PACERONE- amiodarone hydrochloride tablet
Upsher-Smith Laboratories, Inc.
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)].
1 INDICATIONS AND USAGE
Pacerone® is 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
Initiate treatment with a loading doses of 800 to 1600 mg/day until initial therapeutic response occurs (usually 1 to 3 weeks). Once adequate arrhythmia control is achieved, or if side effects become prominent, reduce Pacerone® dose to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day.
Administer Pacerone® consistently with regard to meals [see Clinical Pharmacology (12.3)]. Administration of Pacerone® in divided doses with meals is suggested for total daily doses of 1000 mg or higher, or when gastrointestinal intolerance occurs.
3 DOSAGE FORMS AND STRENGTHS
400 mg tablets: light yellow, oval-shaped, scored, uncoated tablets, debossed with “P400” on the unscored side, and “01” to the left and “45” to the right of the score on the reverse side.
- 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 WARNINGS AND PRECAUTIONS
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 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 (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. 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.
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