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Amiodarone
Pronunciation
U.S. Brand Names
Generic Available
Synonyms
Pharmacological Index
Use
Pregnancy Risk Factor
Contraindications
Warnings/Precautions
Adverse Reactions
Overdosage/Toxicology
Drug Interactions
Stability
Mechanism of Action
Pharmacodynamics/Kinetics
Usual Dosage
Dietary Considerations
Monitoring Parameters
Reference Range
Test Interactions
Cardiovascular Considerations
Mental Health: Effects on Mental Status
Mental Health: Effects on Psychiatric Treatment
Dental Health: Local Anesthetic/Vasoconstrictor Precautions
Dental Health: Effects on Dental Treatment
Patient Information
Nursing Implications
Dosage Forms
Extemporaneous Preparations
References

Pronunciation
(a MEE oh da rone)

U.S. Brand Names
Cordarone®; Pacerone®

Generic Available

No


Synonyms
Amiodarone Hydrochloride

Pharmacological Index

Antiarrhythmic Agent, Class III


Use

Oral: Management of life-threatening recurrent ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT)

I.V.: Initiation of treatment and prophylaxis of frequency recurring VF and unstable VT in patients refractory to other therapy. Also, used for patients for whom oral amiodarone is indicated but who are unable to take oral medication.


Pregnancy Risk Factor

D


Contraindications

Hypersensitivity to amiodarone or any component; severe sinus-node dysfunction; second- and third-degree heart block (except in patients with a functioning artificial pacemaker); bradycardia causing syncope (except in patients with a functioning artificial pacemaker);cisapride, ritonavir, sparfloxacin, moxifloxacin, gatifloxacin; pregnancy


Warnings/Precautions

Not considered first line therapy due to toxicity profile especially with large doses. Reserve for use in arrhythmias refractory to other therapy. Monitor for pulmonary toxicity, liver toxicity, or exacerbation of the arrhythmia. Use very cautiously and with close monitoring in patients with thyroid or liver disease. Significant heart block or sinus bradycardia can occur. Patients should be hospitalized when amiodarone is initiated. Pre-existing pulmonary disease does not increase risk of developing pulmonary toxicity, but if pulmonary toxicity develops then the prognosis is worse. Due to complex pharmacokinetics, it is difficult to predict when an arrhythmia or interaction with a subsequent treatment will occur following discontinuation of amiodarone. May cause optic neuropathy and/or optic neuritis, usually resulting in visual impairment.


Adverse Reactions

With large dosages (>400 mg/day), adverse reactions occur in ~75% of patients and require discontinuance in 5% to 20%.

Cardiovascular: Hypotension (I.V.: 16%)

Central nervous system: Between 20% and 40% of patients experience some form of neurologic adverse events (see central nervous system and neuromuscular effects: 1% to 10% frequencies).

Gastrointestinal: Nausea, vomiting

1% to 10%:

Cardiovascular: Congestive heart failure, arrhythmias (including atropine-resistant bradycardia, heart block, sinus arrest, ventricular tachycardia), proarrhythmic, myocardial depression, flushing, edema. Additional effects associated with I.V. administration include asystole, cardiac arrest, electromechanical dissociation, ventricular tachycardia and cardiogenic shock.

Central nervous system: Fever, fatigue, involuntary movements, incoordination, malaise, sleep disturbances, ataxia, dizziness, headache

Dermatologic: Photosensitivity (10%)

Endocrine & metabolic: Hypothyroidism or hyperthyroidism (less common), decreased libido

Gastrointestinal: Constipation, anorexia, abdominal pain, abnormal salivation, abnormal taste (oral form)

Hematologic: Coagulation abnormalities

Hepatic: Abnormal LFTs

Local: Phlebitis (I.V.: with concentrations >3 mg/mL)

Neuromuscular & skeletal: Paresthesia, tremor, muscular weakness, peripheral neuropathy

Ocular: Visual disturbances, corneal microdeposits

Genitourinary: noninfectious epididymitis (3% to 11%)

Respiratory: Pulmonary toxicity has been estimated to occur at a frequency between 2% and 7% of patients (some reports indicate a frequency as high as 17%). Toxicity may present as hypersensitivity pneumonitis, pulmonary fibrosis (cough, fever, malaise), pulmonary inflammation, interstitial pneumonitis, or alveolar pneumonitis. Other rare pulmonary toxicities are listed under the <1% category.

