FDA Label for Amiodarone Hydrochloride

View Indications, Usage & Precautions

Amiodarone Hydrochloride Product Label

The following document was submitted to the FDA by the labeler of this product Ncs Healthcare Of Ky, Llc Dba Vangard Labs. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.

Warning: Pulmonary, Hepatic And Cardiac Toxicity

Amiodarone hydrochloride tablets is intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity [see Indications and Usage (1)].

Amiodarone hydrochloride tablets can cause pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 17% in some series of patients. Pulmonary toxicity has been fatal about 10% of the time. Obtain a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when amiodarone hydrochloride tablets therapy is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months [see Warnings and Precautions 5.2)].

Amiodarone hydrochloride tablets can cause hepatoxicity, which can be fatal. Obtain baseline and periodic liver transaminases and discontinue or reduce dose if the increase exceeds three times normal, or doubles in a patient with an elevated baseline. Discontinue amiodarone hydrochloride tablets if the patient experiences signs or symptoms of clinical liver injury [see Warnings and Precautions (5.3)].

Amiodarone hydrochloride tablets can exacerbate arrhythmias. Initiate amiodarone hydrochloride tablets in a clinical setting where continuous electrocardiograms and cardiac resuscitation are available [see Warnings and Precautions (5.4)].

1 Indications And Usage

Amiodarone hydrochloride tablets are indicated for the treatment of documented, life-threatening recurrent ventricular fibrillation and life-threatening recurrent hemodynamically unstable tachycardia in adults who have not responded to adequate doses of other available antiarrhythmics or when alternative agents cannot be tolerated.

2 Dosage And Administration

Dosage must be individualized based on severity of arrhythmia and response. Use the lowest effective dose. Obtain baseline chest x-ray, pulmonary function tests, thyroid function tests, and liver aminotransferases. Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment.

3 Dosage Forms And Strengths

100 mg tablets: round, flat-faced, beveled-edge white tablets debossed with "m" on the upper portion and "154" on the lower half on one side of the tablet, and plain on the other.

200 mg tablets: round, flat-faced, beveled-edge, scored white tablets debossed with "m" on the upper portion and "155" on the lower half on one side of the tablet with a score mark between and plain on the other.

400 mg tablets: oval-shaped, convex, scored yellow tablets debossed with "m" on the left and "156" on the right with a score mark between on one side, and plain on the other.

4 Contraindications

Cardiogenic shock.
Sick sinus syndrome, second- or third-degree atrioventricular block, bradycardia leading to syncope without a functioning pacemaker.
Known hypersensitivity to the drug or to any of its components, including iodine.

5.1 Persistence Of Adverse Effects

Because of the long half-life of amiodarone (15 to 142 days) and its active metabolite desethylamiodarone (14 to 75 days), adverse reactions and drug interactions can persist for several weeks following amiodarone discontinuation [see Clinical Pharmacology (12.3)].

5.2 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. Pulmonary toxicity secondary to amiodarone hydrochloride tablets may result from either indirect or direct toxicity as represented by hypersensitivity pneumonitis (including eosinophilic pneumonia) or interstitial/alveolar pneumonitis, respectively. Rates of pulmonary toxicity have been reported to be as high as 17% and is fatal in about 10% of cases. Obtain a baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when amiodarone hydrochloride tablets therapy is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months or if symptoms occur. Consider alternative antiarrhythmic therapy if the patient experiences signs or symptoms of pulmonary toxicity. Prednisone 40 to 60 mg/day tapered over several weeks may be helpful in treating pulmonary toxicity.

5.3 Hepatic Injury

Asymptomatic elevations of hepatic enzyme levels are seen frequently, but amiodarone hydrochloride tablets can cause life-threatening hepatic injury. Histology has resembled that of alcoholic hepatitis or cirrhosis. Obtain baseline and periodic liver transaminases. If transaminases exceed three times normal, or doubles in a patient with an elevated baseline, discontinue or reduce dose of amiodarone hydrochloride tablets, obtain follow-up tests and treat appropriately.

5.4 Worsened Arrhythmia

Amiodarone hydrochloride tablets can exacerbate the presenting arrhythmia in about 2 to 5% of patients or cause new ventricular fibrillation, incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphic ventricular tachycardia associated with QTc prolongation (Torsade de Pointes [TdP]).

Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment with amiodarone hydrochloride tablets, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or receiving drugs affecting electrolyte levels, such as diuretics, laxatives, systemic corticosteroids, or amphotericin B.

5.6 Thyroid Abnormalities

Amiodarone hydrochloride tablets 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. Amiodarone hydrochloride tablets can cause either hypothyroidism (reported in up to 10% of patients) or hyperthyroidism (occurring in about 2% of patients). Monitor thyroid function 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.

