ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described in more detail in other sections of the prescribing information: oPulmonary Toxicity [see Warnings and Precautions (5.2)]oHepatic Injury [see Warnings and Precautions (5.3)]oWorsened Arrhythmia [see Warnings and Precautions (5.4)]oVisual Impairment and Loss of Vision [see Warnings and Precautions (5.5)]oThyroid Abnormalities [see Warnings and Precautions (5.6)]oBradycardia [see Warnings and Precautions (5.7)]oPeripheral Neuropathy [see Warnings and Precautions (5.10)]oPhotosensitivity and Skin Discoloration [see Warnings and Precautions (5.11)]. oPulmonary Toxicity [see Warnings and Precautions (5.2)]oHepatic Injury [see Warnings and Precautions (5.3)]oWorsened Arrhythmia [see Warnings and Precautions (5.4)]oVisual Impairment and Loss of Vision [see Warnings and Precautions (5.5)]oThyroid Abnormalities [see Warnings and Precautions (5.6)]oBradycardia [see Warnings and Precautions (5.7)]oPeripheral Neuropathy [see Warnings and Precautions (5.10)]oPhotosensitivity and Skin Discoloration [see Warnings and Precautions (5.11)]. oPulmonary Toxicity [see Warnings and Precautions (5.2)]. oHepatic Injury [see Warnings and Precautions (5.3)]. oWorsened Arrhythmia [see Warnings and Precautions (5.4)]. oVisual Impairment and Loss of Vision [see Warnings and Precautions (5.5)]. oThyroid Abnormalities [see Warnings and Precautions (5.6)]. oBradycardia [see Warnings and Precautions (5.7)]. oPeripheral Neuropathy [see Warnings and Precautions (5.10)]. oPhotosensitivity and Skin Discoloration [see Warnings and Precautions (5.11)]. oThe most common reactions (>1%) leading to discontinuation of amiodarone include pulmonary toxicity, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. (6)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz, Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oThe most common reactions (>1%) leading to discontinuation of amiodarone include pulmonary toxicity, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. (6). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 retrospective study of 241 patients treated for to 1,515 days (mean 441.3 days):ThyroidCommonHypothyroidism, hyperthyroidism.CardiovascularCommonCongestive heart failure, cardiac arrhythmias, SA node dysfunction.GastrointestinalVery commonNausea, vomiting.CommonConstipation, anorexia, abdominal pain.DermatologicCommonSolar dermatitis/photosensitivity.NeurologicCommonMalaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias, decreased libido, insomnia, headache, sleep disturbances.OphthalmicCommonVisual disturbances.HepaticCommonAbnormal liver-function tests, nonspecific hepatic disorders.RespiratoryCommonPulmonary inflammation or fibrosis.OtherCommonFlushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.UncommonBlue 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.HematologicHemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma.ImmuneAnaphylactic/anaphylactoid reaction (including shock), angioedema.NeurologicPseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), demyelinating polyneuropathy.PsychiatricHallucination, confusional state, disorientation, delirium.CardiacHypotension (sometimes fatal), sinus arrest.RespiratoryEosinophilic pneumonia, acute respiratory distress syndrome in the post-operative setting, bronchospasm, bronchiolitis obliterans organizing pneumonia, pulmonary alveolar hemorrhage, pleural effusion, pleuritis.GastrointestinalPancreatitis, acute pancreatitis.HepaticHepatitis, cholestatic hepatitis, cirrhosis.Skin and Subcutaneous Tissue DisordersUrticaria, 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.MusculoskeletalMyopathy, muscle weakness, rhabdomyolysis.RenalRenal impairment, renal insufficiency, acute renal failure.ReproductiveEpididymitis, impotence.Body as WholeFever, dry mouth.Endocrine and MetabolicThyroid nodules/ thyroid cancer, syndrome of inappropriate antidiuretic hormone secretion (SIADH).VascularVasculitis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amiodarone is considered class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, amiodarone exerts noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption.Amiodarone hydrochloride prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone hydrochloride increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of amiodarone hydrochloride as they are evidence of its pharmacological action, although amiodarone hydrochloride can cause marked sinus bradycardia or sinus arrest and heart block [see Warnings and Precautions (5.4)].HemodynamicsIn animal studies and after intravenous administration in man, amiodarone hydrochloride relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, amiodarone hydrochloride produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, amiodarone hydrochloride may have mild negative inotropic effect.. 12.2 Pharmacodynamics There is no well-established relationship between plasma concentration and effectiveness, but it does appear that concentrations much below mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects.Effects on abnormal rhythms are not seen before to days and usually require to weeks, even when loading dose is used. There may be continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when loading-dose regimen is used.Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after amiodarone hydrochloride is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted.. 12.3 Pharmacokinetics AbsorptionFollowing oral administration in humans, amiodarone hydrochloride is slowly and variably absorbed. The bioavailability of amiodarone hydrochloride is approximately 50%. Maximum plasma concentrations are attained to hours after single dose. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability.Food increases the rate and extent of absorption of amiodarone hydrochloride. The effects of food upon the bioavailability of amiodarone hydrochloride have been studied in 30 healthy subjects who received single 600-mg dose immediately after consuming high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of the major metabolite of amiodarone, DEA increased by 55% (range 58 to 101%) and 32% (range to 84%), respectively, but there was no change in the Tmax in the presence of food.DistributionAmiodarone hydrochloride is highly protein-bound (approximately 96%). Amiodarone hydrochloride has very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen.One major metabolite of amiodarone hydrochloride, DEA, has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEAs precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular class III effects after oral amiodarone hydrochloride administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.EliminationFollowing single dose administration in 12 healthy subjects, amiodarone hydrochloride exhibited multi-compartmental pharmacokinetics with mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone hydrochloride has been shown to have biphasic elimination with an initial 50% reduction of plasma levels after 2.5 to 10 days. much slower terminal plasma-elimination phase shows half-life of the parent compound ranging from 26 to 107 days, with mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.The considerable inter-subject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Individualize maintenance doses of amiodarone hydrochloride [see Dosage and Administration (2)].MetabolismAmiodarone is metabolized to DEA by the cytochrome P450 (CYP) enzyme group, specifically CYP3A and CYP2C8. The CYP3A isoenzyme is present in both the liver and intestines. In vitro, amiodarone and DEA exhibit potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and DEA have also potential to inhibit some transporters such as P-glycoprotein and organic cation transporter (OCT2).ExcretionAmiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.Specific PopulationsEffect of AgeNormal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in 1/2 from about 20 to 47 days.Renal ImpairmentRenal impairment does not influence the pharmacokinetics of amiodarone or DEA.Hepatic ImpairmentAfter single dose of intravenous amiodarone to cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged.Cardiac DiseaseIn patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal elimination 1/2 of DEA is prolonged.Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.Drug InteractionsEffects of Other Agents on AmiodaroneGrapefruit juiceGrapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations.CimetidineInhibits CYP3A and can increase serum amiodarone levels.CholestyramineReduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life.Effects of Amiodarone on AgentsCYP3A substratesAmiodarone taken concomitantly with quinidine increases the quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively.LoratadineA non-sedating antihistaminic, is metabolized primarily by CYP3A and its metabolism can be inhibited by amiodarone.Metabolism of lidocaine can be inhibited by amiodarone.CyclophosphamideA prodrug, metabolized by CYP450 including CYP3A to an active metabolite. The metabolism of cyclophosphamide may be inhibited by amiodarone.ClopidogrelAn inactive thienopyridine prodrug, is metabolized in the liver by CYP3A to an active metabolite. potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.Macrolide/Ketolide AntibioticsAmiodarone can inhibit the metabolism of macrolide/ketolide antibiotics (except for azithromycin) and systemic azole antifungal drugs.P-Glycoprotein SubstratesAmiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day.Dabigatran EtexilateWhen taken concomitantly with oral amiodarone can result in elevated serum concentration of dabigatran.DextromethorphanA substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6. Chronic (> weeks) oral amiodarone administration impairs metabolism of dextromethorphan can lead to increased serum concentrations.