic response occurs. (Administration of amiodarone in divided doses at meals is suggested for total daily doses of 1000mg or higher, when gastrointestinal intolerance occurs).
Maintenance Dose: When adequate arrhythmia control has been achieved, or if adverse drug reactions become prominent, the amiodarone dose should be reduced to 600to 800mg/day for 1month and then to the maintenance dose, usually 200to 400mg/day (occasionally 600mg/day). Amiodarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation, and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity.
The lowest effective dose should be used to prevent the occurrence of adverse drug reactions. In all instances, the physician must be guided by the severity of the individual patient's arrhythmia and response to therapy.
Amiodarone shows considerable interindividual variation in response. Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose is essential. The recommended starting dose of amiodaronei.v. is about 1000mg over the first 24hours of therapy, delivered by the infusion regimen in TableXI. It is important that the recommended infusion regimen be followed closely.
After the first 24 hours, the maintenance infusion rate of 0.5mg/min (720mg/24 hours) should be continued utilizing a concentration of 1to 6mg/mL (amiodaronei.v. concentrations greater than 2mg/mL should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, 150mg supplemental infusions of amiodaronei.v. mixed in 100mL of D 5W may be administered. Such infusions should be administered over 10minutes to minimize the potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.
The first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2100mg were associated with an increased risk of hypotension. The initial rate of infusion should not exceed 30mg/min.
Based on the experience from clinical studies of amiodaronei.v., a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2to 3weeks regardless of the patient's age, renal function, or left ventricular function. There has been limited experience in patients receiving amiodaronei.v. for longer than 3weeks.
I.V. to Oral Transition: Patients whose arrhythmias have been suppressed by amiodaronei.v. may be switched to oral amiodarone. The optimal dose for changing from i.v. to oral administration of amiodarone will depend on the dose of amiodaronei.v. already administered as well as the bioavailability of oral amiodarone. When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients.
Oral: General Considerations: Amiodarone therapy should be initiated in hospital and continued in a monitored environment until adequate control of the arrhythmia has occurred. Patients treated with amiodarone should be under the supervision of a cardiologist or a physician with equivalent experience in cardiology. Dose administration must be individualized, particularly taking into account concomitant antiarrhythmic therapy.
The dosage schedule for amiodarone is still somewhat controversial, probably in part due to its poor absorption, unusually long elimination half-life, and huge volume of distribution. Extensive tissue stores of amiodarone must be established before the effects on the heart of oral dose administration are apparent. Intersubject variability as well as differences in dosage regimens and methods of assessment have made it difficult to precisely define the time of onset of initial and maximal antiarrhythmic effect in an individual patient. In order to ensure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of amiodarone has not been determined. Because of the food effect on the absorption of amiodarone, administration of amiodarone should be consistent with regard to meals (see Pharmacology, Pharmacokinetics). Amiodarone's antiarrhythmic effect after oral administration may be noted in as early as 3days (72hours) but more often takes 1to 3weeks.
Because of the slow rate of elimination of amiodarone, its antiarrhythmic effects may persist for weeks or months after its discontinuation, but the time of arrhythmia recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established more rapidly relative to the initial response, possibly because tissue stores were not wholly depleted at the time of recurrence.
The combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening arrhythmias who are unresponsive to adequate doses of a single agent (see Precautions, Drug Interactions).
Adults: Ventricular Arrhythmias: Loading Dose: Loading doses of 800to 1600mg/day are required for 1to 3weeks (occasionally longer) until therapeutic response occurs. (Administration of amiodarone in divided doses at meals is suggested for total daily doses of 1000mg or higher, when gastrointestinal intolerance occurs).
Maintenance Dose: When adequate arrhythmia control has been achieved, or if adverse drug reactions become prominent, the amiodarone dose should be reduced to 600to 800mg/day for 1month and then to the maintenance dose, usually 200to 400mg/day (occasionally 600mg/day). Amiodarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation, and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity.
The lowest effective dose should be used to prevent the occurrence of adverse drug reactions. In all instances, the physician must be guided by the severity of the individual patient's arrhythmia and response to therapy.
Amiodarone shows considerable interindividual variation in response. Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose is essential. The recommended starting dose of amiodaronei.v. is about 1000mg over the first 24hours of therapy, delivered by the infusion regimen in TableXI. It is important that the recommended infusion regimen be followed closely.
After the first 24 hours, the maintenance infusion rate of 0.5mg/min (720mg/24 hours) should be continued utilizing a concentration of 1to 6mg/mL (amiodaronei.v. concentrations greater than 2mg/mL should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, 150mg supplemental infusions of amiodaronei.v. mixed in 100mL of D 5W may be administered. Such infusions should be administered over 10minutes to minimize the potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.
The first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2100mg were associated with an increased risk of hypotension. The initial rate of infusion should not exceed 30mg/min.
Based on the experience from clinical studies of amiodaronei.v., a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2to 3weeks regardless of the patient's age, renal function, or left ventricular function. There has been limited experience in patients receiving amiodaronei.v. for longer than 3weeks.
I.V. to Oral Transition: Patients whose arrhythmias have been suppressed by amiodaronei.v. may be switched to oral amiodarone. The optimal dose for changing from i.v. to oral administration of amiodarone will depend on the dose of amiodaronei.v. already administered as well as the bioavailability of oral amiodarone. When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients.
Supplied / Packaging
I.V.: Each mL of clear, pale yellow solution contains: amiodarone HCl 50mg. Nonmedicinal ingredients: benzyl alcohol, polysorbate80 and water for injection. Clear type1 flint glass ampuls of 5mL containing 3mL of solution. Store at controlled room temperature, 15 to 25°C. Protect from light and excessive heat. Use carton to protect contents from light until use.
I.V.: Each mL of clear, pale yellow solution contains: amiodarone HCl 50mg. Nonmedicinal ingredients: benzyl alcohol, polysorbate80 and water for injection. Clear type1 flint glass ampuls of 5mL containing 3mL of solution. Store at controlled room temperature, 15 to 25°C. Protect from light and excessive heat. Use carton to protect contents from light until use.
Search for a drug
Brand Name
Cordarone I.V.
Cordarone I.V.
Generic Name
Amiodarone HCl
Amiodarone HCl
General Indications
Antiarrhythmic Agent
Antiarrhythmic Agent
