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Amiodarone (Systemic)


VA CLASSIFICATION
Primary: CV300

Commonly used brand name(s): Cordarone; Cordarone I.V.; Cordarone Intravenous; pms-Amiodarone.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiarrhythmic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Arrhythmias, ventricular (prophylaxis and treatment)—Amiodarone in the oral dosage form is indicated only for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation unresponsive to documented adequate doses of other available antiarrhythmic medications or when alternative agents cannot be tolerated {35}1. In patients for whom the oral form of amiodarone is indicated, but who are unable to take oral medication, the intravenous form of amiodarone may be used {35}0.
—Amiodarone in the intravenous dosage form is indicated for the initiation of treatment (acute treatment) and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy {35}9.

[Arrhythmias, supraventricular (prophylaxis and treatment)]1—Amiodarone is used to suppress and prevent recurrence of supraventricular arrhythmias refractory to conventional treatment, especially when associated with Wolff-Parkinson-White (W-P-W) syndrome, including paroxysmal atrial fibrillation, atrial flutter, ectopic atrial tachycardia, and paroxysmal supraventricular tachycardia from both atrioventricular (AV) nodal re-entrant and AV re-entrant tachycardia in patients with W-P-W syndrome {35}8 {35}7 {35}6 {35}5 {35}4 {35}3 {35}2 {35}1 {35}0 {35}9 {35}8.

Note: Controlled clinical trials have not demonstrated that the use of amiodarone improves patient survival {35}7.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    681.8

pKa—
    5.6 {35}6


Other
    Contains 37.3% iodine by weight {35}5 {35}4 {35}3; highly lipophilic {35}2 {35}1.

Mechanism of action/Effect:

Amiodarone prolongs the action potential duration {35}0 {35}9 {35}8 {35}7 {35}6 {35}5 {35}4 and the refractory period {35}3 {35}2 {35}1 {35}0 {35}9 {35}8 {35}7 in all cardiac tissues (including the sinus node, atrium, atrioventricular [AV] node, and ventricle) {35}6 {35}5 {35}4 {35}3 {35}2 {35}1 by a direct action on the tissues {35}0 {35}9, without significantly affecting the membrane potential {35}8 {35}7 {35}6. Amiodarone also decreases sinus node automaticity {35}5 {35}4 {35}3 {35}2 {35}1 and junctional automaticity {35}0, prolongs AV conduction {35}9 {35}8 {35}7 {35}6 {35}5, and slows automaticity of spontaneously firing fibers in the Purkinje system {35}4 {35}3. Refractoriness is prolonged and conduction is slowed in accessory pathway tissue in patients with Wolff-Parkinson-White (W-P-W) syndrome {35}2 {35}1 {35}0 {35}9 {35}8. Noncompetitive alpha- and beta-adrenergic receptor antagonism and calcium channel inhibition also occur {35}7 {35}6 {35}5 {35}4 {35}3 {35}2 {35}1 {35}0 {35}9 and thyroid hormone metabolism is affected {35}8 {35}7 {35}6 {35}5 {35}4 {35}3 {35}2 {35}1 {35}0 {35}9, but the relationship of these effects to the antiarrhythmic action of amiodarone is unknown. In the Vaughan Williams classification of antiarrhythmics, amiodarone is considered to be a predominantly class III agent {35}8, with some class I properties.


Other actions/effects:

Amiodarone has a mild negative inotropic effect {35}7 {35}6 {35}5 {35}4 {35}3 {35}2 {35}1 that is more prominent with intravenous than with oral administration but that usually does not depress left ventricular function. {35}0 {35}9 {35}8 Amiodarone causes coronary {35}7 {35}6 {35}5 {35}4 and peripheral {35}3 {35}2 {35}1 {35}0 vasodilation and, therefore, decreases peripheral vascular resistance (afterload) {35}9 {35}8 {35}7 {35}6 but only causes hypotension with large oral doses {35}5.

Absorption:

Slow and variable {35}4 {35}3 {35}2 {35}1 {35}0 {86}; about 20 to 55% of an oral dose is absorbed. {08} {09} {10} {14} {90}

Distribution:

Volume of distribution is large and variable, a consequence of extensive accumulation in adipose tissue and highly perfused organs (liver, lung, spleen), and leads to slow achievement of steady-state and therapeutic plasma concentrations and prolonged elimination. {01} {03} {08} {09} {10} {127}

Protein binding:

Very high (96%) {01} {108}.

Biotransformation:

Hepatic, extensive {01} {08} {14}; one active metabolite (desethylamiodarone) {01} {03}; possibly also by deiodination (a dose of 300 mg releases approximately 9 mg of elemental iodine) {02} {03} {50} {56}.

Half-life:


Elimination (biphasic):


Initial—

Amiodarone—2.5 to 10 days {01} {08}.



Terminal—

Amiodarone—26 to 107 days (mean 53 days; 40 to 55 days in most patients). {01} {08} {14}

Desethylamiodarone—Mean 61 days {01} {08}.



Onset of antiarrhythmic action

2 to 3 days to 2 to 3 months {127}, even with loading doses. {01}

Time to peak plasma concentration

3 to 7 hours {01} {08} {09} {10} {41} {86} {89}.