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Because of amiodarones long half-life, expect drug interactions to persist for weeks to months after discontinuation of amiodarone.Drug interactions with amiodarone are described in Table below.Table 1: Amiodarone Drug InteractionsConcomitant DrugClass/NameExamplesClinical CommentPharmacodynamic InteractionsQT Prolonging Drugs class and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agentsIncreased risk of Torsade de Pointes.Avoid concomitant use.Negative Chronotropes digoxin, beta blockers, verapamil, diltiazem,clonidine, ivabradinePotentiates the electrophysiologic andhemodynamic effects of amiodarone,resulting in bradycardia, sinus arrest, andAV block. Monitor heart rate.Pharmacokinetic InteractionsCYP450 Inhibitors grapefruit juice, certain fluoroquinolone andmacrolide antibiotics, azole antifungals,cimetidine, certain protease inhibitorsIncreased exposure of amiodarone. Avoid concomitant use.CYP450 Inducers St. Johns WortReduced 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, flecainideReserve concomitant use for patients who are unresponsive to single agent.Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at 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 ReductaseInhibitorssimvastatin, lovastatin, atorvastatinIncreased 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 to 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 DirectActing AntiviralsofosbuvirCases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with sofosbuvir.CYP3A Substrate lidocaineSinus bradycardia has been reported with oral amiodarone in combination with lidocaine given for local anesthesia. Monitor heart rate. lower starting dose of lidocaine may be required.CYP3A Substrate fentanylFentanyl in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.. oAvoid coadministration of amiodarone with other antiarrhythmics and drugs known to prolong the QT interval. (7)oAmiodarone is substrate for CYP3A and CYP2C8, so inhibitors and inducers affect amiodarone exposure. (7)oAmiodarone inhibits P-glycoprotein and CYP1A2, CYP2C9, CYP2D6, and CYP3A, increasing exposure to other drugs. (7). oAvoid coadministration of amiodarone with other antiarrhythmics and drugs known to prolong the QT interval. (7). oAmiodarone is substrate for CYP3A and CYP2C8, so inhibitors and inducers affect amiodarone exposure. (7). oAmiodarone inhibits P-glycoprotein and CYP1A2, CYP2C9, CYP2D6, and CYP3A, increasing exposure to other drugs. (7).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics AbsorptionFollowing oral administration in humans, amiodarone hydrochloride is slowly and variably absorbed. The bioavailability of amiodarone hydrochloride is approximately 50%. Maximum plasma concentrations are attained to hours after single dose. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability.Food increases the rate and extent of absorption of amiodarone hydrochloride. The effects of food upon the bioavailability of amiodarone hydrochloride have been studied in 30 healthy subjects who received single 600-mg dose immediately after consuming high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (Tmax) by 37%. The mean AUC and mean Cmax of the major metabolite of amiodarone, DEA increased by 55% (range 58 to 101%) and 32% (range to 84%), respectively, but there was no change in the Tmax in the presence of food.DistributionAmiodarone hydrochloride is highly protein-bound (approximately 96%). Amiodarone hydrochloride has very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen.One major metabolite of amiodarone hydrochloride, DEA, has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEAs precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular class III effects after oral amiodarone hydrochloride administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation.EliminationFollowing single dose administration in 12 healthy subjects, amiodarone hydrochloride exhibited multi-compartmental pharmacokinetics with mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone hydrochloride has been shown to have biphasic elimination with an initial 50% reduction of plasma levels after 2.5 to 10 days. much slower terminal plasma-elimination phase shows half-life of the parent compound ranging from 26 to 107 days, with mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat.The considerable inter-subject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Individualize maintenance doses of amiodarone hydrochloride [see Dosage and Administration (2)].MetabolismAmiodarone is metabolized to DEA by the cytochrome P450 (CYP) enzyme group, specifically CYP3A and CYP2C8. The CYP3A isoenzyme is present in both the liver and intestines. In vitro, amiodarone and DEA exhibit potential to inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6 and CYP2C8. Amiodarone and DEA have also potential to inhibit some transporters such as P-glycoprotein and organic cation transporter (OCT2).ExcretionAmiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable.Specific PopulationsEffect of AgeNormal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in 1/2 from about 20 to 47 days.Renal ImpairmentRenal impairment does not influence the pharmacokinetics of amiodarone or DEA.Hepatic ImpairmentAfter single dose of intravenous amiodarone to cirrhotic patients, significantly lower Cmax and average concentration values are seen for DEA, but mean amiodarone levels are unchanged.Cardiac DiseaseIn patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal elimination 1/2 of DEA is prolonged.Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction.Drug InteractionsEffects of Other Agents on AmiodaroneGrapefruit juiceGrapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, and decreased DEA to unquantifiable concentrations.CimetidineInhibits CYP3A and can increase serum amiodarone levels.CholestyramineReduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life.Effects of Amiodarone on AgentsCYP3A substratesAmiodarone taken concomitantly with quinidine increases the quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively.LoratadineA non-sedating antihistaminic, is metabolized primarily by CYP3A and its metabolism can be inhibited by amiodarone.Metabolism of lidocaine can be inhibited by amiodarone.CyclophosphamideA prodrug, metabolized by CYP450 including CYP3A to an active metabolite. The metabolism of cyclophosphamide may be inhibited by amiodarone.ClopidogrelAn inactive thienopyridine prodrug, is metabolized in the liver by CYP3A to an active metabolite. potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.Macrolide/Ketolide AntibioticsAmiodarone can inhibit the metabolism of macrolide/ketolide antibiotics (except for azithromycin) and systemic azole antifungal drugs.P-Glycoprotein SubstratesAmiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day.Dabigatran EtexilateWhen taken concomitantly with oral amiodarone can result in elevated serum concentration of dabigatran.DextromethorphanA substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6. Chronic (> weeks) oral amiodarone administration impairs metabolism of dextromethorphan can lead to increased serum concentrations.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryAvailable 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 risk to the mother and fetus (see Clinical Considerations). In animal studies, administration of amiodarone to rabbits, rats, and mice during organogenesis resulted in embryofetal toxicity at doses less than the maximum recommended human maintenance dose (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 ConsiderationsDisease-Associated Maternal and or Embryo/Fetal RiskThe 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 ReactionsAmiodarone 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 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 DeliveryRisk of arrhythmias may increase during labor and delivery. Patients treated with amiodarone hydrochloride should be monitored continuously during labor and delivery [see Warnings and Precautions (5.4)]. DataAnimal DataIn 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 dose of mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose).600 mg in 60 kg patient (doses compared on body surface area basis).

SPL MEDGUIDE SECTION.

Medication GuideAmiodarone Hydrochloride Tablets(A mi OH da rone). What is the most important information should know about amiodarone hydrochloride tabletsAmiodarone hydrochloride tablets can cause serious side effects that can lead to death including:olung problemsoliver problemsoworsening of heartbeat problemsCall your healthcare provider or get medical help right away if you have any of the following symptoms during treatment with amiodarone hydrochloride tablets:otrouble breathing, wheezing, shortness of breath, coughing chest pain, spitting up of blood, or feveronausea or vomiting, brown or dark-colored urine, feel more tired than usual, yellowing of your skin or the whites of your eyes (jaundice), or right upper stomach-area painoheart pounding, skipping beat, beating fast or slowly, feel light-headed, or if you faintovision problems, including blurred vision, see halos, or your eyes become sensitive to light. You should have regular eye exams before and during treatment with amiodarone hydrochloride tablets.Amiodarone hydrochloride tablets should be started in hospital so that your medical condition can be carefully monitored.Amiodarone hydrochloride tablets should only be used to treat people who have been diagnosed with life-threatening heartbeat problems called ventricular arrhythmias, when other treatments did not work or you cannot tolerate them. Amiodarone hydrochloride tablets can cause other serious side effects. See What are the possible side effects of amiodarone hydrochloride tablets If you get serious side effects during treatment you may need to stop amiodarone hydrochloride tablets, have your dose changed, or get medical treatment. Talk with your healthcare provider before you stop taking amiodarone hydrochloride tablets.You may still have side effects after stopping amiodarone hydrochloride tablets because the medicine stays in your body for months after treatment is stopped. You should have regular check-ups, blood tests, chest x-rays before and during treatment with amiodarone hydrochloride tablets to check for serious side effects. You should also have lung function tests before starting treatment with amiodarone hydrochloride tablets.What are amiodarone hydrochloride tabletsAmiodarone hydrochloride tablets are prescription medicine used to treat people who have been diagnosed with life-threatening heartbeat problems called ventricular