Amiodarone Hydrochloride

Class: Class III Antiarrhythmics
VA Class: CV300
Chemical Name: (2-Butyl-3-benzafuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]-methanone hydrochloride
Molecular Formula: C₂₅H₂₉I₂NO₃•HCl
CAS Number: 19774-82-4
Brands: Cordarone, Pacerone

Special Alerts:

FDA and Wyeth notified pharmacists and physicians of a new Medication Guide for amiodarone hydrochloride tablets (Cordarone, Pacerone). The FDA regulation 21CFR 208 requires a Medication Guide to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. The Medication Guide and current Prescribing Information for amiodarone hydrochloride and its generic equivalents are also provided below. For more information visit the FDA website at: and .

Introduction

Class III antiarrhythmic agent;^{1 2 4 5 8 12 17 18 21 24 25 26 28 31 38 355} also exhibits activity in each of the 4 Vaughn-Williams antiarrhythmic classes, including some class I (membrane-stabilizing) antiarrhythmic action.^{5 7 8 21 25 32 35 44 46 355 364}

Uses for Amiodarone Hydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Ventricular Arrhythmias

Treatment to suppress or prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., recurrent VF; recurrent, hemodynamically unstable VT) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents are not tolerated.^{1 3 355 364 399 440}

Adjunctive therapy for treatment of VF or VT resistant to CPR, cardioversion (e.g., after 2–3 shocks), and a vasopressor (e.g., epinephrine, vasopressin)†.^{364 399 440} Considered by some experts to be the preferred†antiarrhythmic agent for this use.^{399 440}

Initial treatment of sustained monomorphic VT not associated with angina, pulmonary edema, or hypotension†,^{364 399 440} or of hemodynamically stable VT† .⁴⁴⁰

Control of polymorphic VT† with a normal QT interval.⁴⁴⁰

Primary prevention† of sustained VT (i.e., VT lasting >30 seconds and/or associated with hemodynamic compromise),³⁶⁴ VF, or sudden cardiac death in patients with nonsustained ventricular arrhythmia following MI.^{344 368 370 384 394}

Management of life-threatening ventricular arrhythmias associated with post-infarction aneurysm† or with chronic myocarditis induced by Chagas’ disease†.^{26 72 172}

Supraventricular Tachyarrhythmias

Conversion of atrial fibrillation† to normal sinus rhythm (i.e., rhythm control)⁴⁴⁰ in patients with atrial fibrillation† of ≤48 hours of duration.^{399 440} The preferred drug or one of several preferred drugs when antiarrhythmic drug therapy is indicated for this use in patients with preserved or impaired left ventricular function, Wolff-Parkinson-White syndrome, CHF, or pre-excited atrial fibrillation or flutter†.^{399 440}

Suppression and prevention of refractory atrial fibrillation†.^{4 5 9 10 12 25 26 27 35 62 66 71 72 92 109 110 111 113 116 119 120 122 399}

Termination of paroxysmal supraventricular tachycardias†, including those associated with accessory bypass tracts (e.g., Wolff-Parkinson-White syndrome).^{9 38 48 399}

Control of rapid ventricular rate associated with accessory pathway conduction in pre-excited atrial arrhythmias†.^{399 440}

Suppression and prevention of paroxysmal supraventricular tachycardias† (AV nodal reentrant tachycardia, AV reentrant tachycardia [e.g., Wolff-Parkinson-White syndrome]),^{4 5 8 9 25 26 27 28 29 37 39 41 47 48 66 71 72 109 110 112 113 122 128 318} including those refractory to other antiarrhythmic agents.^{5 26 27 39 66 71 110 113 122 128 318}

Termination of narrow-complex tachycardias that originated from a reentry mechanism (reentrant SVT)†, if the rhythm remains uncontrolled by adenosine, vagal maneuvers, and AV nodal blockade in patients with preserved or impaired ventricular function.⁴⁴⁰

Prevention of supraventricular arrhythmias associated with bradycardia-tachycardia syndrome†.^{4 9 25 110 129 130 131}