Therapeutic plasma concentration

1 to 2.5 mcg (0.001 to 0.0025 mg) per mL {01} {08} {09} {46} {57} {86} at steady-state (after 2 months of therapy). However, antiarrhythmic effect is difficult to predict by means of plasma concentrations {08} {09}, and toxicity may occur even at therapeutic concentrations.

Elimination:
    Biliary {01}.
    In breast milk—About 25% of maternal dose is distributed into breast milk. {09} {29}
    In dialysis—Not removable by hemodialysis {01} {08} {121}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

Studies in rats at doses one-half the maximum recommended human maintenance dose and greater found a dose-related increase in the incidence of thyroid follicular adenomas and/or carcinomas {01} {78}.

Mutagenicity

Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with amiodarone were negative {01} {78}.

Pregnancy/Reproduction
Fertility—
Studies in male and female rats at doses eight times the maximum recommended human maintenance dose found that amiodarone reduced fertility {01} {78}.

Pregnancy—
Amiodarone crosses the placenta {08} {09} {43} {110}; neonatal plasma concentrations of amiodarone and desethylamiodarone are 10% {43} {110} and 25% {29} {110} of maternal plasma concentrations, respectively. Although studies in humans have not been done, some reports have indicated an absence of adverse effects when amiodarone was administered late in pregnancy {43} {110}. However, amiodarone can cause fetal harm when administered to pregnant women. {78} Potential adverse effects include bradycardia {09} {29} and effects on thyroid status {08} {09} {29} {110} (iodine is known to cause fetal goiter, hypothyroidism, and mental retardation {110}) in the neonate. There have been a small number of reports of congenital goiter/hypothyroidism and hyperthyroidism. {78}
Note: An expert panel concluded that (based on animal studies) amiodarone I.V. administration may indirectly but adversely affect male reproductive tract development during fetal, infant, and toddler stages of development. The indirect effects may be linked to plasticizers that leach out from the I.V. tubing during certain administration conditions, such as higher amiodarone concentrations and lower flow rates.{129}



Studies in rats and one strain of mice at doses 18 times and one half the maximum recommended human maintenance dose, respectively, have shown that amiodarone is embryotoxic. {78} Amiodarone was not embryotoxic in a second strain of mice or in rabbits at doses up to nine times the maximum recommended human maintenance dose. {01}

FDA Pregnancy Category D. {78}


Labor and delivery—

Although studies in humans have not been done, studies in rodents found no adverse effects of amiodarone on duration of gestation or on parturition {01}.

Breast-feeding

Amiodarone is distributed into human breast milk. {01} {29} {78} The infant receives approximately 25% of the maternal dose {09} {29}. Amiodarone has been shown to cause reduced viability and growth of offspring when used in lactating rats. Mothers should be advised to contact physician before nursing, since use by nursing mothers is not recommended {01} {29} {78}.

Pediatrics

Appropriate studies on the relationship of age to the effects of amiodarone have not been performed in the pediatric population. However, when amiodarone was used concurrently with digoxin, the interaction has been reported to be more acute in children than in adults {107}. In addition, onset and duration of action of amiodarone may be shorter in pediatric patients {17} {127}.

Note: I.V. administration of amiodarone is not recommended for use in the pediatric population due to recent findings that show a potential for adverse male reproductive tract development during infant and toddler ages. In addition, amiodarone I.V. contains the preservative benzyl alcohol which has been associated with the potentially fatal “gasping syndrome” in neonates.{129}



Geriatrics


Appropriate studies on the relationship of age to the effects of amiodarone have not been performed in the geriatric population. However, the elderly tend to be more sensitive to the effects of thyroid hormones and may also, therefore, be more sensitive to the effects of amiodarone on thyroid function. Thyroid function monitoring is particularly important in these patients {88}. In addition, the elderly may experience an increased incidence of ataxia {03} and other neurotoxic effects {99}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Because of its slow elimination, amiodarone may interact with other medications for weeks to months after it is discontinued. {52}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, inhalation    (amiodarone may potentiate hypotension and atropine-resistant bradycardia {03} {06} {07} {09})


» Antiarrhythmics, other    (amiodarone may produce additive cardiac effects with other antiarrhythmics and increase the risk of tachyarrhythmias {01}; amiodarone increases plasma concentrations of quinidine, procainamide, flecainide, and phenytoin {01} {07} {08} {09} {108}; concurrent use of amiodarone with quinidine, disopyramide, procainamide, or mexiletine has been reported to result in a more prolonged QT interval and, rarely {127}, torsades de pointes , {07} {08} {09} {12} and therefore, concurrent use with all class I antiarrhythmics requires great caution {03} {08}; the doses of previously given antiarrhythmics should be reduced by 30 to 50% several days after initiation of amiodarone therapy and gradually withdrawn {01} {08} {09}; if antiarrhythmic therapy is needed in addition to amiodarone, it should be initiated at one half the usual recommended dose {01} {07})


» Anticoagulants, coumarin-derivative    (amiodarone inhibits metabolism {105} and potentiates the anticoagulant effect {01} {03} {07} {08} {09} {12} {24} {84} {86} {108} {119}, beginning as early as 4 to 6 days after initiation of amiodarone therapy {08} {09} {84} and persisting as long as weeks or months after it is withdrawn {09} {119}; prothrombin times may double or triple {08}, but effect is very erratic {127}; it is recommended that the dose of anticoagulant be reduced by one third to one half and that prothrombin times be monitored closely {01} {07} {08} {09} {24} {84} {119})


