Amiodarone (tablet)

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# Black Box Warning

# Overview
Amiodarone (tablet) is an antiarrhythmic that is FDA approved for the treatment of ventricular arrhythmia. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include bradyarrhythmia, hypotension, photodermatitis, photosensitivity, thyroid dysfunction, constipation, loss of appetite, nausea, vomiting, increased liver enzymes, abnormal gait, coordination problem, dizziness, movement disorder, paresthesia, peripheral neuropathy, corneal deposit, visual disturbances, malaise, and fatigue.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Because of its life-threatening side effects and the substantial management difficulties associated with its use, amiodarone hydrochloride tablets are indicated only for the treatment of the following documented, life-threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated.
- Recurrent ventricular fibrillation.
- Recurrent hemodynamically unstable ventricular tachycardia.
- As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of amiodarone hydrochloride tablets favorably affects survival.
- Amiodarone hydrochloride tablets should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life-threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologic techniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with amiodarone hydrochloride tablets should be carried out in the hospital.
- Because of the unique pharmacokinetic properties, difficult dosing schedule, and severity of the side effects if patients are improperly monitored, amiodarone hydrochloride tablets should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias who are thoroughly familiar with the risks and benefits of amiodarone hydrochloride tablet therapy, and who have access to laboratory facilities capable of adequately monitoring the effectiveness and side effects of treatment.
- In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of amiodarone hydrochloride tablets has not been determined. Because of the food effect on absorption, amiodarone hydrochloride tablets should be administered consistently with regard to meals. Individual patient titration is suggested according to the following guidelines:
- For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia: Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 mg/day to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of amiodarone hydrochloride tablets in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats.
- Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone .
- Upon starting amiodarone hydrochloride tablet therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs. When adequate arrhythmia control is achieved, or if side effects become prominent, amiodarone hydrochloride tablets dose should be reduced to 600 mg/day to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day. Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Amiodarone hydrochloride tablets may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity.
- The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patients arrhythmia and response to therapy.
- When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of amiodarone hydrochloride tablets and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below:

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone (tablet) in adult patients.

### NonGuideline-Supported Use
- Amiodarone (5 milligrams/kilogram (mg/kg)) by rapid infusion.
- Intravenous administration of amiodarone (300 milligram (mg) bolus followed by a continuous infusion for 72 hours (900 mg in the first 48 hours then reduced to 600 mg/24 hours)).
- Oral amiodarone in doses of 200 to 600 milligrams daily.
- At a dose of 200 to 400 mg daily, amiodarone significantly reduces the incidence of nonsustained ventricular tachycardia.
- Amiodarone (600 to 1000 milligrams orally daily) is effective in the treatment of ventricular arrhythmias in patients with myocarditis secondary to Chagas disease (South American trypanosomiasis).
- Amiodarone 200 to 600 mg/day.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Amiodarone (tablet) in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone (tablet) in pediatric patients.

### NonGuideline-Supported Use
- Transplacentally treated by administering to mothers oral amiodarone (loading dose 1800 to 2400 milligrams (mg)/day for 2 to 7 days followed by a maintenance dose of 200 to 400 mg/day).
- Amiodarone (usual dose, intravenous (IV) bolus of 5 milligrams (mg)/kg over 1 to 4 hours, followed by a continuous IV infusion of 7 to 21 mg/kg/day).

# Contraindications
- Amiodarone hydrochloride is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third-degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker).
- Amiodarone hydrochloride is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.