arrhythmias, when other treatment did not work or you cannot tolerate them.It is not known if amiodarone hydrochloride tablets is safe and effective in children.Who should not take amiodarone hydrochloride tabletsDo not take amiodarone hydrochloride tablets if you:ohave serious heart problem called cardiogenic shockohave certain types of the heart condition called heart block, with or without slow heart rateohave slow heart rate with dizziness or lightheadedness, and you do not have an implanted pacemakeroare allergic to amiodarone, iodine, or any of the other ingredients in amiodarone hydrochloride tablets. See the end of this Medication Guide for complete list of ingredients in amiodarone hydrochloride tablets.Before taking amiodarone hydrochloride tablets tell your doctor about all of your medical conditions, including if you:ohave lung or breathing problemsohave liver problemsohave or had thyroid problemsohave slow heart rate or blood pressure problemsohave diarrhea or have had diarrhea for long period of timeohave been told that you have low levels of potassium, magnesium, or calcium in your bloodohave an implanted pacemaker or defribrillatoroif you plan to have surgery with general anesthesiaoare pregnant or plan to become pregnant. Amiodarone hydrochloride tablets may harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with amiodarone hydrochloride tablets. Amiodarone hydrochloride tablets can stay in your body for months after treatment is stopped. oare breast-feeding or plan to breast-feed. Amiodarone hydrochloride can pass into your breast milk and may harm your baby. You should not breast-feed while taking amiodarone hydrochloride tablets. Amiodarone hydrochloride tablets can stay in your body for months after treatment is stopped. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. Amiodarone hydrochloride tablets and certain other medicines can affect with each other and cause serious side effects. You can ask your pharmacist for list of medicines that interact with amiodarone hydrochloride tablets.How should take amiodarone hydrochloride tabletsoWhen you are discharged from the hospital, take amiodarone hydrochloride tablets exactly as your doctor tells you to take it.oYour healthcare provider will tell you how many amiodarone hydrochloride tablets to take and when to take them.oYour healthcare provider may change your dose of amiodarone hydrochloride tablets as needed if your heart rhythm is controlled, or if you have certain side effects. Your healthcare provider should monitor you carefully when your dose of amiodarone hydrochloride tablets is being changed.oTake your dose of amiodarone hydrochloride tablets the same way each time, either with or without food.oIf you take too many amiodarone hydrochloride tablets, call your healthcare provider or go to the nearest hospital emergency room right away. If you miss dose, wait and take your next dose at your regular time. Do not take two doses at the same. Continue with your next regularly scheduled dose.What should avoid while taking amiodarone hydrochloride tabletsoAvoid drinking grapefruit juice during treatment with amiodarone hydrochloride tablets.Drinking grapefruit juice with amiodarone hydrochloride tablets may increase the amount of amiodarone hydrochloride tablets in your blood, and this may lead to side effects.oAmiodarone hydrochloride tablets can make your skin sensitive to sunlight. You could get severe sunburn. Use sunscreen and wear hat and clothes that cover your skin to help protect you if you must be in sunlight. Talk to your healthcare provider if you get sunburn. See Skin problems in the Medication Guide section What are the possible side effects of amiodarone hydrochloride tablets below.What are the possible side effects of amiodarone hydrochloride tabletsAmiodarone hydrochloride tablets can cause serious side effects, including:oSee What is the most important information should know about amiodarone hydrochloride tabletsoNerve problems. Amiodarone hydrochloride tablets can cause nerve problems. Call your healthcare provider if you develop symptoms of nerve problems, including: feeling of pins and needles or numbness in your hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, or trouble walking.oSkin problems. Amiodarone hydrochloride tablets can cause your skin to be more sensitive to the sun or turn bluish-gray color. People who have fair skin or people who have lot of sun exposure may be at risk for these skin problems. Some of the bluish-gray skin color may return to normal after stopping amiodarone hydrochloride tabletsoThyroid problems. Amiodarone hydrochloride tablets can cause you to have either decreased thyroid function (hypothyroidism), which can sometimes be severe, or an overactive thyroid (hyperthyroidism), which can be severe.oIf you develop decreased thyroid function during treatment with amiodarone hydrochloride tablets, your healthcare provider may need to reduce your dose or stop your treatment with amiodarone hydrochloride tablets, and possibly prescribe medicine to replace your thyroid hormone.oAn overactive thyroid can cause you to produce too much thyroid hormone. You