FDA label ef39009a-bfcc-4aa2-99ce-cac848266ef7

WARNING: PULMONARY, HEPATIC and CARDIAC TOXICITY • Pacerone ® 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)]. • Pacerone ® 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 Pacerone ® therapy is initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months [see Warnings and Precautions 5.2)]. • Pacerone ® 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 Pacerone ® if the patient experiences signs or symptoms of clinical liver injury [see Warnings and Precautions (5.3)]. • Pacerone ® can exacerbate arrhythmias. Initiate Pacerone ® in a clinical setting where continuous electrocardiograms and cardiac resuscitation are available [see Warnings and Precautions (5.4)]. WARNING: PULMONARY, HEPATIC, and CARDIAC TOXICITY See full prescribing information for complete boxed warning. • Reserve Pacerone ® for patients with the indicated life-threatening arrhythmias because its use is accompanied by substantial toxicity, some also life-threatening. Utilize alternative agents first. (1) • Pacerone ® ’s life-threatening toxicities include pulmonary (5.2), hepatic (5.3), and proarrhythmic (5.4). • Initiate under hospital or specialist supervision. (5)

5 WARNINGS AND PRECAUTIONS • Persistence of Adverse Effects: Adverse reactions and drug interaction can persist for several weeks following discontinuation. (5.1) • Impaired Vision: Corneal microdeposits (common; reversible), optic neuropathy/neuritis (rare; may lead to blindness). (5.5) • Thyroid Abnormalities: Hyperthyroidism or hypothyroidism. (5.6) 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 Pacerone ® 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 Pacerone ® 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 Pacerone ® 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. Adult Respiratory Distress Syndrome (ARDS) Postoperatively, occurrences of ARDS have been reported in patients receiving Pacerone ® 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. 5.3 Hepatic Injury Asymptomatic elevations of hepatic enzyme levels are seen frequently, but Pacerone ® 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 Pacerone ® , obtain follow-up tests and treat appropriately. 5.4 Worsened Arrhythmia Pacerone ® 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 Pacerone ® , 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. 5.5 Visual Impairment and Loss of Vision Optic Neuropathy and Optic Neuritis Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment and sometimes permanent blindness, have been reported in patients treated with amiodarone and may occur at any time during therapy. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, consider discontinuing Pacerone ® and promptly refer for ophthalmic examination. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of Pacerone ® [see Adverse Reactions (6.1)] . Corneal Microdeposits Corneal microdeposits appear in the majority of adults treated with Pacerone ® . 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 [see Adverse Reactions (6.1)] . 5.6 Thyroid Abnormalities Pacerone ® inhibits peripheral conversion of thyroxine (T 4 ) to triiodothyronine (T 3 ) and may cause increased thyroxine levels, decreased T 3 levels, and increased levels of inactive reverse T 3 (rT 3 ) in clinically euthyroid patients. Pacerone ® 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. Pacerone ® -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 Pacerone ® and thyroid hormone supplementation. 5.7 Bradycardia Pacerone ® causes 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 Pacerone ® 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 Pacerone ® may lead to peripheral neuropathy, which may not resolve when Pacerone ® is discontinued. 5.11 Photosensitivity and Skin Discoloration Pacerone ® induces 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. 5.12 Surgery Volatile Anesthetic Agents Patients on Pacerone ® therapy may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

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)] The most common reactions (>1%) leading to discontinuation of Pacerone ® include pulmonary toxicity, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. (6) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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, Pacerone ® causes 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 Pacerone ® , the adverse reactions most frequently requiring discontinuation of Pacerone ® 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 Pacerone ® . 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.