Miscellaneous: Abnormal smell (oral form)

<1% (Limited to important or life-threatening symptoms): Hypotension (with oral form), vasculitis, atrial fibrillation, increased QT interval, ventricular fibrillation, nodal arrhythmia, sinus bradycardia, optic neuropathy, optic neuritis, photophobia, pseudotumor cerebri, hyperglycemia, hypertriglyceridemia, epididymitis, thrombocytopenia, pancreatitis, cirrhosis, severe hepatotoxicity (potentially fatal hepatitis), hepatitis, cholestasis, cirrhosis, increased ALT/AST, abnormal renal function, diarrhea, pulmonary edema, bronchiolitis obliterans organizing pneumonia (BOOP), pleuritis, rash, alopecia, discoloration of skin (slate-blue), Stevens-Johnson syndrome, toxic epidermal necrolysis, thrombocytopenia, pancytopenia, neutropenia, ventricular fibrillation, vomiting, angioedema, anaphylactic shock, aplastic anemia, myoclonic jerks, jaw tremor, dyskinesias, parkinsonian symptoms, delirium, encephalopathy, brain stem dysfunction, impotence, loss of libido

Case reports: Bone marrow granuloma, leukocytoclastic vasculitis, acute intracranial hypertension (I.V.), gynecomastia, toxic epidermal necrolysis


Overdosage/Toxicology

Symptoms include extensions of pharmacologic effect, sinus bradycardia and/or heart block, hypotension and Q-T prolongation

Patients should be monitored for several days following ingestion. Intoxication with amiodarone necessitates EKG monitoring; bradycardia may be atropine resistant; injectable isoproterenol or a temporary pacemaker may be required.


Drug Interactions

CYP3A3/4 enzyme substrate; CYP3A3/4, CYP2C9, CYP2D6 enzyme inhibitor.

Beta-blockers may cause excessive AV block; monitor response.

Cimetidine may increase amiodarone blood levels.

Cholestyramine may decrease amiodarone blood levels.

Cisapride and amiodarone may increase risk of malignant arrhythmias; concurrent use is contraindicated.

Codeine: Analgesic efficacy may be reduced.

Clonazepam effects may be increased by amiodarone.

Cyclosporine blood levels may be increased by amiodarone.

Digoxin levels may be increased by amiodarone; consider reducing digoxin dose by 50% and monitor digoxin blood levels closely.

Diltiazem may cause additive/excessive AV block; monitor response.

Fentanyl: Concurrent use may lead to bradycardia, sinus arrest, and hypotension.

Flecainide blood levels may be increased; consider reducing flecainide dose by 25% to 33% with concurrent use.

Metoprolol blood levels may be increased; monitor response.

Phenytoin blood levels may be increased by amiodarone; amiodarone blood levels may be decreased by phenytoin.

Drugs which prolong the QT interval include amitriptyline, astemizole, bepridil, disopyramide, erythromycin, haloperidol, imipramine, quinidine, pimozide, procainamide, sotalol, and thioridazine. Effect/toxicity increased; use with caution.

Propranolol blood levels may be increased.

Procainamide and NAPA plasma levels may be increased; consider reducing procainamide dosage by 25% with concurrent use.

Quinidine blood levels may be increased; monitor quinidine trough concentration.

Rifampin may decrease amiodarone blood levels.

Ritonavir and amprenavir may increase amiodarone levels and toxicity; concurrent use is contraindicated.

Sparfloxacin, gatifloxacin, and moxifloxacin may result in additional prolongation of the QT interval; concurrent use is contraindicated.

Theophylline blood levels may be increased.

Thyroid supplements: Amiodarone may alter thyroid function; monitor closely.