can have abnormal heartbeats even while you are receiving amiodarone hydrochloride tablets. Your healthcare provider may prescribe certain medicines to treat your overactive thyroid. Call your healthcare provider if you get any abnormal heart beats during treatment with amiodarone hydrochloride tablets. This may mean that you have an overactive thyroid.oYour healthcare provider should do tests to check your thyroid function before you start and during treatment with amiodarone hydrochloride tablets.oCall your healthcare provider if you develop any of the following symptoms of thyroid problem during treatment with amiodarone hydrochloride tablets:oweaknessonervousnessoweight loss or weight gainoirritabilityoheat or cold intoleranceorestlessnessohair thinningodecreased concentration osweatingofeeling depressed (in the elderly)ochanges in your menstrual periodsotremoroswelling of your neck (goiter)The most common side effects of amiodarone hydrochloride tablets include:olung problemsoheartbeat problemsoheart problemsoliver problemsAmiodarone hydrochloride tablets may affect fertility in males and females. It is not known if the effects are reversible. Talk to your healthcare provider if you have concerns about fertility.These are not all the possible side effects of amiodarone hydrochloride tablets. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store amiodarone hydrochloride tabletsoStore amiodarone hydrochloride tablets at room temperature between 68 to 77F (20 to 25C). oKeep amiodarone hydrochloride tablets in tightly closed container, and keep amiodarone hydrochloride tablets out of the light.Keep amiodarone hydrochloride tablets and all medicines out of the reach of children.General information about the safe and effective use of amiodarone hydrochloride tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use amiodarone hydrochloride tablets for condition for which they were not prescribed. Do not give amiodarone hydrochloride tablets to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about amiodarone hydrochloride tablets that was written for health professionals. For more information call 1-800-525-8747 or go to www.us.sandoz.com.What are the ingredients in amiodarone hydrochloride tabletsActive Ingredient: amiodarone hydrochlorideInactive Ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone and D&C yellow No. 10 aluminum lake.For Medication Guides, please visit www.us.sandoz.com or call 1-800-507-2130.Distributed bySandoz Inc.Princeton, NJ 08540Rev. November 2018MF0144REV11/18This Medication Guide has been approved by the U.S. Food and Drug Administration.. olung problems. oliver problems. oworsening of heartbeat problems. otrouble breathing, wheezing, shortness of breath, coughing chest pain, spitting up of blood, or fever. onausea or vomiting, brown or dark-colored urine, feel more tired than usual, yellowing of your skin or the whites of your eyes (jaundice), or right upper stomach-area pain. oheart pounding, skipping beat, beating fast or slowly, feel light-headed, or if you faint. ovision problems, including blurred vision, see halos, or your eyes become sensitive to light. You should have regular eye exams before and during treatment with amiodarone hydrochloride tablets.. ohave serious heart problem called cardiogenic shock. ohave certain types of the heart condition called heart block, with or without slow heart rate. ohave slow heart rate with dizziness or lightheadedness, and you do not have an implanted pacemaker. oare allergic to amiodarone, iodine, or any of the other ingredients in amiodarone hydrochloride tablets. See the end of this Medication Guide for complete list of ingredients in amiodarone hydrochloride tablets.. ohave lung or breathing problems. ohave liver problems. ohave or had thyroid problems. ohave slow heart rate or blood pressure problems. ohave diarrhea or have had diarrhea for long period of time. ohave been told that you have low levels of potassium, magnesium, or calcium in your blood. ohave an implanted pacemaker or defribrillator. oif you plan to have surgery with general anesthesia. oare pregnant or plan to become pregnant. Amiodarone hydrochloride tablets may harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with amiodarone hydrochloride tablets. Amiodarone hydrochloride tablets can stay in your body for months after treatment is stopped. oare breast-feeding or plan to breast-feed. Amiodarone hydrochloride can pass into your breast milk and may harm your baby. You should not breast-feed while taking amiodarone hydrochloride tablets. Amiodarone hydrochloride tablets can stay in your body for months after treatment is stopped. Talk to your healthcare provider about the best way to feed your baby during this time. oWhen you are discharged from the hospital, take amiodarone hydrochloride tablets exactly as your doctor tells you to take it.. oYour healthcare provider will tell you how many amiodarone hydrochloride tablets to take and when to take them.. oYour healthcare provider may change your dose of amiodarone hydrochloride tablets as needed if your heart rhythm is controlled, or if you have certain side effects. Your