Wide-Complex Tachycardia of Uncertain Mechanism

The preferred antiarrhythmic agent for treatment of wide-complex tachycardias of uncertain mechanism† in patients with preserved or impaired cardiac function.^{399 440}

Angina

Treatment of chronic stable angina pectoris† in patients receiving the drug for the management of arrhythmias.^{17 50 133 229}

Treatment of Prinzmetal variant angina† in patients receiving the drug for the management of arrhythmias.^{17 134 229}

Hypertrophic Cardiomyopathy

Management of ventricular and supraventricular arrhythmias associated with hypertrophic cardiomyopathy†.^{25 258 259 278 292}

Amiodarone Hydrochloride Dosage and Administration

General

• 
  

  Administer lowest effective dosage to minimize the risk and occurrence of adverse effects.¹

  
  


• 
  

  Adjust dosage carefully according to individual requirements and response and the general condition and cardiovascular status of the patient.^{1 355} Adjustment of maintenance dosage is difficult due to variable absorption and elimination of amiodarone; dosage reduction or temporary withdrawal or discontinuance of the drug may be required.^{1 284}

  
  


• 
  

  When dosage adjustment is necessary, close monitoring for an extended period of time is recommended.^{1 355}

  
  


• 
  

  Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring) and/or programmed electrical stimulation (PES), as appropriate, is recommended.^{1 440}

  
  


• 
  

  Monitor plasma amiodarone concentrations if patient does not respond or experiences unexpectedly severe toxicity.^{1 2 3 5 25 35 62 63 64 70 71 75 81}

  
  


• 
  

  Monitor BP.⁴⁴⁰ (See Hypotension under Cautions.)

  
  


• 
  

  When initiating therapy in patients receiving other antiarrhythmic agents, attempt to gradually discontinue the other antiarrhythmic agents.¹ (See Antiarrhythmic Agents under Interactions.)

  
  


• 
  

  Use caution when administering with other drugs that prolong the QT interval (e.g., procainamide); consider expert consultation.⁴⁴⁰ (See Drugs Affecting QT Interval under Interactions.)

  
  

Administration

Administer orally or by IV infusion.^{1 3 9 10 25 35 355}

For ACLS during CPR, may be administered via intraosseous (IO) injection†.⁴⁴⁰

Oral Administration

Usually administered once daily.^{1 3} Administer in divided doses (e.g., twice daily) with meals when dosages ≥1 g daily are administered (e.g., during the loading-dose phase of therapy) or when intolerable adverse GI effects occur.^{1 3}

Administer in a consistent manner relative to food intake.¹

Administration of a loading-dose phase of therapy is required for the management of life-threatening ventricular arrhythmias;^{1 2 3 5 23 25 35 42 59 64 68 72 73} administer oral loading dose in hospital setting and monitor closely until risk of recurrent VT or VF has abated.^{1 35}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

IV therapy may be used for acute antiarrhythmic therapy until cardiac rhythm is stabilized and oral therapy can be initiated.³⁵⁵ IV therapy may be required for 48–96 hours, but may be administered safely for longer periods.³⁵⁵ Experience with IV administration of amiodarone exceeding 3 weeks is limited.³⁵⁵

Administer in 3-phase sequence: rapid loading phase, slow loading phase, and maintenance infusion phase.³⁵⁵

Dilute amiodarone hydrochloride concentrate prior to administration by IV infusion.³⁵⁵

Administer solutions containing an amiodarone hydrochloride concentration >2 mg/mL via central venous catheter.³⁵⁵

Use in-line filter.³⁵⁵

Amiodarone hydrochloride infusions exceeding 2 hours should be administered in 5% dextrose in glass or polyolefin containers (see Solution Compatibility under Stability).³⁵⁵ Manufacturer recommends using PVC tubing (used in clinical studies).³⁵⁵

Dilution

For the first rapid loading infusion or for supplemental infusions, add 3 mL of amiodarone hydrochloride concentrate to 100 mL of 5% dextrose, resulting in a final concentration of 1.5 mg/mL.³⁵⁵