Hyperthyroidism may induce arrhythmia breakthrough. If any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered. Antithyroid drugs, β-adrenergic blockers, temporary corticosteroid therapy may be necessary to treat the symptoms of hyperthyroidism. The action of antithyroid drugs may be 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 tablets-induced hyperthyroidism may be followed by a transient period of hypothyroidism.

Hypothyrodism may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. 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 tablets and thyroid hormone supplementation.

5.7 Bradycardia

Amiodarone hydrochloride tablets cause symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients. The risk is increased by electrolytic disorders or use of concomitant antiarrhythmics or negative chronotropes [see Drug Interactions (7)]. Bradycardia may require a pacemaker for rate control.

Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases presented up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment. The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment [see Drug Interactions (7)].

5.8 Implantable Cardiac Devices

In patients with implanted defibrillators or pacemakers, chronic administration of antiarrhythmic drugs may affect pacing or defibrillation thresholds. Therefore, at the inception of and during amiodarone treatment, pacing and defibrillation thresholds should be assessed.

5.9 Fetal Toxicity

Amiodarone hydrochloride tablets may cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for cardiac, thyroid, neurodevelopmental, neurological, and growth effects in neonate [see Use in Specific Populations (8.1)].

5.10 Peripheral Neuropathy

Chronic administration of amiodarone hydrochloride tablets may lead to peripheral neuropathy, which may not resolve when amiodarone hydrochloride tablets is discontinued.

5.11 Photosensitivity And Skin Discoloration

Amiodarone hydrochloride tablets induce photosensitization in about 10% of patients; some protection may be afforded 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. Some reversal of discoloration may occur upon drug discontinuation.

6 Adverse Reactions

The following serious adverse reactions are described in more detail in other sections of the prescribing information:

Pulmonary Toxicity [see Warnings and Precautions (5.2)]
Hepatic Injury [see Warnings and Precautions (5.3)]
Worsened Arrhythmia [see Warnings and Precautions (5.4)]
Visual Impairment and Loss of Vision [see Warnings and Precautions (5.5)]
Thyroid Abnormalities [see Warnings and Precautions (5.6)]
Bradycardia [see Warnings and Precautions (5.7)]
Peripheral Neuropathy [see Warnings and Precautions (5.10)]
Photosensitivity and Skin Discoloration [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

At the usual maintenance dose (400 mg/day) and above, amiodarone hydrochloride tablets cause adverse reactions in about three-fourths of all patients, resulting in discontinuation in 7 to 18%.

In surveys of almost 5,000 patients treated in open U.S. studies and in published reports of treatment with amiodarone hydrochloride tablets, the adverse reactions most frequently requiring discontinuation of amiodarone hydrochloride tablets 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, photosensitivity, blue skin discoloration, hyperthyroidism, and hypothyroidism.

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):

Thyroid

Common: Hypothyroidism, hyperthyroidism.

Cardiovascular

Common: Congestive heart failure, cardiac arrhythmias, SA node dysfunction.

Gastrointestinal

Very common: Nausea, vomiting.

Common: Constipation, anorexia, abdominal pain.

Dermatologic

Common: Solar dermatitis/photosensitivity.

Neurologic

Common: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias, decreased libido, insomnia, headache, sleep disturbances.

Ophthalmic

Common: Visual disturbances.

Hepatic

Common: Abnormal liver-function tests, nonspecific hepatic disorders.

Respiratory

Common: Pulmonary inflammation or fibrosis.

Other

Common: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.

Uncommon: Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amiodarone hydrochloride tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematologic: hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma.

Immune: anaphylactic/anaphylactoid reaction (including shock), angioedema.

Neurologic: pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), demyelinating polyneuropathy.

Psychiatric: hallucination, confusional state, disorientation, delirium.

Cardiac: hypotension (sometimes fatal), sinus arrest.

Respiratory: eosinophilic pneumonia, acute respiratory distress syndrome in the post-operative setting, bronchospasm, bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, pleural effusion, pleuritis.

Gastrointestinal: pancreatitis, acute pancreatitis.

Hepatic: hepatitis, cholestatic hepatitis, cirrhosis.

Skin and Subcutaneous Tissue Disorders: urticaria, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, pruritus, skin cancer, lupus-like syndrome.

Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis.

Renal: renal impairment, renal insufficiency, acute renal failure.

Reproductive: epididymitis, impotence.

Body as a whole: fever, dry mouth.

Endocrine and metabolic: thyroid nodules/ thyroid cancer, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Vascular: vasculitis.

7 Drug Interactions

Because of amiodarone's long half-life, expect drug interactions to persist for weeks to months after discontinuation of amiodarone.

Drug interactions with amiodarone are described in Table 1 below.