# Warnings
- Mortality
- In the National Heart, Lung and Blood Institutes Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-centered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had had myocardial infarctions more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with encainide or flecainide (56/730) compared with that seen in patients assigned to matched placebo-treated groups (22/725). The average duration of treatment with encainide or flecainide in this study was ten months.
- Amiodarone hydrochloride therapy was evaluated in two multi-centered, randomized, double-blind, placebo-controlled trials involving 1202 (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial; CAMIAT) and 1486 (European Myocardial Infarction Amiodarone Trial; EMIAT) post-MI patients followed for up to 2 years. Patients in CAMIAT qualified with ventricular arrhythmias, and those randomized to amiodarone received weight- and response-adjusted doses of 200 mg/day to 400 mg/day. Patients in EMIAT qualified with ejection fraction <40%, and those randomized to amiodarone received fixed doses of 200 mg/day. Both studies had weeks-long loading dose schedules. Intent-to-treat all-cause mortality results were as follows:
- These data are consistent with the results of a pooled analysis of smaller, controlled studies involving patients with structural heart disease (including myocardial infarction).
- Pulmonary Toxicity
- There have been post-marketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral amiodarone hydrochloride with or without initial I.V. therapy. Findings have included pulmonary infiltrates and/or mass on X-ray, pulmonary alveolar hemorrhage, pleural effusion, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure and/or death. Post-marketing reports describe cases of pulmonary toxicity in patients treated with low doses of amiodarone hydrochloride; however, reports suggest that the use of lower loading and maintenance doses of amiodarone hydrochloride are associated with a decreased incidence of amiodarone hydrochloride-induced pulmonary toxicity.
- Amiodarone hydrochloride tablets may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium-scan, and pathological data consistent with pulmonary toxicity, the frequency of which varies from 2% to 7% in most published reports, but is as high as 10% to 17% in some reports. Therefore, when amiodarone hydrochloride therapy is initiated, a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, should be performed. The patient should return for a history, physical exam, and chest X-ray every 3 to 6 months.
- Pulmonary toxicity secondary to amiodarone hydrochloride seem to result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively.
- Patients with preexisting pulmonary disease have a poorer prognosis if pulmonary toxicity develops.
- Hypersensitivity Pneumonitis usually appears earlier in the course of therapy, and rechallenging these patients with amiodarone hydrochloride results in a more rapid recurrence of greater severity.
- Bronchoalveolar lavage is the procedure of choice to confirm this diagnosis, which can be made when a T suppressor/cytotoxic (CD8-positive) lymphocytosis is noted. Steroid therapy should be instituted and amiodarone hydrochloride therapy discontinued in these patients.
- Interstitial/Alveolar Pneumonitis may result from the release of oxygen radicals and/or phospholipidosis and is characterized by findings of diffuse alveolar damage, interstitial pneumonitis or fibrosis in lung biopsy specimens. Phospholipidosis (foamy cells, foamy macrophages), due to inhibition of phospholipase, will be present in most cases of amiodarone hydrochloride-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone hydrochloride therapy. These cells should be used as markers of therapy, but not as evidence of toxicity. A diagnosis of amiodarone hydrochloride-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of the amiodarone hydrochloride to establish reversibility, especially if other acceptable antiarrhythmic therapies are available. Where these measures have been instituted, a reduction in symptoms of amiodarone-induced pulmonary toxicity was usually noted within the first week, and a clinical improvement was greatest in the first two to three weeks. Chest X-ray changes usually resolve within two to four months. According to some experts, steroids may prove beneficial. Prednisone in doses of 40 mg/day to 60 mg/day or equivalent doses of other steroids have been given and tapered over the course of several weeks depending upon the condition of the patient. In some cases rechallenge with amiodarone hydrochloride at a lower dose has not resulted in return of toxicity.
- In a patient receiving amiodarone hydrochloride, any new respiratory symptoms should suggest the possibility of pulmonary toxicity, and the history, physical exam, chest X-ray, and pulmonary-function tests (with diffusion capacity) should be repeated and evaluated. A 15% decrease in diffusion capacity has a high sensitivity but only a moderate specificity for pulmonary toxicity; as the decrease in diffusion capacity approaches 30%, the sensitivity decreases but the specificity increases. A gallium-scan also may be performed as part of the diagnostic workup.
- Fatalities, secondary to pulmonary toxicity, have occurred in approximately 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of amiodarone hydrochloride therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution, as the most common cause of death in these patients is sudden cardiac death. Therefore, every effort should be made to rule out other causes of respiratory impairment (i.e., congestive heart failure with Swan-Ganz catheterization if necessary, respiratory infection, pulmonary embolism, malignancy, etc.) before discontinuing amiodarone hydrochloride in these patients. In addition, bronchoalveolar lavage, transbronchial lung biopsy and/or open lung biopsy may be necessary to confirm the diagnosis, especially in those cases where no acceptable alternative therapy is available.
- If a diagnosis of amiodarone hydrochloride-induced hypersensitivity pneumonitis is made, amiodarone hydrochloride should be discontinued, and treatment with steroids should be instituted. If a diagnosis of amiodarone hydrochloride-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, amiodarone hydrochloride discontinued or, at a minimum, reduced in dosage. Some cases of amiodarone hydrochloride-induced interstitial/alveolar pneumonitis may resolve following a reduction in amiodarone hydrochloride dosage in conjunction with the administration of steroids. In some patients, rechallenge at a lower dose has not resulted in return of interstitial/alveolar pneumonitis; however, in some patients (perhaps because of severe alveolar damage) the pulmonary lesions have not been reversible.
- Worsened Arrhythmia
- Amiodarone hydrochloride, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia, a risk that may be enhanced by the presence of concomitant antiarrhythmics. Exacerbation has been reported in about 2% to 5% in most series, and has included new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes ). In addition, amiodarone hydrochloride has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2% to 4% of patients.
- Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.
- The need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient.
- A careful assessment of the potential risks and benefits of administering amiodarone hydrochloride must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia in these patients.
- Implantable Cardiac Devices
- In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillating thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.
- Thyrotoxicosis
- Amiodarone hydrochloride-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. There have been reports of death associated with amiodarone-induced thyrotoxicosis. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered.
- Liver Injury
- Elevations of hepatic enzyme levels are seen frequently in patients exposed to amiodarone hydrochloride and in most cases are asymptomatic. If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of amiodarone hydrochloride or dosage reduction should be considered. In a few cases in which biopsy has been done, the histology has resembled that of alcoholic hepatitis or cirrhosis. Hepatic failure has been a rare cause of death in patients treated with amiodarone hydrochloride.
- Loss of Vision
- Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of amiodarone hydrochloride therapy. The risks and complications of antiarrhythmic therapy with amiodarone hydrochloride must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of amiodarone hydrochloride.
- Neonatal Hypo- or Hyperthyroidism
- Amiodarone hydrochloride can cause fetal harm when administered to a pregnant woman. Although amiodarone hydrochloride use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism. If amiodarone hydrochloride is used during pregnancy, or if the patient becomes pregnant while taking amiodarone hydrochloride, the patient should be apprised of the potential hazard to the fetus.
- In general, amiodarone hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the unknown risk to the fetus.
- In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose*) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose*) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose*.) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose*).
- 600 mg in a 50 kg patient (doses compared on a body surface area basis)