Beta-adrenergic blocking agents or
Calcium channel blocking agents    (amiodarone may cause potentiation of bradycardia, sinus arrest, and atrioventricular [AV] block {01} {07} {08} {23} {85}, especially in patients with underlying sinus function impairment {07} {85}. If this occurs, dosage reduction of amiodarone or the beta-blocking agent or calcium channel blocking agent is recommended {99}; in some cases, amiodarone therapy may be continued after insertion of a pacemaker {01})


» Digitalis glycosides    (amiodarone increases serum concentrations of digoxin and probably other digitalis glycosides {01} {03} {07} {08} {09} {12} {13} {79} {85} {107} {108} {111} {112}, possibly to toxic levels; when amiodarone therapy is initiated, the digitalis glycoside should be withdrawn or the dose reduced by 50% {01} {07} {08} {09} {79}; if digitalis glycoside therapy is continued, serum concentrations should be carefully monitored {01} {08} {24} {79} {107}; amiodarone and digitalis glycosides may also produce additive effects on sinoatrial [SA] and AV nodes {09})


Diuretics, loop or
Diuretics, thiazide or
Indapamide    (concurrent use of amiodarone with potassium-depleting diuretics may lead to an increased risk of arrhythmias associated with hypokalemia {127})


» Phenytoin    (amiodarone may increase plasma concentrations of phenytoin, resulting in increased effects and/or toxicity {01} {36} {58} {91})


Photosensitizing medications, other    (concurrent use with amiodarone may cause additive photosensitizing effects )


Sodium iodide I 123 or
Sodium iodide I 131 or
Sodium pertechnetate Tc 99m    (thyroidal uptake may be inhibited by amiodarone {11} {48})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase {127} and
Aspartate aminotransferase (AST [SGOT])    (serum values are commonly increased; hepatotoxicity is rare {01} {08} {24} {73} {85} {97} {122})


Antinuclear antibody (ANA) titer concentration    (may be increased but usually not symptomatic; elevated concentrations may be associated with pulmonary toxicity {24} {85})


Electrocardiogram (ECG) changes, such as:
PR prolongation {02} {03} {08} {09} {24} and
QRS widening, {08} {09} slight and
QT prolongation {01} {02} {03} {08} {09} {12} {20} {24} {85} and
T-wave amplitude reduction with T-wave widening and bifurcation {01} {08} {09} {24} and
U-wave development {02} {03} {08} {09} {24}    (occur in most patients; QT prolongation may in some cases be associated with worsening of arrhythmias {09} {20} {24})

Thyroid function changes, such as
Free and total serum thyroxine (T 4) concentrations    (may be increased {01} {08} {09} {22} {47} {50} {56} {63} {85})


Free and total serum triiodothyronine (T 3) concentrations    (may be decreased {56} {85})


Serum reverse T 3 (rT 3) concentrations    (may be increased {01} {08} {09} {47} {50} {56} {63} {85})


Serum thyroid-stimulating hormone (TSH) concentrations    (may be increased initially {50} {56} {85}; increase in TSH with continued amiodarone treatment, along with a decrease in T 3, is the determining sign of hypothyroidism {01} {08} {09} {50} {56} {65})


Note: Amiodarone inhibits peripheral conversion of T 4 to T 3, leading to increased serum T 4 and rT 3 and a slight decrease in serum T 3 {01} {08} {09} {19} {24} {56} {85}.
Thyroid function abnormalities may persist for several weeks or months after withdrawal of amiodarone {88}.


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Atrioventricular (AV) block, pre-existing 2nd or 3rd degree, without pacemaker {01} {07} {09} {12} {85} {107} {78}    (risk of complete heart block)


» Bradycardic episodes resulting in syncope, unless controlled by pacemaker {01} {07} {85} {107} {78} , or
» Sinus node function impairment, severe, causing marked sinus bradycardia, unless controlled by pacemaker {01} {07} {85} {107} {78}    (amiodarone reduces sinus node automaticity {04} {07} {08} {09} {23} and may cause atropine-resistant sinus bradycardia {01} {03} {08} {09} {10} {14} {23})


» Hepatitis, acute{128}
» Hypersensitivity to amiodarone {01}
Risk-benefit should be considered when the following medical problems exist
Congestive heart failure    (mild negative inotropic effect of amiodarone usually does not cause problems {08} {09} {12} {27} {53} {104}; hemodynamic deterioration may occur secondary to sympatholytic blockage of augmented sympathetic drive {08} {27})


Hepatic function impairment    (reduced metabolism; lower doses may be required {14})


Hypokalemia    (amiodarone may be ineffective or arrhythmogenic; should be corrected prior to initiation of amiodarone therapy {01} {20} {31})


Thyroid function impairment, including goiter or nodules    (increased risk of hypothyroidism or hyperthyroidism {01} {12} {14} {22} {24} {33} {50} {51} {56} {63})


Caution is recommended also during open-heart surgery in patients receiving amiodarone because of the risk of hypotension upon discontinuation of cardiopulmonary bypass {01} {08} {09} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]) and
» Alkaline phosphatase and
» Aspartate aminotransferase (AST [SGOT])    (serum value determinations recommended at regular intervals, especially in patients receiving high maintenance doses {01} {04} {46} {127}; dosage reduction of amiodarone is recommended if concentrations increase to three times normal or double in patients with elevated baseline concentrations, or if hepatomegaly occurs {01} {97} {98})