Verapamil may cause additive/excessive AV block; monitor response.

Warfarin: Hypoprothrombinemic response increased. Monitor INR closely when amiodarone is initiated or discontinued. Reduce warfarin's dose when amiodarone is started.


Stability

I.V. infusions >2 hours must be administered in glass or polyolefin bottles; incompatible with aminophylline, cefamandole, cefazolin, heparin, mezlocillin, and sodium bicarbonate; store at room temperature; protect from light


Mechanism of Action

Class III antiarrhythmic agent which inhibits adrenergic stimulation, prolongs the action potential and refractory period in myocardial tissue; decreases A-V conduction and sinus node function


Pharmacodynamics/Kinetics

Onset of effect: 3 days to 3 weeks after starting therapy; onset of I.V. form may be more rapid

Peak effect: 1 week to 5 months

Duration of effect after discontinuation of therapy: 7-50 days

Note: Mean onset of effect and duration after discontinuation may be shorter in children versus adults

Distribution: Vd: 66 L/kg (range: 18-148 L/kg); crosses placenta; distributes into breast milk in concentrations higher than maternal plasma concentrations

Protein binding: 96%

Metabolism: In liver, major metabolite active

Bioavailability: ~50%

Half-life: Oral chronic therapy: 40-55 days (range: 26-107 days); shortened in children versus adults

Elimination: Via biliary excretion; possible enterohepatic recirculation; <1% excreted unchanged in urine


Usual Dosage

Oral:

Children (calculate doses for children <1 year on body surface area): Loading dose: 10-15 mg/kg/day or 600-800 mg/1.73 m2/day for 4-14 days or until adequate control of arrhythmia or prominent adverse effects occur (this loading dose may be given in 1-2 divided doses/day). Dosage should then be reduced to 5 mg/kg/day or 200-400 mg/1.73 m2/day given once daily for several weeks. If arrhythmia does not recur, reduce to lowest effective dosage possible. Usual daily minimal dose: 2.5 mg/kg/day; maintenance doses may be given for 5 of 7 days/week.

Adults: Ventricular arrhythmias: 800-1600 mg/day in 1-2 doses for 1-3 weeks, then when adequate arrhythmia control is achieved, decrease to 600-800 mg/day in 1-2 doses for 1 month; maintenance: 400 mg/day. Lower doses are recommended for supraventricular arrhythmias.

I.V.:

First 24 hours: 1000 mg according to following regimen

Step 1: 150 mg (100 mL) over first 10 minutes (mix 3 mL in 100 mL D5W)

Step 2: 360 mg (200 mL) over next 6 hours (mix 18 mL in 500 mL D5W): 1 mg/minute

Step 3: 540 mg (300 mL) over next 18 hours: 0.5 mg/minute

After the first 24 hours: 0.5 mg/minute utilizing concentration of 1-6 mg/mL

Breakthrough VF or VT: 150 mg supplemental doses in 100 mL D5W over 10 minutes

Note: When switching from I.V. to oral therapy, use the following as a guide:

<1-week I.V. infusion 800-1600 mg/day

1- to 3-week I.V. infusion 600-800 mg/day

>3-week I.V. infusion 400 mg/day

Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, greater than or equal to 4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2 weeks, since any changes in serum amiodarone concentrations during this period may not be clinically significant.

Dosing adjustment in hepatic impairment: Probably necessary in substantial hepatic impairment.

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary.

Peritoneal dialysis effects: Not dialyzable (0% to 5%); supplemental dose is not necessary.