### Precautions
- Optic Neuropathy and/or Neuritis
- Cases of optic neuropathy and optic neuritis have been reported.
- Corneal Microdeposits
- Corneal microdeposits appear in the majority of adults treated with amiodarone hydrochloride. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment.
- Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.
- Amiodarone hydrochloride has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.
- Amiodarone hydrochloride inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased thyroxine levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, amiodarone hydrochloride can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone hydrochloride and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following amiodarone hydrochloride withdrawal.
- Hypothyroidism has been reported in 2% to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing amiodarone hydrochloride and considering the need for thyroid hormone supplement.
- Hyperthyroidism occurs in about 2% of patients receiving amiodarone hydrochloride, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone hydrochloride-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone hydrochloride-induced thyrotoxicosis. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered.
- Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T3 RIA, and further elevations of serum T4, and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany amiodarone hydrochloride-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone hydrochloride.
- The institution of antithyroid drugs, -adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Amiodarone hydrochloride-induced hyperthyroidism may be followed by a transient period of hypothyroidism.
- When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.
- There have been post-marketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone hydrochloride. In some instances hyperthyroidism was also present.
- Volatile Anesthetic Agents
- Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.
- Hypotension Postbypass
- Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving amiodarone hydrochloride have been reported. The relationship of this event to amiodarone hydrochloride therapy is unknown.
- Adult Respiratory Distress Syndrome (ARDS)
- Postoperatively, occurrences of ARDS have been reported in patients receiving amiodarone hydrochloride therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on amiodarone hydrochloride.
- Corneal Refractive Laser Surgery
- Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking amiodarone hydrochloride.

# Adverse Reactions

## Clinical Trials Experience
- Adverse reactions have been very common in virtually all series of patients treated with amiodarone hydrochloride for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7% to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury, but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of amiodarone hydrochloride treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study.
- Neurologic problems are extremely common, occurring in 20% to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation. There have been spontaneous reports of demyelinating polyneuropathy.
- Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (i.e., loading dose) and usually respond to dose reduction or divided doses.
- Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported.
- Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed.
- Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to amiodarone hydrochloride occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only.
- Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug.
- The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days).
- The following side effects were each reported in 10% to 33% of patients:
Nausea and vomiting.
- The following side effects were each reported in 4% to 9% of patients:
Solar dermatitis/photosensitivity.
Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias.
Constipation, anorexia.
Visual disturbances.
Abnormal liver-function tests.
Pulmonary inflammation or fibrosis.
- The following side effects were each reported in 1% to 3% of patients:
Hypothyroidism, hyperthyroidism.
Decreased libido, insomnia, headache, sleep disturbances.
Congestive heart failure, cardiac arrhythmias, SA node dysfunction.
Abdominal pain.
Nonspecific hepatic disorders.
Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.
- The following side effects were each reported in less than 1% of patients:
- Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities.
- In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with amiodarone hydrochloride, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism.