Auscultation of the chest    (recommended at periodic intervals; presence of rales, decreased breath sounds, or pleuritic friction rub may indicate pulmonary toxicity {01} {09} {16} {49} {80} {115} {126})


Bronchoscopy with lung biopsy    (may be useful if symptoms of pulmonary toxicity occur {08} {09} {25} {49} {83} {101} {126} that cannot be diagnosed from a chest x-ray {127})


Chest x-ray    (recommended prior to initiation of therapy {11} and at 3- to 6-month intervals {01} {03} {08} {09} {24} {46} during therapy to detect diffuse interstitial changes or alveolar infiltrates associated with pulmonary toxicity {08} {09} {16} {24} {25} {49} {80} {82} {83} {101} {115} {126})


» ECG    (continuous Holter monitoring may assist in assessing efficacy and adjusting dosage {01} {05} {08} {24} {32} {34} {46} {53} {80}; usefulness of programmed electrical stimulation in clinical management is controversial {09} {32} {39} {45} {53} {94}, although it may be useful for predicting efficacy of amiodarone {08} {26} {32} {39} {45} {94})


Gallium radionuclide scan    (may be useful if symptoms of pulmonary toxicity occur {01} that cannot be diagnosed from a chest x-ray {127}; may show marked uptake in the lung {09} {16} {25} {126})


Ophthalmologic examinations    (slit-lamp examinations {01} {08} {18} {26} {80} recommended prior to initiation of therapy and if symptoms of ocular toxicity occur)


Plasma amiodarone determinations    (may be useful in dosage adjustment or to assess lack of response or unexpectedly severe toxicity {01} {08} {28} {46} {57} {86}, although correlation does not always occur {08} {09}, especially within first 2 months of therapy)


Pulmonary function determinations, including diffusion capacity {01} {08} {49} {76} {80} {126} and total lung capacity {80}    (recommended prior to initiation of amiodarone therapy and if symptoms of pulmonary toxicity occur that cannot be diagnosed from a chest x-ray {127})


» Thyroid function determinations    (because amiodarone can cause either hypothyroidism or hyperthyroidism, it is recommended that thyroid function be monitored prior to initiation of and at periodic intervals during amiodarone therapy {01} {03} {08} {17} {19} {22} {33} {46} {50} {51} {98}, especially in patients with a history of thyroid nodules, goiter, or other thyroid dysfunction and in patients who are elderly {01}; interpretation of thyroid function tests in patients receiving amiodarone can be difficult because its effects are complex {64}; a flat TSH response to protirelin will help confirm the presence of hyperthyroidism {88})




Side/Adverse Effects

Note: Incidence of side/adverse effects is generally related to dose and duration of therapy {08}. Side/adverse effects may occur even at therapeutic plasma amiodarone concentrations {08} but are more common at concentrations over 2.5 mcg per mL {08} {24} {46} {57} {86} and with continuous treatment for longer than 6 months {01}.
Side/adverse effects may not appear until several days, weeks, or years after initiation of amiodarone therapy and may persist for several months after withdrawal.
Sinus bradycardia is symptomatic in only 2 to 4% of patients taking amiodarone {01} {12}. Sinus arrest and heart block occur rarely {01} {03} {12} {72}. Atrioventricular (AV) block occurs infrequently {09} {53}. New or exacerbated arrhythmias occur in 2 to 5% of patients and may include paroxysmal ventricular tachycardia, ventricular fibrillation, increased resistance to cardioversion, and torsades de pointes {01} {20} {24} {54} {55} {100}; they may be associated with marked {127} QT prolongation {09} {20}. New or exacerbated arrhythmias may also be a sign of hyperthyroidism {88}.
Amiodarone concentrations of > 3 mg per mL (mg/mL) in 5% Dextrose Injection USP (D 5W) have been associated with a high incidence of peripheral vein phlebitis; concentrations £ 2.5 mg/mL appear to be less irritating {35}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypotension{35} (dizziness, lightheadedness, or fainting)
    
neurotoxicity (trouble in walking{01}{03}{09}{12}{15}{24}{101}{106}{117}{125}; numbness or tingling in fingers or toes{01}{08}{09}{10}{12}{15}{73}{85}{106}{117}{118}{125}; trembling or shaking of hands{01}{08}{09}{10}{12}{15}{117}; unusual and uncontrolled movements of body{01}{09}{12}; weakness of arms or legs{08}{09}{15}{25}{26}{73}{85}{101}{106}{117}{118})
    
photosensitivity{01}{03}{08}{12}{24}{61}{71}{85}{101}{113}{116} , particularly to long-wave ultraviolet-A [UVA] light{61}{71}{113} (sensitivity of skin to sunlight)
    