Dietary Considerations

May be administered with food


Monitoring Parameters

Monitor heart rate (EKG) and rhythm throughout therapy; assess patient for signs of thyroid dysfunction (thyroid function tests and liver enzymes), lethargy, edema of the hands, feet, weight loss, and pulmonary toxicity (baseline pulmonary function tests)


Reference Range

Therapeutic: 0.5-2.5 mg/L (SI: 1-4 mmol/L) (parent); desethyl metabolite is active and is present in equal concentration to parent drug


Test Interactions

Thyroid function tests: Amiodarone partially inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine (T3); serum T4 and reverse triiodothyronine (RT3) concentrations may be increased and serum T3 may be decreased; most patients remain clinically euthyroid, however, clinical hypothyroidism or hyperthyroidism may occur


Cardiovascular Considerations

Amiodarone is associated with less proarrhythmic effects compared to other antiarrhythmic drugs. Bradycardia often accompanies amiodarone use and should be anticipated. Clinical trials demonstrate that amiodarone is a safe and effective antiarrhythmic for the treatment of supraventricular and ventricular arrhythmias in patients with underlying cardiovascular disease (myocardial infarction, heart failure). In a recent study, early amiodarone administration prolonged survival to hospitalization in patients suffering out-of-hospital cardiac arrest. In the setting of acute myocardial infarction, beta-blocker therapy should still be initiated even though concomitant amiodarone therapy provides beta-blockade. To avoid potential side effects, chronic amiodarone therapy, when possible, should be maintained at the lowest effective dose ( less than or equal to 400 mg/day). The potential for drug interaction should be evaluated prior to amiodarone therapy (see Drug Interactions).


Mental Health: Effects on Mental Status

Insomnia, nightmares, and fatigue are common


Mental Health: Effects on Psychiatric Treatment

May cause hypotension which may be exacerbated by psychotropics; may cause hypothyroidism; use caution with lithium


Dental Health: Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions


Dental Health: Effects on Dental Treatment

This drug is indicated only for life-threatening arrhythmias; dental treatment would not be a consideration during these emergencies


Patient Information

Emergency use: Patient condition will determine amount of patient education. Oral: May be taken with food to reduce GI disturbance, but be consistent. Always take with food or always take without food. Do not change dosage or discontinue drug without consulting prescriber. Regular blood work, ophthalmic exams, and cardiac assessment will be necessary while taking this medication on a long-term basis. You may experience dizziness, weakness, or insomnia (use caution when driving, climbing stairs, or engaging in tasks requiring alertness until response to drug is known); hypotension (use caution changing position - rising from sitting or lying); nausea, vomiting, loss of appetite, or stomach discomfort, abnormal taste (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); or decreased libido (reversible). Report persistent dry cough or shortness of breath; chest pain, palpitations, irregular or slow heartbeat; unusual bruising or bleeding; blood in urine, feces (black stool), vomitus; pain, swelling, or warmth in calves; muscle tremor, weakness, numbness, or changes in gait; skin rash or irritation; or changes in urinary patterns. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Do not breast-feed.


Nursing Implications

Muscle weakness may present a great hazard for ambulation


Dosage Forms

Injection, as hydrochloride: 50 mg/mL with benzyl alcohol (3 mL)

Tablet, scored, as hydrochloride: 200 mg


Extemporaneous Preparations

A 5 mg/mL oral suspension has been made from tablets and has an expected stability of 7 days under refrigeration; three 200 mg tablets are crushed in a mortar, 90 mL of methylcellulose 1%, and 10 mL of syrup (syrup NF (85% sucrose in water) or flavored syrup) are added in small amounts and triturated until uniform; purified water USP is used to make a quantity sufficient to 120 mL


References

Ahmad S, "Amiodarone and Reversible Alopecia," Arch Intern Med, 1995, 155(10):1106.

Bonnet C, Zabraniecki L, Bertin P, et al, "Amiodarone-Induced Neuromyopathy Mimicking Polymyositis," Rev Rhum Engl Ed, 1995, 62(6):468.

Breithardt G, "Amiodarone in Patients With Heart Failure," N Engl J Med, 1995, 333(2):121-2.

Coumel P and Fidelle J, "Amiodarone in the Treatment of Cardiac Arrhythmias in Children: One Hundred Thirty-Five Cases," Am Heart J, 1980, 100(6 Pt 2):1063-9.

Dotti MT and Federico A, "Amiodarone-Induced Parkinsonism: A Case Report and Pathogenetic Discussion," Mov Disord, 1995, 10(2):233-4.

