Amiodarone Hydrochloride

Description

11 DESCRIPTION Amiodarone hydrochloride tablets, USP is an antiarrhythmic drug, available for oral administration as white to off-white, scored tablets containing 200 mg of amiodarone hydrochloride USP. The inactive ingredients present are colloidal silicon dioxide, lactose monohydrate, magnesium stearate, povidone, and sodium starch glycolate. Amiodarone hydrochloride is a benzofuran derivative: 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]- 3,5-diiodophenyl ketone hydrochloride. The structural formula is as follows: Amiodarone hydrochloride USP is a white or almost white, fine crystalline powder. It is slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. It contains 37.3% iodine by weight. Chemical Structure

What Is Amiodarone Hydrochloride Used For?

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. Amiodarone hydrochloride is an antiarrhythmic indicated for: Recurrent ventricular fibrillation. ( 1 ) Recurrent hemodynamically unstable ventricular tachycardia. ( 1 )

Dosage and Administration

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 Recommended Dosage: 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 amiodarone hydrochloride dose to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day. Administration: Administer amiodarone hydrochloride tablets consistently with regard to meals [see Clinical Pharmacology (12.3) ] . Administration of amiodarone hydrochloride tablets in divided doses with meals is suggested for total daily doses of 1000 mg or higher, or when gastrointestinal intolerance occurs. 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 amiodarone hydrochloride dose to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day. ( 2 )

Side Effects (Adverse Reactions)

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 amiodarone hydrochloride include pulmonary toxicity, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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, amiodarone hydrochloride 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 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, 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. 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,...

Drug Interactions

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,tricyclicantidepressants,certainfluoroquinoloneandmacrolideantibiotics, azole antifungals,halogenatedinhalationanestheticagents Increasedrisk of Torsade de Pointes.Avoidconcomitantuse. Negative Chronotropes digoxin, beta blockers,verapamil,diltiazem,clonidine,ivabradine Potentiatestheelectrophysiologicandhemodynamiceffects of amiodarone, resultinginbradycardia, sinusarrest,andAVblock. Monitor heartrate. Pharmacokinetic Interactions CYP450 Inhibitors grapefruitjuice,certainfluoroquinoloneandmacrolideantibiotics, azole antifungals,cimetidine,certain protease inhibitors Increasedexposure of amiodarone. Avoidconcomitant use. CYP450 Inducers St.John’sWort Reducedamiodarone serum levels. Cyclosporine Increasedplasmalevelsofcyclosporinehave been reported resultinginelevatedcreatinine,despitereduction of cyclosporinedose. Monitorcyclosporinedruglevelsand renal functionwithconcomitant use. Cholestyramine Reducedamiodarone serum levels. Antiarrhythmics quinidine,procainamide,flecainide Reserveconcomitantuseforpatientswho are unresponsiveto a singleagent.Antiarrhythmicmetabolisminhibitedbyamiodarone.Initiateantiarrhythmic at a lowerthanusual dose and monitorpatientcarefully. Reduce dose levels of previouslyadministeredantiarrhythmic by 30 to 50% forseveraldaysaftertransitioningto oral amiodarone.Evaluatecontinuedneedforantiarrhythmic. Digoxin Increaseddigoxinconcentration.Reducedigoxinby half or discontinue. If continued,monitorforevidenceoftoxicity. HMG-CoA ReductaseInhibitors simvastatin,lovastatin,atorvastatin Increasedplasma concentration of HMG-CoA reductaseinhibitor. Limitthe dose of lovastatinto 40 mg.Limit the coadministered dose of simvastatinto 20 mg. Lowerstarting dose of other CYP3A4substratesmay be required. Warfarin Potentiatesanticoagulant response and can resultinserious or fatalbleeding.Coadministrationincreasesprothrombintimeby 100% after 3 to 4 days.Reducewarfarin dose byone-thirdtoone-halfandmonitorprothrombin times. Phenytoin Increasedsteady-state levels of phenytoin.Monitorphenytoin levels. Hepatitis C DirectActingAntiviral sofosbuvir Casesofsymptomaticbradyarrhythmiarequiringpacemaker insertion have been reported inpatientson oral maintenanceamiodaronewhoinitiatedtherapywithsofosbuvir. 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...

Contraindications

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. Amiodarone hydrochloride tablets are contraindicated in patients with ( 4 ): Cardiogenic shock. Sick sinus syndrome, second- or third-degree AV block, bradycardia leading to syncope without a functioning pacemaker. Known hypersensitivity to the drug or any of its components.

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Available data from postmarketing reports and published case series indicate that amiodarone use in pregnant women may increase the risk for fetal adverse effects including neonatal hypo- and hyperthyroidism, neonatal bradycardia, neurodevelopmental abnormalities, preterm birth and fetal growth restriction. Amiodarone and its metabolite, desethylamiodarone (DEA), cross the placenta. Untreated underlying arrhythmias, including ventricular arrhythmias, during pregnancy pose a risk to the mother and fetus (see Clinical Considerations) . In animal studies, administration of amiodarone to rabbits, rats, and mice during organogenesis resulted in embryo- fetal toxicity at doses less than the maximum recommended human maintenance dose (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and or embryo/fetal Risk The incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may therefore, increase during pregnancy due to the increased propensity to ectopic activity. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state. Fetal/Neonatal adverse...

8.3 Females and Males of Reproductive Potential Infertility Based on animal fertility studies, amiodarone hydrochloride may reduce female and male fertility. It is not known if this effect is reversible. [see Nonclinical Toxicology (13.1) ].

Overdosage

10 OVERDOSAGE There have been cases, some fatal, of amiodarone hydrochloride 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 nor its metabolite is dialyzable.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Amiodarone Hydrochloride Tablets USP, 200 mg are white to off-white, round biconvex uncoated tablets debossed with “8” and “4” separated by a breakline on one side and “A” on the other side. Bottles of 30 NDC 65862-732-30 Bottles of 60 NDC 65862-732-60 Bottles of 90 NDC 65862-732-90 Bottles of 100 NDC 65862-732-01 Bottles of 250 NDC 65862-732-25 Bottles of 500 NDC 65862-732-05 Bottles of 1,000 NDC 65862-732-99 Keep tightly closed. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in a light-resistant, tight container.