For the slow loading infusion and maintenance infusion, add 18 mL of amiodarone hydrochloride concentrate to 500 mL of 5% dextrose, resulting in a final concentration of 1.8 mg/mL.³⁵⁵ For subsequent maintenance infusions, solutions containing a final amiodarone hydrochloride concentration of 1–6 mg/mL may be used.³⁵⁵

Alternatively, for cardiac arrest secondary to pulseless tachycardia or VF, initial loading dose may be diluted in 20–30 mL of a compatible IV solution.³⁹⁹

Rate of Administration

For treatment of ventricular arrhythmias in adults, 15 mg/minute for 10 minutes (rapid loading phase), then 1 mg/minute for 6 hours (slow loading phase), then 0.5 mg/minute (initial maintenance phase) for 18 hours;^{355 440} infuse supplemental doses of 150 mg over 10 minutes (at a rate of 15 mg/minute).^{355 364 399 440} Initial (rapid) loading infusion rate should not exceed 30 mg/minute.^{355 364 397} Monitor initial rate of infusion closely; do not exceed recommended rate.³⁵⁵ (See Hypotension under Cautions.)

Use volumetric infusion pump.³⁵⁵ Do not use drop-counter infusion sets; may result in underdosage.³⁵⁵

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as amiodarone hydrochloride; dosage expressed in terms of the salt.^{1 355}

Pediatric Patients

Ventricular Arrhythmias†

Oral

Initially (as loading dose), 10–15 mg/kg daily^{40 242} or 600–800 mg/1.73 m² daily^{9 69 189 242} for approximately 4–14 days^{40 69 189 242} and/or until adequate control of cardiac arrhythmias is achieved or adverse effects become prominent.^{40 242} Subsequently, reduce dosage to 5 mg/kg daily^{40 242} or 200–400 mg/1.73 m² daily^{9 69 189 242} for several weeks; if possible, reduce dosage to the lowest effective level.^{69 189 242}

Children <1 year of age may require higher oral loading and maintenance dosages than older children when dosage is calculated on the basis of body weight, but not on the basis of body surface area†.^{280 282}

IV

Initially, 5 mg/kg infused over several (usually 20) minutes to 1 hour, depending on the need to achieve a rapid drug effect (i.e., urgency).^{400 440} If adequate control of cardiac arrhythmia is not achieved, infuse additional doses as needed in 5-mg/kg increments (maximum single dose of 300 mg)^h up to a total dose of 15 mg/kg in 24 hours.^{400 440 h}

Alternatively, to minimize pediatric exposure to diethylhexyl phthalate (DEHP),⁴⁰⁸ infuse a loading dose of 5 mg/kg given in 5 divided doses of 1 mg/kg (each dose infused over 5–10 minutes).⁴¹⁶

Intraosseous†

CPR: Initially, 5 mg/kg; may repeat as needed in 5-mg/kg increments (maximum single dose of 300 mg)^h up to a total dose of 15 mg/kg in 24 hours.^{400 440 h}

Supraventricular Arrhythmias†

Oral

Initially (as loading dose), 10–15 mg/kg daily^{40 242} or 600–800 mg/1.73m² daily^{9 69 189 242} for approximately 4–14 days^{40 69 189 242} and/or until adequate control of cardiac arrhythmias is achieved or adverse effects become prominent.^{40 242} Subsequently, reduce dosage to 5 mg/kg daily^{40 242} or 200–400 mg/1.73 m² daily^{9 69 189 242} for several weeks; if possible, reduce dosage to the lowest effective level.^{69 189 242}

Children <1 year of age may require higher oral loading and maintenance dosages than older children when dosage is calculated on the basis of body weight, but not on the basis of body surface area.†^{280 282}

IV

Initially, 5 mg/kg infused over several (usually 20) minutes to 1 hour, depending on the need to achieve a rapid drug effect (i.e., urgency).^{400 440} If adequate control of cardiac arrhythmia is not achieved, infuse additional doses as needed in 5-mg/kg increments (maximum single dose of 300 mg)^h up to a total dose of 15 mg/kg in 24 hours.^{400 440 h}