Ector H, Rubens A, De Geest H, et al, "Amiodarone and Thyroid Function Tests," Acta Cardiol, 49:538-9.

Figa FH, Gow RM, Hamilton RM, et al, "Clinical Efficacy and Safety of Intravenous Amiodarone in Infants and Children," Am J Cardiol, 1994, 74(6):573-7.

Garson A Jr, Gillette PC, McVey P, et al, "Amiodarone Treatment of Critical Arrhythmias in Children and Young Adults," J Am Coll Cardiol, 1984, 4(4):749-55.

Goddard CJ and Whorwell PJ, "Amiodarone Overdose and Its Management," Br J Clin Pharmacol, 1989, 43(5):184-6.

Magee LA, Downar E, Sermer M, et al, "Pregnancy Outcome After Gestational Exposure to Amiodarone in Canada," Am J Obstet Gynecol, 1995, 172(4 Pt 1):1307-11.

Marchlinski FE, Gansler TS, Waxman HL, et al, "Amiodarone Pulmonary Toxicity," Am J Med, 1982, 97(6):839-45.

Monk BE, "Basal Cell Carcinoma Following Amiodarone Therapy," Br J Dermatol, 1995, 133(1):148-9.

Nitsch J and Luderitz B, "Acceleration of Amiodarone Elimination by Cholestyramine," Dtsch Med Wochenschr, 1986, 111(33):1241-4.

Paul T and Guccione P, "New Antiarrhythmic Drugs in Pediatric Use: Amiodarone," Pediatr Cardiol, 1994, 15(3):132-8.

Perry JC, Fenrich AL, Hulse JE, et al, "Pediatric Use of Intravenous Amiodarone: Efficacy and Safety in Critically Ill Patients From a Multicenter Protocol," J Am Coll Cardiol, 1996, 27(5):1246-50.

Podrid PJ, "Amiodarone: Reevaluation of an Old Drug," Ann Intern Med, 1995, 122(9):689-700.

Raja P, Hawker RE, Chaikitpinyo A, et al, "Amiodarone Management of Junctional Ectopic Tachycardia After Cardiac Surgery in Children," Br Heart J, 1994, 72(3):261-5.

Richer M and Robert S, "Fatal Hepatotoxicity Following Oral Administration of Amiodarone," Ann Pharmacother, 1995, 29(6):582-6.

Rigas B, Rosenfeld LE, and Barwick KW, "Amiodarone Hepatotoxicity," Ann Intern Med, 1986, 104(3):348-51.

Shahar E, Barzilay Z, Frand M, et al, "Amiodarone in Control of Sustained Tachyarrhythmias in Children With Wolff-Parkinson-White Syndrome," Pediatrics, 1983, 72(6):813-6.

Shuler CO, Case CL, and Gillette PC, "Efficacy and Safety of Amiodarone in Infants," Am Heart J, 1993, 125(5 Pt 1):1430-2.

Singh SN, Fletcher RD, Fisher SG, et al, "Amiodarone in Patients With Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure," N Engl J Med, 1995, 333(2):77-82.

Snir Y, Pick N, Riesenberg K, et al, "Fatal Hepatic Failure Due to Prolonged Amiodarone Treatment," J Clin Gastroenterol, 1995, 20(3):265-6.

Soult JA, Munoz M, Lopez JD, et al, "Efficacy and Safety of Intravenous Amiodarone for Short-Term Treatment of Paroxysmal Supraventricular Tachycardia in Children," Pediatr Cardiol, 1995, 16(1):16-9.

Tisdale JE, Follin SL, Ordelova A, et al, "Risk Factors for the Development of Specific Noncardiovascular Adverse Effects Associated With Amiodarone," J Clin Pharmacol, 1995, 35(4):351-6.

Valle JM, Alvarez D, Antunez J, et al, "Bronchiolitis Obliterans Organizing Pneumonia Secondary to Amiodarone: A Rare Aetiology," Eur Respir J, 1995, 8(3):470-1.


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