pulmonary fibrosis or interstitial pneumonitis/alveolitis{01}{03}{08}{09}{49}{62}{76}{80}{85}{95}{96}{115}{126} (cough{01}{08}{09}{15}{16}{24}{25}{49}{80}{81}{126}; painful breathing{09}{15}{49}{83}{115}; shortness of breath{01}{08}{15}{16}{24}{25}{49}{80}{81}{115}{126}; slight fever{08}{09}{15}{16}{49}{80}{81}{126})
Note: Neurotoxicity is the most common adverse effect occurring with oral amiodarone therapy {127}; it occurs in 20 to 40% of patients {01}, especially during administration of loading doses {09} {85}; neurotoxicity may occur within 1 week to several months after initiation of therapy {15} and may persist for more than a year after withdrawal {106} {118} {125}.
Hypotension is the most common adverse effect occurring with intravenous amiodarone therapy {35}. In clinical trials, hypotension occurred in 16% of patients treated with intravenous amiodarone {35}. Clinically significant hypotension during infusion of amiodarone was seen most often in the first several hours of treatment and appeared to be related to the rate of infusion, rather than the dose {35}. However, mean daily doses of above 2100 mg are associated with an increased risk of hypotension {35}. Alteration in amiodarone therapy to alleviate hypotension was required in 3% of patients {35}. Permanent discontinuation of amiodarone therapy because of hypotension was necessary in fewer than 2% of patients {35}.
Photosensitivity may occur even through window glass and thin cotton clothing {113} and is not dose-related {127}. Use of protective clothing and a topical product that prevents sunburn is recommended, especially for patients with fair skin or with excessive sun exposure {01}.
Pulmonary fibrosis or interstitial pneumonitis/alveolitis is clinically significant in up to 10 to 15% of patients {01} {09} {16} {77} {126}, but abnormal diffusion capacity occurs in a much higher percentage {01} {49} {80}; it may occur more frequently with doses of 400 mg per day and after several months of treatment {01} {09} {24} {49} but may also occur with small doses {80} {95} {96}; usually reversible after withdrawal of amiodarone, with or without steroid treatment, but is fatal in about 10% of cases {01} {08} {09} {15} {16} {49} {77} {80} {115} {126} {78}, especially when not diagnosed promptly {127}; recurrence has been reported after withdrawal of several months of steroid therapy {77} {81}; often mistaken for but rarely related to congestive heart failure {08} {09} {80} or pneumonic infection {127}.



Incidence less frequent
    
Arrhythmias, new or exacerbated{127} (fast or irregular heartbeat)
    
blue-gray coloring of skin on face, neck, and arms{01}{03}{08}{09}{12}{24}{60}{71}{85}{102}{116}{127}
    
congestive heart failure (swelling of feet or lower legs)
    
hyperthyroidism{01}{03}{08}{09}{12}{19}{22}{24}{51}{56}{124} (nervousness; sensitivity to heat; sweating; trouble in sleeping; weight loss)
    
hypothyroidism{01}{03}{08}{09}{12}{19}{22}{24}{56}{65}{85} (coldness; dry, puffy skin; unusual tiredness; weight gain)
    
noninfectious epididymitis (pain and swelling in scrotum)
    
ocular toxicity (blurred vision or blue-green{85} halos seen around objects; dry eyes; sensitivity of eyes to light), including optic neuropathy and/or optic neuritis
    
sinus bradycardia{01}{12} (slow heartbeat)

Note: Blue-gray skin coloring occurs with prolonged use, usually longer than 1 year {01} {08} {09} {24} {60} {85} {102} {103}, especially in patients with fair skin {01} or with excessive sun exposure {01} {03} {08} {24}; slowly, {01} {08} {24} {85} and occasionally incompletely, {01} {12} {60} {102} reversible {01} {09} {60} {102} after withdrawal.
Hyperthyroidism occurs in about 2% {88} of patients, although thyroid hormone concentration changes are common and may persist for several months after withdrawal of amiodarone {19} {50} {51} {65}. If signs of a new arrhythmia appear, hyperthyroidism should be considered {01}. Amiodarone-associated hyperthyroidism may be followed by a transient period of hypothyroidism {01}.
Hypothyroidism occurs in less than 10% of patients, although thyroid hormone concentration changes are common and may persist for several months after withdrawal of amiodarone {19} {50} {51} {65} {88}.
Optic neuropathy and/or optic neuritis, usually resulting in visual impairment and sometimes progressing to permanent blindness, have been reported and may occur at any time during treatment with amiodarone {01}. If symptoms of visual impairment, such as changes in visual acuity and decreases in peripheral vision, occur, a prompt ophthalmologic examination is recommended and amiodarone treatment should be re-evaluated {01}. Regular ophthalmologic examinations that include funduscopy and slit-lamp procedures are recommended during treatment with amiodarone {01}. Bilateral and symmetric {08} {18} {66} asymptomatic corneal deposits appearing as yellow-brown pigmentation on slit-lamp examination occur in all patients after 6 months of treatment {01} {03} {08} {09} {10} {12} {18} {24} {26} {66} {67}, but may appear sooner {09} {10} {18} {66} {85}; symptomatic corneal deposits occur in up to 10% of patients {01} {08} {09} {18} {24} {26} {85}; macular degeneration and decreased visual acuity are rare {03} {24}; corneal deposits are reversible after withdrawal of amiodarone {08} {09} {66}, although it may take up to 7 months {08} {18}.
Sinus bradycardia usually responds to dosage reduction but may require a pacemaker {01} {08} {09} {26} {53}; atropine-resistant {09} {14} {23}.