healthcare provider should monitor you carefully when your dose of amiodarone hydrochloride tablets is being changed.. oTake your dose of amiodarone hydrochloride tablets the same way each time, either with or without food.. oIf you take too many amiodarone hydrochloride tablets, call your healthcare provider or go to the nearest hospital emergency room right away. If you miss dose, wait and take your next dose at your regular time. Do not take two doses at the same. Continue with your next regularly scheduled dose.. oAvoid drinking grapefruit juice during treatment with amiodarone hydrochloride tablets.Drinking grapefruit juice with amiodarone hydrochloride tablets may increase the amount of amiodarone hydrochloride tablets in your blood, and this may lead to side effects.. oAmiodarone hydrochloride tablets can make your skin sensitive to sunlight. You could get severe sunburn. Use sunscreen and wear hat and clothes that cover your skin to help protect you if you must be in sunlight. Talk to your healthcare provider if you get sunburn. See Skin problems in the Medication Guide section What are the possible side effects of amiodarone hydrochloride tablets below.. oSee What is the most important information should know about amiodarone hydrochloride tablets. oNerve problems. Amiodarone hydrochloride tablets can cause nerve problems. Call your healthcare provider if you develop symptoms of nerve problems, including: feeling of pins and needles or numbness in your hands, legs, or feet, muscle weakness, uncontrolled movements, poor coordination, or trouble walking.. oSkin problems. Amiodarone hydrochloride tablets can cause your skin to be more sensitive to the sun or turn bluish-gray color. People who have fair skin or people who have lot of sun exposure may be at risk for these skin problems. Some of the bluish-gray skin color may return to normal after stopping amiodarone hydrochloride tablets. oThyroid problems. Amiodarone hydrochloride tablets can cause you to have either decreased thyroid function (hypothyroidism), which can sometimes be severe, or an overactive thyroid (hyperthyroidism), which can be severe.oIf you develop decreased thyroid function during treatment with amiodarone hydrochloride tablets, your healthcare provider may need to reduce your dose or stop your treatment with amiodarone hydrochloride tablets, and possibly prescribe medicine to replace your thyroid hormone.oAn overactive thyroid can cause you to produce too much thyroid hormone. You can have abnormal heartbeats even while you are receiving amiodarone hydrochloride tablets. Your healthcare provider may prescribe certain medicines to treat your overactive thyroid. Call your healthcare provider if you get any abnormal heart beats during treatment with amiodarone hydrochloride tablets. This may mean that you have an overactive thyroid.oYour healthcare provider should do tests to check your thyroid function before you start and during treatment with amiodarone hydrochloride tablets.oCall your healthcare provider if you develop any of the following symptoms of thyroid problem during treatment with amiodarone hydrochloride tablets:. oIf you develop decreased thyroid function during treatment with amiodarone hydrochloride tablets, your healthcare provider may need to reduce your dose or stop your treatment with amiodarone hydrochloride tablets, and possibly prescribe medicine to replace your thyroid hormone.. oAn overactive thyroid can cause you to produce too much thyroid hormone. You can have abnormal heartbeats even while you are receiving amiodarone hydrochloride tablets. Your healthcare provider may prescribe certain medicines to treat your overactive thyroid. Call your healthcare provider if you get any abnormal heart beats during treatment with amiodarone hydrochloride tablets. This may mean that you have an overactive thyroid.. oYour healthcare provider should do tests to check your thyroid function before you start and during treatment with amiodarone hydrochloride tablets.. oCall your healthcare provider if you develop any of the following symptoms of thyroid problem during treatment with amiodarone hydrochloride tablets:. oweakness. onervousness. oweight loss or weight gain. oirritability. oheat or cold intolerance. orestlessness. ohair thinning. odecreased concentration osweating. ofeeling depressed (in the elderly). ochanges in your menstrual periods. otremor. oswelling of your neck (goiter). olung problems. oheartbeat problems. oheart problems. oliver problems. oStore amiodarone hydrochloride tablets at room temperature between 68 to 77F (20 to 25C). oKeep amiodarone hydrochloride tablets in tightly closed container, and keep amiodarone hydrochloride tablets out of the light.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: May cause fetal harm. (8.1)oLactation: Breastfeeding not recommended. (8.2). oPregnancy: May cause fetal harm. (8.1). oLactation: Breastfeeding not recommended. (8.2). 