## Postmarketing Experience
- In post-marketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, acute pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, impotence and dry mouth, also have been reported with amiodarone therapy.

# Drug Interactions
- Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is an inhibitor of CYP3A4 and p-glycoprotein. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4 and substrates of p-glycoprotein. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone.
- Since amiodarone is a substrate for CYP3A4 and CYP2C8, drugs/substances that inhibit CYP3A4 may decrease the metabolism and increase serum concentrations of amiodarone. Reported examples include the following:
- Protease Inhibitors
- Protease inhibitors are known to inhibit CYP3A4 to varying degrees. A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0.9 mg/L to 1.3 mg/L. DEA concentrations were not affected. There was no evidence of toxicity. Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered.
- Histamine H1 Antagonists
- Loratadine, a non-sedating antihistaminic, is metabolized primarily by CYP3A4. QT prolongation and Torsade de Pointes have been reported with the co-administration of loratadine and amiodarone.
- Histamine H2 Antagonists
- Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels.
- Antidepressants
- Trazodone, an antidepressant, is metabolized primarily by CYP3A4. QT prolongation and Torsade de Pointes have been reported with the co-administration of trazodone and amiodarone.
- Other substances
- Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when changing from intravenous amiodarone to oral amiodarone.
- Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6 and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of p-glycoprotein. Reported examples of this interaction include the following:
- Immunosuppressives
- Cyclosporine (CYP3A4 substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.
- HMG-CoA Reductase Inhibitors
- The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis.
- Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.
- Cardiovasculars
- Cardiac Glycosides
- In patients receiving digoxin therapy, administration of oral amiodarone regularly results in an increase in the serum digoxin concentration that may reach toxic levels with resultant clinical toxicity. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity. These precautions probably should apply to digitoxin administration as well.
- Antiarrhythmics
- Other antiarrhythmic drugs, such as quinidine, procainamide, disopyramide, and phenytoin, have been used concurrently with oral amiodarone.
- There have been case reports of increased steady-state levels of quinidine, procainamide, and phenytoin during concomitant therapy with amiodarone. Phenytoin decreases serum amiodarone levels. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Quinidine and procainamide doses should be reduced by one-third when either is administered with amiodarone. Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone; because of this, the dosage of flecainide should be adjusted when these drugs are administered concomitantly. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring.
- Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transfer to amiodarone the dose levels of previously administered agents should be reduced by 30% to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.
- Antihypertensives
- Amiodarone should be used with caution in patients receiving -receptor blocking agents (e.g., propranolol, a CYP3A4 inhibitor) or calcium channel antagonists (e.g., verapamil, a CYP3A4 substrate, and diltiazem, a CYP3A4 inhibitor) because of the possible potentiation of bradycardia, sinus arrest, and AV block; if necessary, amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest.
- Anticoagulants
- Potentiation of warfarin-type (CYP2C9 and CYP3A4 substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely.
- Clopidogrel, an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and amiodarone hydrochloride resulting in ineffective inhibition of platelet aggregation has been reported.
- Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:
- Antibiotics
- Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.
- Other substances, including herbal preparations
- St. Johns Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. Johns Wort in patients receiving amiodarone could result in reduced amiodarone levels.
- Other reported interactions with amiodarone
- Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.
- Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.
- Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.
- Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t1/2.
- Disopyramide increases QT prolongation which could cause arrhythmia.
- Fluoroquinolones, macrolide antibiotics and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.
- Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem and verapamil.
- Volatile Anesthetic Agents
- In addition to the interactions noted above, chronic (> 2 weeks) oral amiodarone hydrochloride administration impairs metabolism of phenytoin, dextromethorphan and methotrexate.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amiodarone (tablet) in women who are pregnant.

### Labor and Delivery
- It is not known whether the use of amiodarone hydrochloride during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of amiodarone hydrochloride on the duration of gestation or on parturition.

### Nursing Mothers
- Amiodarone hydrochloride and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breastfeeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone hydrochloride have been shown to be less viable and have reduced body-weight gains. Therefore, when amiodarone hydrochloride therapy is indicated, the mother should be advised to discontinue nursing.