Incidence rare
    
Allergic reaction{09}{24}{74}{85} (skin rash)
    
hepatitis{03}{08}{09}{24}{73} (yellow eyes or skin)

Note: Allergic reaction usually occurs within the first 2 weeks of therapy {85}.
In hepatitis, hepatic enzymes are commonly elevated {01} {03} {08} {09} {122} to several times normal {09} {122} {123} within 2 months after initiation of therapy {08}; deaths as a result of hepatic failure resembling alcoholic cirrhosis {01} {03} {08} {59} {73} {97} {98} {122} have occurred rarely {01} {59} {73} {123}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—approximately 25%, especially during administration of high doses, as during loading{01}{53}    
Constipation{01}{24}
    
headache
    
loss of appetite{01}{03}{08}{09} —may lead to severe weight loss{09}{13}{101}
    
nausea and vomiting

Incidence less frequent
    
Bitter or metallic taste{01}{12}{24}{26}
    
decreased sexual ability in males{09}
    
decrease in sexual interest{01}
    
dizziness (central nervous system [CNS] effect{01}{10}{12}; hypotension is rare{01})
    
flushing of face



Those indicating possible pulmonary toxicity and the need for medical attention if they occur after medication is discontinued
    
Cough
    
fever, slight
    
painful breathing
    
shortness of breath




Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Decrease absorption—Recent oral ingestion may benefit from emesis and/or lavage {12}.


Specific treatment:
Primarily supportive and symptomatic.

Monitoring of cardiac rhythm and blood pressure is important {01}.

For bradycardia, a beta-adrenergic agonist or pacemaker may be indicated {01} {12}.

Hypotension may respond to positive inotropic and/or vasopressor agents {01}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Amiodarone (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to amiodarone

Pregnancy—Potential risk of bradycardia and iodine toxicity in fetus





Breast-feeding—Distributed into breast milk




Use in children—Shorter onset and duration of action; intravenous administration is not recommended






Use in the elderly—Increased sensitivity to effects on thyroid function and increased incidence of ataxia and other neurotoxic effects
Other medications, especially other antiarrhythmics, coumarin-derivative anticoagulants, digitalis glycosides, or phenytoin
Other medical problems, especially pre-existing atrioventricular (AV) block without pacemaker, bradycardic episodes resulting in syncope (unless controlled by pacemaker), severe sinus node function impairment causing marked bradycardia (unless controlled by pacemaker), or acute hepatitis.

Proper use of this medication
» Compliance with therapy; taking as directed even if feeling well

» Proper dosing
Not taking at all; notifying physician if two or more doses in a row are missed; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

Carrying medical identification card or bracelet

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required

» Protecting skin from sunlight during and for several months following withdrawal of treatment; sunburns may occur even through window glass and thin cotton clothing; use of protective clothing and a topical product that prevents sunburn; checking with physician if severe sunburn occurs

Checking with physician if blue-gray discoloration of skin occurs

» Checking with physician if changes in vision, such as a decrease in peripheral vision or a decrease in clarity of vision, occur


Side/adverse effects
Signs and symptoms of potential side effects, especially hypotension; neurotoxicity; photosensitivity, particularly to long-wave ultraviolet-A (UVA) light; pulmonary fibrosis or interstitial pneumonitis/alveolitis; new or exacerbated arrhythmias; blue-gray coloring of skin on face, neck, and arms; congestive heart failure; hyperthyroidism; hypothyroidism; noninfectious epididymitis; ocular toxicity, including optic neuropathy and/or optic neuritis; sinus bradycardia; allergic reaction; and hepatitis


General Dosing Information
Because of its delayed onset of action, difficulty in dosage adjustment, and potentially serious adverse effects, it is recommended that amiodarone administration be initiated in the hospital and that the patient remain in the hospital at least for the loading dose phase {01} {45} {94}. Amiodarone should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, are thoroughly familiar with the risks and benefits of amiodarone therapy, and have access to laboratory facilities equipped to adequately monitor the effectiveness and side effects of amiodarone therapy {01}.

Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response, appearance or severity of toxicity, and in some cases, plasma amiodarone concentrations {127}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Hypotension associated with intravenous amiodarone administration should be treated initially by slowing the infusion rate {35}. Additional therapy, if needed, may include volume expansion and administration of vasopressor agents and/or positive inotropic agents {35}.
   • If hypothyroidism occurs, dosage reduction or withdrawal of amiodarone is recommended {09} {50} {85}, along with addition of thyroid hormone supplementation {01} {08} {09} {50} {85}.
   • Hyperthyroidism, which may be associated with signs of new or breakthrough arrhythmias, should be treated by reducing the dose of or withdrawing amiodarone {01}. Additional therapy may include the use of antithyroid drugs, beta adrenergic blocking agents, and/or temporary corticosteroid therapy {01}. However, the effects of antithyroid drugs may be delayed due to substantial quantities of preformed thyroid hormones in the gland {01}. Because amiodarone-induced hyperthyroidism is associated with low radioiodine uptake, radioactive iodine therapy is contraindicated {01}. Thyroid surgery in this setting may be associated with a risk of inducing thyroid storm {88}.
   • If signs or symptoms of pulmonary toxicity occur, it is recommended that amiodarone therapy be withdrawn until the cause has been determined {01} {15} {49}. If pulmonary toxicity is related to amiodarone, withdrawal of amiodarone {01} {09} {80} is recommended. Usefulness of steroid therapy is controversial {01} {09} {24} {81} {101} {115} {120} {126}, but such therapy may be useful for severe toxicity {127}.
   • Nausea and vomiting may be relieved by reduction of dose or administration of amiodarone in divided doses {01}.
   • If epididymitis occurs, dosage reduction or withdrawal of amiodarone is recommended {14} {109} {114}.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