Alternatively, to minimize pediatric exposure to DEHP,⁴⁰⁸ infuse a loading dose of 5 mg/kg given in 5 divided doses of 1 mg/kg (each dose infused over 5–10 minutes).⁴¹⁶

Intraosseous†

CPR: Initially, 5 mg/kg; may repeat as needed in 5-mg/kg increments (maximum single dose of 300 mg)^h up to a total dose of 15 mg/kg in 24 hours.^{400 440 h}

Adults

Ventricular Arrhythmias

Oral

Oral Loading and Maintenance Dosages

Loading Dose	800–1600 mg daily for 1–3 weeks or until initial therapeutic response occurs1
Dosage Adjustment	When adequate control of ventricular arrhythmias is achieved or adverse effects become prominent, decrease dosage to 600–800 mg daily for about 1 month1 3 284
Maintenance Dosage	400–600 mg daily;1 3 284 if possible, cautiously reduce dosage to 200 mg daily70 284

Consult published protocols for specific information about oral loading doses >1600 mg daily^{35 64 73 301} or IV loading-dose regimens† ^{64 250} followed by oral therapy.³⁰¹ If an IV loading-dose regimen is used, initiate oral therapy as soon as possible after an adequate response is obtained and gradually eliminate IV amiodarone.³⁰¹

IV

Total initial dosage during first 24 hours is approximately 1000 mg.³⁵⁵

Table 1. IV Dosage Over First 24 Hours

Loading Phase	Initial rapid loading phase: 150 mg administered at rate of 15 mg/minute (i.e., over 10 minutes) 355 364 399 440
	Followed by slow loading phase: 360 mg administered at rate of 1 mg/minute (i.e., over 6 hours)355 364 397 399 440
Maintenance Phase	First maintenance phase: 540 mg administered at rate of 0.5 mg/minute (i.e., over 18 hours)355 364 397 399 440

Table 2. IV Dosage After First 24 Hours

Maintenance Phase	0.5 mg/minute (i.e., 720 mg over 24 hours); can be administered for 2–3 weeks 355
Breakthrough Episodes of VF or Hemodynamically Unstable VT	Supplemental infusion of 150 mg administered at rate of 15 mg/minute (i.e., over 10 minutes)355

Alternatively, for cardiac arrest secondary to pulseless VT or VF: Initially, 300 mg infused rapidly; consider a supplemental 150-mg dose infused rapidly for recurrent or refractory VT or VF.^{399 440}

Intraosseous†

Cardiac arrest secondary to pulseless VT or VF: Initially, 300 mg; consider a supplemental 150-mg dose.⁴⁴⁰

IV/Oral

When switching from IV to oral therapy, oral dosage depends on dose and duration of IV therapy, as well as bioavailability of oral drug.³⁵⁵ When switching from IV to oral therapy, clinical monitoring is recommended, particularly for geriatric patients.³⁵⁵

Assuming 720-mg/day infusion (0.5 mg/minute)

IV amiodarone not intended for maintenance treatment

Table 3. Switching to Oral Therapy Following IV Therapy355

Duration of IV Therapy	Initial Oral Daily Dosage
<1 week	800–1600 mg
1–3 weeks	600–800 mg
>3 weeks	400 mg

Supraventricular Arrhythmias†

Oral

Initially (as loading dose), 600–800 mg daily for approximately 1–4 weeks and/or until adequate control of supraventricular arrhythmias is achieved or adverse effects become prominent.^{28 72 242} Gradually reduce dosage to the lowest effective maintenance dosage, usually 100–400 mg daily.^{2 25 28 71 72 153 242}

Consult published protocols for specific information about oral loading-dose regimens using higher dosages.