### Pediatric Use
- The safety and effectiveness of amiodarone hydrochloride in pediatric patients have not been established.

### Geriatic Use
- Clinical studies of amiodarone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

### Gender
There is no FDA guidance on the use of Amiodarone (tablet) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Amiodarone (tablet) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Amiodarone (tablet) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Amiodarone (tablet) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Amiodarone (tablet) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Amiodarone (tablet) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Monitoring of Amiodarone (tablet) in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Amiodarone (tablet) in the drug label.

# Overdosage

## Acute Overdose
- There have been cases, some fatal, of amiodarone hydrochloride overdose.
- In addition to general supportive measures, the patients cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a -adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither amiodarone hydrochloride nor its metabolite is dialyzable.
- The acute oral LD50 of amiodarone hydrochloride in mice and rats is greater than 3,000 mg/kg.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Amiodarone (tablet) in the drug label.

# Pharmacology
There is limited information regarding Amiodarone (tablet) Pharmacology in the drug label.

## Mechanism of Action
- In animals, amiodarone hydrochloride is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of amiodarone hydrochloride may be due to at least two major properties: 1) a prolongation of the myocardial cell-action potential duration and refractory period and 2) noncompetitive - and -adrenergic inhibition.
- Amiodarone hydrochloride prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone hydrochloride increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15% to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of amiodarone hydrochloride as there is evidence of its pharmacological action, although amiodarone hydrochloride can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia (see WARNINGS).

## Structure
- Amiodarone hydrochloride tablets are a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams classification) effects, available for oral administration as yellow, scored tablets. Each tablet for oral administration contains 200 mg of amiodarone hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, and D&C yellow No. 10 aluminum lake. Amiodarone hydrochloride tablets are a benzofuran derivative: 2-butyl-3-benzofuranyl 4--3,5-diiodophenyl ketone hydrochloride.
- The structural formula is as follows:
- Amiodarone hydrochloride is a white to cream-colored crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight.

## Pharmacodynamics
- There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.

## Pharmacokinetics
- Following oral administration in man, amiodarone hydrochloride is slowly and variably absorbed. The bioavailability of amiodarone hydrochloride is approximately 50%, but has varied between 35% and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 mg/day to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of amiodarone hydrochloride. The effects of food upon the bioavailability of amiodarone hydrochloride has been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of desethylamiodarone increased by 55% (range 58% to 101%) and 32% (range 4% to 84%), respectively, but there was no change in the Tmax in the presence of food.
- Amiodarone hydrochloride has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of amiodarone hydrochloride, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEAs precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class lll effects after oral amiodarone hydrochloride administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.
- Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines.
- Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.
- In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 mL/hr/kg and 440 mL/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in t1/2 from about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t1/2 of DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with amiodarone hydrochloride, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.
- Following single dose administration in 12 healthy subjects, amiodarone hydrochloride exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone hydrochloride has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of amiodarone hydrochloride should be based on individual patient requirements (see DOSAGE AND ADMINISTRATION).
- Amiodarone hydrochloride and its metabolite have a limited transplacental transfer of approximately 10% to 50%. The parent drug and its metabolite have been detected in breast milk.
- Amiodarone hydrochloride is highly protein-bound (approximately 96%).
- Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of amiodarone hydrochloride, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used.
- Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after amiodarone hydrochloride is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence.

## Nonclinical Toxicology
- Amiodarone hydrochloride was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose*).
- Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with amiodarone hydrochloride were negative.
- In a study in which amiodarone hydrochloride was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose*).
- 600 mg in a 50 kg patient (dose compared on a body surface area basis)

# Clinical Studies
There is limited information regarding Clinical Studies of Amiodarone (tablet) in the drug label.

# How Supplied
- Amiodarone Hydrochloride Tablets for oral administration are available as:
- 200 mg: Round, flat-faced, beveled edge, yellow tablets debossed E over bisect, 144 below bisect, plain on the reverse side and supplied as:
- NDC 0185-0144-60 bottles of 60
- NDC 0185-0144-09 bottles of 90
- NDC 0185-0144-01 bottles of 100
- NDC 0185-0144-05 bottles of 500
- Keep tightly closed.
- Store at 20 to 25C (68 to 77F).
- Protect from light.
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure as required.

## Storage
There is limited information regarding Amiodarone (tablet) Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

# Precautions with Alcohol
- Alcohol-Amiodarone (tablet) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- AMIODARONE

# Look-Alike Drug Names
- amiodarone  amantadine

# Drug Shortage Status

# Price