WARNINGS

Pacerone ® (Amiodarone HCl) Tablets are intended for use only in patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity.

Amiodarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) that has resulted in clinically manifest disease at rates as high as 10 to 17% in some series of patients with ventricular arrhythmias given doses around 400 mg/day, and as abnormal diffusion capacity without symptoms in a much higher percentage of patients.

Pulmonary toxicity has been fatal about 10% of the time.

Liver injury is common with amiodarone, but is usually mild and evidenced only by abnormal liver enzymes.

Overt liver disease can occur, however, and has been fatal in a few cases.

Like other antiarrhythmics, amiodarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse.

This has occurred in 2 to 5% of patients in various series, and significant heart block or sinus bradycardia has been seen in 2 to 5%.

All of these events should be manageable in the proper clinical setting in most cases.

Although the frequency of such proarrhythmic events does not appear greater with amiodarone than with many other agents used in this population, the effects are prolonged when they occur.

Even in patients at high risk of arrhythmic death, in whom the toxicity of amiodarone is an acceptable risk, Pacerone ® Tablets pose major management problems that could be life-threatening in a population at risk of sudden death, so that every effort should be made to utilize alternative agents first.

The difficulty of using Pacerone ® Tablets effectively and safely itself poses a significant risk to patients.

Patients with the indicated arrhythmias must be hospitalized while the loading dose of Pacerone ® Tablets is given, and a response generally requires at least one week, usually two or more.

Because absorption and elimination are variable, maintenance-dose selection is difficult, and it is not unusual to require dosage decrease or discontinuation of treatment.

In a retrospective survey of 192 patients with ventricular tachyarrhythmias, 84 required dose reduction and 18 required at least temporary discontinuation because of adverse effects, and several series have reported 15 to 20% overall frequencies of discontinuation due to adverse reactions.

The time at which a previously controlled life-threatening arrhythmia will recur after discontinuation or dose adjustment is unpredictable, ranging from weeks to months.

The patient is obviously at great risk during this time and may need prolonged hospitalization.

Attempts to substitute other antiarrhythmic agents when Pacerone ® Tablets must be stopped will be made difficult by the gradually, but unpredictably, changing amiodarone body burden.

A similar problem exists when amiodarone is not effective; it still poses the risk of an interaction with whatever subsequent treatment is tried.

Mortality In the National Heart, Lung and Blood Institute’s 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 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 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: Placebo Amiodarone Relative Risk N Deaths N Deaths 95% CI EMIAT 743 102 743 103 0.99 0.76-1.31 CAMIAT 596 68 606 57 0.88 0.58-1.16 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 postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with oral amiodarone 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.

Postmarketing reports describe cases of pulmonary toxicity in patients treated with low doses of amiodarone; however, reports suggest that the use of lower loading and maintenance doses of amiodarone are associated with a decreased incidence of amiodarone-induced pulmonary toxicity.

Amiodarone 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 Pacerone ® Tablets 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 seems 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 Pacerone ® Tablets 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 Pacerone ® Tablets 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-induced pulmonary toxicity; however, these changes also are present in approximately 50% of all patients on amiodarone therapy.

These cells should be used as markers of therapy, but not as evidence of toxicity.

A diagnosis of amiodarone-induced interstitial/alveolar pneumonitis should lead, at a minimum, to dose reduction or, preferably, to withdrawal of Pacerone ® Tablets 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 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 at a lower dose has not resulted in return of toxicity.

In a patient receiving Pacerone ® Tablets, 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 Pacerone ® Tablets 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 Pacerone ® Tablets 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-induced hypersensitivity pneumonitis is made, Pacerone ® Tablets should be discontinued, and treatment with steroids should be instituted.

If a diagnosis of amiodarone-induced interstitial/alveolar pneumonitis is made, steroid therapy should be instituted and, preferably, Pacerone ® Tablets discontinued or, at a minimum, reduced in dosage.

Some cases of amiodarone-induced interstitial/alveolar pneumonitis may resolve following a reduction in Pacerone ® Tablets 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, like other antiarrhythmics, can cause serious exacerbation of the presenting arrhythmia and 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 [TdP]).

In addition, amiodarone has caused symptomatic bradycardia or sinus arrest with suppression of escape foci in 2 to 4% of patients.

The risk of exacerbation may be increased when other risk factors are present such as electrolytic disorders or use of concomitant antiarrhythmics or other interacting drugs.

Correct hypokalemia, hypomagnesemia or hypocalcemia whenever possible before initiating treatment with amiodarone, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP.

Give special attention to electrolyte and acidbase balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics and laxatives, systemic corticosteroids, amphotericin B (IV) or other drugs affecting electrolyte levels.

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.

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-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 (see “PRECAUTIONS, Thyroid Abnormalities” ).

Liver Injury Elevations of hepatic enzyme levels are seen frequently in patients exposed to amiodarone and in most cases are asymptomatic.

If the increase exceeds three times normal, or doubles in a patient with an elevated baseline, discontinuation of Pacerone ® Tablets 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.

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 Pacerone ® Tablets therapy.

The risks and complications of antiarrhythmic therapy with Pacerone ® Tablets 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 Pacerone ® Tablets (see “ADVERSE REACTIONS” ).

Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman.

Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism.

If Pacerone ® (Amiodarone HCl) Tablets are used during pregnancy, or if the patient becomes pregnant while taking Pacerone ® Tablets, the patient should be apprised of the potential hazard to the fetus.

In general, Pacerone ® Tablets 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)