Table 1: Amiodarone Drug Interactions
Concomitant Drug Class/Name	Examples	Clinical Comment
Pharmacodynamic Interactions
QT Prolonging Drugs	class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents	Increased risk of Torsade de Pointes. Avoid concomitant use.
Negative Chronotropes	digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradine	Potentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate.
Pharmacokinetic Interactions
CYP450 Inhibitors	grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors	Increased exposure of amiodarone. Avoid concomitant use.
CYP450 Inducers	St. John's Wort	Reduced amiodarone serum levels.
Cyclosporine		Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use.
Cholestyramine		Reduced amiodarone serum levels.
Antiarrhythmics	quinidine, procainamide, flecainide	Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic.
Digoxin		Increased digoxin concentration. Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity.
HMG-CoA Reductase Inhibitors	simvastatin, lovastatin, atorvastatin	Increased plasma concentration of HMG- CoA reductase inhibitor. Limit the dose of lovastatin to 40 mg. Limit the coadministered dose of simvastatin to 20 mg. Lower starting dose of other CYP3A4 substrates may be required.
Warfarin		Potentiates anticoagulant response and can result in serious or fatal bleeding. Coadministration increases prothrombin time by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one-half and monitor prothrombin times.
Phenytoin		Increased steady-state levels of phenytoin. Monitor phenytoin levels.
Hepatitis C Direct Acting Antiviral	sofosbuvir	Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with sofosbuvir.
CYP3A Substrate	lidocaine	Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine given for local anesthesia. Monitor heart rate. A lower starting dose of lidocaine may be required.
CYP3A Substrate	fentanyl	Fentanyl in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

8.4 Pediatric Use

The safety and effectiveness of amiodarone hydrochloride tablets in pediatric patients have not been established.

8.5 Geriatric Use

Normal subjects over 65 years of age show lower clearances and increased drug half-life than younger subjects [see Clinical Pharmacology (12.3)]. 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.

10 Overdosage

There have been cases, some fatal, of amiodarone hydrochloride tablets overdose.

Monitor the patient's cardiac rhythm and blood pressure, and, if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Treat hypotension with inadequate tissue perfusion with positive inotropic and vasopressor agents. Neither amiodarone hydrochloride tablets nor its metabolite is dialyzable.

11 Description

Amiodarone hydrochloride tablets, USP is an antiarrhythmic drug, available for oral administration as white tablets containing 100 mg of amiodarone hydrochloride, white, scored tablets containing 200 mg of amiodarone hydrochloride, and yellow, scored tablets containing 400 mg of amiodarone hydrochloride. The inactive ingredients present are lactose, starch, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicon dioxide, magnesium stearate, and D&C Yellow #10. Amiodarone is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]- 3,5-diiodophenyl ketone hydrochloride.

The structural formula is as follows:

chemical-structure - amiodarone 8538 1

C₂₅H₂₉I₂NO₃ ∙ HCl Molecular Weight: 681.8

Amiodarone HCl 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.

Meets USP Dissolution Test 4. FDA approved dissolution test specifications differ from USP.

12.1 Mechanism Of Action

Amiodarone is considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, amiodarone exerts a noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption.

Amiodarone hydrochloride tablets 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 tablets increase 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 tablets as they are evidence of its pharmacological action, although amiodarone hydrochloride tablets can cause marked sinus bradycardia or sinus arrest and heart block [see Warnings and Precautions (5.4)].

12.2 Pharmacodynamics

There is no well-established relationship between plasma concentration and 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. 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.

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 tablets 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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Amiodarone HCl 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 at the lowest dose level tested, i.e., 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose

600 mg in a 60 kg patient (dose compared on a body surface area basis)

Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with amiodarone hydrochloride tablets were negative.

In a study in which amiodarone HCl 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).

16 How Supplied/Storage And Handling

Amiodarone hydrochloride tablets, USP are available as follows:

100 mg, white, round, flat-faced, beveled-edge tablet. Debossed with "m" on the upper portion and "154" on the lower half on one side of the tablet, and plain on the other.

Blistercards of 30 tablets

NDC 0615-8538-39

200 mg, white, round, flat-faced, beveled-edge, scored tablet. Debossed with "m" on the upper portion and "155" on the lower half on one side of the tablet with a score mark between and plain on the other.

400 mg, Oval-shaped, convex, yellow, scored tablet. Debossed with "m" on the left and "156" on the right with a score mark between on one side, and plain on the other.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Advise women that breastfeeding is not recommended during treatment with amiodarone hydrochloride tablets [see Use in Specific Populations (8.2)].

Advise patients to avoid grapefruit juice and St. John's Wort.

Advise patients to seek medical attention if they experience the signs and symptoms of pulmonary toxicity, worsening arrhythmia, bradycardia, visual impairment, or hypo- and hyperthyroidism.

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