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Pronunciation |
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(a
MEE oh da
rone) |
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U.S. Brand
Names |
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Cordarone®;
Pacerone® |
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Generic
Available |
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No |
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Synonyms |
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Amiodarone Hydrochloride |
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Pharmacological Index |
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Antiarrhythmic Agent, Class III |
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Use |
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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.
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Pregnancy Risk
Factor |
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D |
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Contraindications |
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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 |
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Warnings/Precautions |
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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. |
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Adverse
Reactions |
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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
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Overdosage/Toxicology |
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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. |
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Drug
Interactions |
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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. |
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Stability |
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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 |
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Mechanism of
Action |
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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 |
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Pharmacodynamics/Kinetics |
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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 |
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Usual Dosage |
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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. |
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Dietary
Considerations |
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May be administered with food |
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Monitoring
Parameters |
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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) |
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Reference Range |
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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 |
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Test
Interactions |
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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 |
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Cardiovascular
Considerations |
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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). |
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Mental Health: Effects
on Mental Status |
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Insomnia, nightmares, and fatigue are common |
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Mental Health:
Effects on Psychiatric
Treatment |
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May cause hypotension which may be exacerbated by psychotropics; may cause
hypothyroidism; use caution with lithium |
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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |
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Dental Health:
Effects on Dental Treatment |
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This drug is indicated only for life-threatening arrhythmias; dental
treatment would not be a consideration during these
emergencies |
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Patient
Information |
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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. |
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Nursing
Implications |
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Muscle weakness may present a great hazard for
ambulation |
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Dosage Forms |
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Injection, as hydrochloride: 50 mg/mL with benzyl alcohol (3 mL)
Tablet, scored, as hydrochloride: 200 mg |
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Extemporaneous
Preparations |
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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
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References |
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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
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Magee LA, Downar E, Sermer M, et al,
"Pregnancy Outcome After Gestational Exposure to Amiodarone in Canada," Am J
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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
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"New Antiarrhythmic Drugs in Pediatric Use: Amiodarone," Pediatr Cardiol,
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"Pediatric Use of Intravenous Amiodarone: Efficacy and Safety in Critically Ill Patients From a Multicenter Protocol,"
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Podrid PJ, "Amiodarone: Reevaluation of an Old Drug," Ann Intern Med,
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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,
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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,"
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