FDA

Amiodarone Hydrochloride

Approved 16 Sept 2008OralTablet

The FDA lists this product in 42 strengths and forms.

Indications

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 tablet is an antiarrhythmic indicated for: Recurrent ventricular fibrillation ( 1 ).

Recurrent hemodynamically unstable ventricular tachycardia ( 1 ).

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 tablet is 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.

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 )] .

5.2Pulmonary 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.

At a glance

Brand name: Amiodarone Hydrochloride
Route: Oral
Dosage form: Tablet
Applicant: Zydus Pharms USA Inc
Status: Prescription
FDA approval: 16 Sept 2008
Application: ANDA079029-003

Indications

Recurrent hemodynamically unstable ventricular tachycardia ( 1 ).

Contraindications

Known hypersensitivity to the drug or any of its components.

Warnings and precautions

5.2Pulmonary Toxicity

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 HMGCoA 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. Avoid coadministration of amiodarone with other antiarrhythmics and drugs known to prolong the QT interval ( 7 ). Amiodarone is a substrate for CYP3A and CYP2C8, so inhibitors and inducers affect amiodarone exposure ( 7 ).

Amiodarone inhibits P-glycoprotein and CYP1A2, CYP2C9, CYP2D6, and CYP3A, increasing exposure to other drugs ( 7 ).

Pregnancy and breastfeeding

8.1Pregnancy 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 reactions Amiodarone and its metabolite have been shown to cross the placenta.

Adverse fetal effects associated with maternal amiodarone use during pregnancy may include neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles, neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure, neonatal hyperthyroxinemia, neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia, jerk nystagmus with synchronous head titubation, fetal growth restriction, and premature birth.

Monitor the newborn for signs and symptoms of thyroid disorder and cardiac arrhythmias. Labor and Delivery Risk of arrhythmias may increase during labor and delivery. Patients treated with amiodarone hydrochloride tablets should be monitored continuously during labor and delivery [see Warnings and Precautions ( 5.4 )]. Data Animal Data In pregnant rats and rabbits during the period of organogenesis, 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 60 kg patient (doses compared on a body surface area basis)

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 tablets include pulmonary toxicity, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes ( 6 ).

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1- 877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 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 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.

6.2Postmarketing 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.

Amiodarone Hydrochloride

Indications

Contraindications

Warnings and precautions

5.2Pulmonary Toxicity

At a glance

Two medicines in one question?

Amiodarone Hydrochloride

Indications

Contraindications

Warnings and precautions

5.2Pulmonary Toxicity

At a glance

Two medicines in one question?

5.3Hepatic Injury

5.4Worsened Arrhythmia

5.5Visual Impairment and Loss of Vision Optic Neuropathy and Optic Neuritis Cases

5.6Thyroid Abnormalities

5.7Bradycardia

5.8Implantable Cardiac Devices

5.9Fetal Toxicity

5.10Peripheral Neuropathy

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information