Acute Management of Atrial Fibrillation†

IV

125 mg/hour for 24 hours (3 g total).^{399 440}

Long-term Management of Recurrent Atrial Fibrillation†

Oral

Initially, 10 mg/kg daily for 14 days, followed by 300 mg daily for 4 weeks, and then 200 mg daily.⁴⁰²

Prescribing Limits

Pediatric Patients

Ventricular Arrhythmias†

IV

Maximum single dose: 300 mg,^h up to a total dose of 15 mg/kg in 24 hours.^{400 440 h}

Supraventricular Arrhythmias†

IV

Maximum single dose: 300 mg,^h up to a total dose of 15 mg/kg in 24 hours.^{400 440 h}

Adults

Ventricular Arrhythmias

IV

Mean daily doses >2.1 g are associated with an increased risk of hypotension.³⁵⁵

Limited experience with IV administration of amiodarone for >3 weeks.³⁵⁵

CPR: Maximum 2-2.2 g.^{399 440}

Special Populations

Hepatic Impairment

Dosage reduction recommended in patients with substantial hepatic impairment.^{35 283 284}

Renal Impairment

Routine dosage reduction not required.^{1 35}

Geriatric Patients

Select dosage with caution, usually starting at low end of dosage range, because of possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy; however, dosage requirements generally similar in geriatric and younger adults.^{1 355}

Use caution with high dosages due to increased susceptibility to drug-induced bradycardia and conduction disturbances.³⁰¹

Cautions for Amiodarone Hydrochloride

Contraindications

• 
  

  Cardiogenic shock.^{1 355}

  
  


• 
  

  Severe sinus node dysfunction resulting in marked sinus bradycardia (unless a functioning pacemaker is present).^{1 355}

  
  


• 
  

  Second- or third-degree AV block (unless a functioning pacemaker is present).^{1 355} (See Effects on Cardiac Conduction under Cautions.)

  
  


• 
  

  Bradycardia that has caused syncope (unless a functioning pacemaker is present).¹

  
  


• 
  

  Known hypersensitivity to amiodarone or any ingredient in the formulation, including iodine.^{1 355}

  
  

Warnings/Precautions

Warnings

Mortality

Potentially fatal toxicities and severe adverse effects;^{1 106 355} use principally for documented life-threatening ventricular arrhythmias.¹

Amiodarone therapy should be administered only by physicians experienced in the management of life-threatening arrhythmias who have access to laboratory facilities necessary to adequately monitor efficacy and adverse effects, including continuous ECG monitoring and electrophysiologic techniques for evaluating the patient in both ambulatory and hospital settings.^{1 106 355}

Pulmonary Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible acute-onset (days to weeks) pulmonary injury; findings may include pulmonary infiltrates and/or mass on radiograph, pulmonary alveolar hemorrhage, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, or hypoxia, sometimes leading to respiratory failure and/or death.^{1 355}

Potentially fatal pulmonary toxicity^{1 3 9 25 136 324 325 326 327 333 338 370} may result from pulmonary interstitial pneumonitis (or alveolitis) or hypersensitivity pneumonitis (see Hypersensitivity Reactions under Cautions).^{1 325 326 338 339 345 346} Toxicity is usually reversible following discontinuance of the drug (with or without corticosteroid therapy).^{1 3 75 136 138 139 140 142 272 308 327 329 333 336 337 338 350}

Baseline pulmonary function testing (prior to initiating therapy)^{1 25 325 326 327 328 335 338} and periodic (e.g., every 3–6 months) chest radiographs, clinical evaluation, and pulmonary function testing recommended.^{1 25 148 284 325 327 338}

If hypersensitivity pneumonitis occurs, discontinue amiodarone and initiate corticosteroid therapy.^{1 350}

If interstitial pneumonitis occurs, reduce dosage or discontinue therapy, especially if other acceptable antiarrhythmic therapies are available.^{1 326 327 328 333 338} Supportive treatment, including mechanical ventilation, may be required.^{136 140 142}

Use with caution, if at all, in patients with preexisting pulmonary disease³⁵ (e.g., chronic obstructive disease,²⁵² reduced pulmonary diffusion capacity^{35 138 324} ); poorer prognosis if pulmonary toxicity develops in such patients.¹