AMIODARONE HYDROCHLORIDE TABLETS

Note: Because amiodarone has a long terminal plasma elimination half-life, the time to reach steady-state would take several months if the drug were administered at usual doses; therefore, loading doses are necessary in order to ensure that an antiarrhythmic effect occurs within a reasonable period of time {01}. The patient should be closely monitored during the loading phase of therapy, especially until the risk of recurrent ventricular tachycardia or fibrillation has subsided {01}. Elimination of ventricular fibrillation and tachycardia, along with a reduction in complex and total ventricular ectopic beats, usually occurs within 1 to 3 weeks {01}.
Because of the potential for interactions with other antiarrhythmic drugs, it is recommended that an attempt be made to gradually discontinue the administration of prior antiarrhythmic drugs upon starting amiodarone therapy {01}.


Usual adult dose
Ventricular arrhythmias (ventricular fibrillation or hemodynamically unstable ventricular tachycardia)
Loading: Oral, 800 mg to 1.6 grams per day for one to three weeks (or longer, if necessary) until an initial therapeutic response {01} {03} {08} {38} {45} {78} or side effects {127} occur; may be given in divided doses with meals for doses greater than 1 gram per day or if gastrointestinal side effects occur {01} {78}. When adequate control is achieved or excessive side effects occur, the dose is reduced to 600 to 800 mg per day for one month {01} {38} {45} and then decreased again to the lowest effective maintenance dose {01}. The lowest effective maintenance dose should be used to prevent the occurrence of side effects {01}.

Maintenance: Oral, approximately 400 mg per day {01} {38} {45}, the dosage being increased or decreased as necessary. Higher maintenance doses (up to 600 mg per day) or lower maintenance doses may be required in some patients {01}. The long-term maintenance dose should be determined according to the antiarrhythmic effect as assessed by symptoms, tolerance, and Holter recordings and/or programmed electrical stimulation {01}. Amiodarone plasma concentration determinations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity {01}.

When dosage adjustments are necessary, patients should be closely monitored for an extended period of time because of the long and variable half-life of amiodarone and the difficulty of predicting the time required to attain a new steady-state amiodarone concentration {01}.

[Supraventricular tachycardia]1
Loading: Oral, 600 to 800 mg per day for one week {24} {46} or until an initial therapeutic response or side effects {127} occur. When adequate control is achieved or excessive side effects occur, the dose is reduced to 400 mg per day for three weeks {24}.

Maintenance: Oral, 200 to 400 mg per day {08} {24} {46}.


Usual pediatric dose
Ventricular arrhythmias
[Supraventricular arrhythmias ]1
Loading: Oral, 10 mg per kg of body weight per day {08} or 800 mg per 1.72 square meters of body surface area per day {09} {17} for ten days or until an initial therapeutic response {08} or side effects {127} occur. When adequate control is achieved or excessive side effects occur, the dose is reduced to 5 mg per kg of body weight or 400 mg per 1.72 square meters of body surface area per day for several weeks and then decreased gradually to the lowest effective maintenance dose {08}.

Maintenance: Oral, 2.5 mg per kg of body weight per day {08} or 200 mg per 1.72 square meters of body surface area per day.


Strength(s) usually available
U.S.—


200 mg (Rx) [Cordarone (scored) ( lactose)]

Canada—


200 mg (Rx) [Cordarone (scored) ( lactose)] [pms-Amiodarone (lactose) (magnesium stearate ) (povidone) (silicon dioxide) (sodium starch glycolate) (FD&C red #40 lake)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Protect from light.



Parenteral Dosage Forms

Note: The surface properties of solutions containing injectable amiodarone are altered, reducing the solution drop size {35}. This phenomenon may result in underdosing the patient by up to 30% if a drop counter infusion set is used; therefore, a volumetric infusion pump must be used to deliver amiodarone {35}. Whenever possible, amiodarone should be administered through a central venous catheter dedicated to this purpose; an in-line filter should also be used during administration {35}.


Note: An expert panel concluded that (based on animal studies) amiodarone I.V. administration may indirectly but adversely affect male reproductive tract development during fetal, infant, and toddler stages of development. The indirect effects may be linked to plasticizers that leach out from the I.V. tubing during certain administration conditions, such as higher amiodarone concentrations and lower flow rates.{129}


AMIODARONE HYDROCHLORIDE INJECTION

Note: Amiodarone shows considerable interindividual variation in response; therefore, monitoring is necessary at dosage initiation, at dosage adjustments, and when switching to oral amiodarone therapy {35}.


Usual adult dose
Ventricular arrhythmias (ventricular fibrillation or hemodynamically unstable ventricular tachycardia)

Note: The recommended starting dose of intravenous amiodarone is about 1000 mg over the first twenty-four hours {35}.



First twenty-four hours:


Loading infusions (may be individualized for each patient)—


First, rapid intravenous infusion—
150 mg administered by rapid intravenous infusion over the first ten minutes (15 mg per minute) {35}.