If new respiratory symptoms develop, consider the possibility of amiodarone-induced pulmonary toxicity; ^{1 136 140 326 327} clinical and radiographic evaluation, as well as scintigraphic and pulmonary function testing (including diffusion capacity), if necessary, are recommended.^{1 138 151 324 326 327 328 333 336 337 338} Carefully assess respiratory symptoms and rule out other causes of respiratory impairment (e.g., CHF, pulmonary embolism, malignancy, infectious causes) before discontinuing therapy.^{1 136 138 140 327 328 338}

Bronchiolitis obliterans organizing pneumonia (possibly fatal) and pleuritis reported during postmarketing experience.¹

Hepatic Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible liver function test abnormalities;^{1 3 9 10 25 30 75 83 108 141 153 154 157 158 159 163 355} abnormalities are usually minor,^{1 25 75} not accompanied by clinical symptoms,^{1 3 9 10 70 72 75 153 158 159 161} and generally return to normal following dosage reduction or discontinuance of the drug.^{9 72 75 141 154 159}

Rarely, potentially fatal hepatic injury (i.e., clinical hepatitis, cholestatic hepatitis, hepatocellular necrosis, cirrhosis) ^{1 3 35 155 156 160 162 341 342 355} has occurred.^{1 3 25 35 155 156 158 160 161 162 163 164 355}

Monitor serum hepatic enzyme concentrations at regular intervals.^{1 153 157 160 164 355} Reduce oral dosage, decrease IV infusion rate, or discontinue therapy if enzyme concentrations are >3 times normal values in patients with normal pretreatment values or twice baseline pretreatment values in patients with elevated pretreatment values or if hepatomegaly or progressive hepatic injury occurs.^{1 156 162 163 164 355}

Possible acute centrolobular confluent hepatic necrosis during IV therapy; may be related to a much higher loading dose concentration and more rapid infusion rate than recommended.³⁵⁵ Closely monitor initial concentration and rate of IV infusion; do not exceed recommended initial drug concentration and infusion rate.³⁵⁵ (See Rate of Administration under Dosage and Administration.)

Arrhythmogenic Effects

Possible worsening of existing arrhythmias^{1 3 9 10 25 35 75 132 141 175 287 355} or occurrence of new arrhythmias.^{1 35 166 167 168 175 176 355} Arrhythmogenic effects include progression of VT to VF,^{1 132 355} sustained VT,^{1 25 141 175 176 355} increased resistance to cardioversion,^{1 25 122 175 304} atrial fibrillation,³⁵⁵ nodal arrhythmia,³⁵⁵ and atypical VT (torsades de pointes).^{1 3 9 25 75 132 171 173 265 355 440}

Monitor for QT_c prolongation during IV infusion of amiodarone.³⁵⁵

If new signs of arrhythmia appear, consider possibility of hyperthyroidism.^{1 355} (See Thyroid Effects under Cautions.)

Chronic administration of antiarrhythmic drugs (e.g., amiodarone) in patients with an implanted cardiac device (e.g., defibrillator, pacemaker) may change electrical conduction properties of the heart and potentially affect pacing and/or defibrillating thresholds.¹ Therefore, manufacturer recommends assessment to ensure appropriate device parameters before and during amiodarone therapy.¹

Electrolyte Abnormalities

Electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia) may increase arrhythmogenic effects (see Arrhythmogenic Effects under Cautions).^{1 3 41} Evaluate patient for potassium or magnesium deficiency; if present, correct deficiency prior to initiation of therapy.^{1 249}

Monitor electrolyte and acid-base balance in patients with severe or prolonged diarrhea and in patients receiving diuretics concomitantly.^{45 47 50 355}

Effects on Cardiac Conduction

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible AV, intraventricular,^{1 3 4 25 26 30 35 355} or SA block;¹⁶⁸ SA node dysfunction (e.g., symptomatic sinus bradycardia),^{1 3 4 9 10 25 26 30 35 50 75 154 169 175 355 393} sinus arrest with suppression of escape foci);^{1 141 166 167 168 169} or bradycardia (usually associated with IV therapy).^{355 440}

Administer IV amiodarone in a setting where a temporary pacemaker is available for patients with known predisposition to bradycardia or AV block.³⁵⁵

Ocular Effects

Optic neuropathy^{1 25 153 154}