Next, slow intravenous infusion—
360 mg administered by slow intravenous infusion over the next six hours (1 mg per minute) {35}.




Maintenance infusion (decreasing the rate of the slow intravenous infusion)—
Intravenous infusion, 540 mg of amiodarone is delivered over the remaining eighteen hours (0.5 mg per minute) {35}.




After the first twenty-four hours:
The maintenance infusion rate of 0.5 mg per minute (720 mg per twenty-four hours) should be continued, using a concentration of 1 to 6 mg per mL (concentrations greater than 2 mg per mL should be administered via a central venous catheter) {35}. In the event of breakthrough episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia, supplemental infusions of 150 mg may be administered {35}. Such infusions should be administered over a period of ten minutes to minimize the potential for hypotension {35}. The rate of the maintenance infusion may be increased to effectively achieve arrhythmia suppression {35}.

Intravenous amiodarone should be used for acute treatment until the patient's ventricular arrhythmias have been stabilized {35}. Most patients will require therapy for forty-eight to ninety-six hours, and intravenous amiodarone may be safely administered for longer periods of time if necessary, although intravenous amiodarone is not intended for maintenance treatment {35}. There has been limited experience in patients receiving intravenous amiodarone for longer than three weeks {35}. Patients whose arrhythmias have been suppressed by intravenous amiodarone may be switched to oral amiodarone {35}.



Usual adult prescribing limits
The initial infusion rate should not exceed 30 mg per minute {35}. Infusions lasting longer than one hour should not exceed a concentration of 2 mg per mL unless a central venous catheter is used {35}. Amiodarone concentrations of > 3 mg/mL in 5% Dextrose Injection USP (D 5W), have been associated with a high incidence of peripheral vein phlebitis; concentrations £ 2.5 mg/mL appear to be less irritating {35}. In clinical trials, mean daily doses of above 2100 mg were associated with an increased risk of hypotension {35}.

A maintenance infusion of up to 0.5 mg per minute of amiodarone can be cautiously continued for two to three weeks, regardless of the patient's age, renal function, or left ventricular function, but experience is limited in patients receiving intravenous amiodarone for longer than three weeks {35}.

Usual pediatric dose
Safety and efficacy have not been established in patients younger than 18 years of age; use is not recommended {35}.

Strength(s) usually available
U.S.—


50 mg per mL (Rx) [Cordarone I.V.]

Canada—


50 mg per mL (Rx) [Cordarone Intravenous{40}]

Packaging and storage:
Store at room temperature, between 15 and 25 ºC (59 and 77 ºF) {35}. Protect from light {35}.

Note: Intravenous amiodarone does not need to be protected from light during administration {35}.


Preparation of dosage form:
To prepare the rapid intravenous infusion, add 3 mL of amiodarone (150 mg) to 100 mL of 5% Dextrose Injection USP (D 5W) {35}. The resulting concentration is 1.5 mg per mL {35}.

To prepare the slow intravenous infusion, add 18 mL of amiodarone (900 mg) to 500 mL of 5% Dextrose Injection USP (D 5W) {35}. The resulting concentration is 1.8 mg per mL {35}.

Stability:
The dose administration schedule used in clinical trials was designed to take into consideration the adsorption of amiodarone to polyvinyl chloride (PVC) tubing {35}. Because clinical trials were conducted using PVC tubing, its use is recommended for delivery of amiodarone {35}. The recommended concentrations and infusion rates reflect those identified in clinical trials; it is important that these recommendations be followed closely {35}. Amiodarone infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing 5% Dextrose Injection USP (D 5W) {35}.


PVC container—
Amiodarone is physically compatible; amiodarone loss is less than 10% at 2 hours in 5% Dextrose Injection USP (D 5W) at a concentration of 1 to 6 mg of amiodarone per mL {35}.



Polyolefin or glass container—
Amiodarone is physically compatible; no amiodarone loss occurs at 24 hours in 5% Dextrose Injection USP (D 5W) at a concentration of 1 to 6 mg of amiodarone per mL {35}.



Incompatibilities:
Amiodarone admixed with 5% Dextrose Injection USP (D 5W) to a concentration of 4 mg per mL is incompatible and forms a precipitate with aminophylline, cefamandole nafate, cefazolin sodium, and mezlocillin sodium {35}. Amiodarone also forms a precipitate with sodium bicarbonate at a concentration of 3 mg per mL and with heparin sodium at an unknown concentration {35}.

Additional information:
Intravenous amiodarone is not intended for long-term (longer than 3 weeks) maintenance treatment; patients whose arrhythmias have been suppressed by intravenous amiodarone may be switched to oral amiodarone {35}. The optimal dose to use when changing from intravenous to oral amiodarone will depend on the dose of intravenous amiodarone already administered, as well as the bioavailability of oral amiodarone {35}. Clinical monitoring is recommended when patients, particularly the elderly, are changed to oral amiodarone therapy {35}.

Recommendations for oral dosage after intravenous infusion * 
Duration of intravenous amiodarone infusion (assuming a 720 mg per day infusion [0.5 mg per minute])  Initial daily dose of oral amiodarone 
< 1 week  800 to 1600 mg 
1 to 3 weeks  600 to 800 mg  
> 3 weeks   400 mg 
* Based on a comparable total body amount of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability of oral amiodarone {35}.




Revised: 06/26/2001



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