8.1 Pregnancy Risk SummaryAvailable 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 risk to the mother and fetus (see Clinical Considerations). In animal studies, administration of amiodarone to rabbits, rats, and mice during organogenesis resulted in embryofetal toxicity at doses less than the maximum recommended human maintenance dose (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 ConsiderationsDisease-Associated Maternal and or Embryo/Fetal RiskThe 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 ReactionsAmiodarone 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 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 DeliveryRisk of arrhythmias may increase during labor and delivery. Patients treated with amiodarone hydrochloride should be monitored continuously during labor and delivery [see Warnings and Precautions (5.4)]. DataAnimal DataIn 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 dose of mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose).600 mg in 60 kg patient (doses compared on body surface area basis). 8.2 Lactation Risk SummaryAmiodarone and one of its major metabolites, DEA, are present in breastmilk at between 3.5% and 45% of the maternal weight-adjusted dosage of amiodarone. There are cases of hypothyroidism and bradycardia in breastfed infants, although it is unclear if these effects are due to amiodarone exposure in breastmilk. Breastfeeding is not recommended during treatment with amiodarone hydrochloride [see Warnings and Precautions (5.6, 5.7)].. 8.3 Females and Males of Reproductive Potential InfertilityBased 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)].. 8.4 Pediatric Use The safety and effectiveness of amiodarone hydrochloride in pediatric patients have not been established.. 8.5 Geriatric Use Normal subjects over 65 years of age show lower clearances and increased drug half-life than younger subjects [see Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosingrange, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drugtherapy.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oPersistence of Adverse Effects: Adverse reactions and drug interaction can persist for several weeks following discontinuation. (5.1)oImpaired Vision: Corneal microdeposits (common; reversible), optic neuropathy/neuritis (rare; may lead to blindness). (5.5)oThyroid Abnormalities: Hyperthyroidism or hypothyroidism. (5.6). oPersistence of Adverse Effects: Adverse reactions and drug interaction can persist for several weeks following discontinuation. (5.1). oImpaired Vision: Corneal microdeposits (common; reversible), optic neuropathy/neuritis (rare; may lead to blindness). (5.5). oThyroid 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 Amiodarone hydrochloride may cause 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 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 baseline chest X-ray and pulmonary-function tests, including diffusion capacity, when amiodarone hydrochloride therapy is initiated. Repeat history, physical exam, and chest X-ray every to 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 amiodarone hydrochloride 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 amiodarone hydrochloride 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 patient with an elevated baseline, discontinue or reduce dose of amiodarone hydrochloride, obtain follow-up tests and treat appropriately.. 5.4 Worsened Arrhythmia Amiodarone hydrochloride can exacerbate the presenting arrhythmia in about 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 amiodarone hydrochloride, 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 NeuritisCases 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 amiodarone and promptly refer for ophthalmic examination. Regular ophthalmic examination, including funduscopy and slit-lamp examination, is recommended during administration of amiodarone hydrochloride [see Adverse Reactions (6.1)].Corneal MicrodepositsCorneal microdeposits appear in the majority of adults treated with amiodarone hydrochloride. 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 reason to reduce dose or discontinue treatment [see Adverse Reactions (6.1)].. 5.6 Thyroid Abnormalities Amiodarone hydrochloride 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. Amiodarone hydrochloride 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 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, -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. Amiodarone hydrochloride-induced hyperthyroidism may be followed by 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 amiodarone hydrochloride and thyroid hormone supplementation.. 5.7 Bradycardia Amiodarone hydrochloride causes symptomatic bradycardia or sinus arrest with suppression of escape foci in 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 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 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 Amiodarone hydrochloride may cause fetal harm when administered to 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 amiodarone hydrochloride may lead to peripheral neuropathy, which may not resolve when amiodarone is discontinued.. 5.11 Photosensitivity and Skin Discoloration Amiodarone hydrochloride induces photosensitization in about 10% of patients; some protection may be afforded sun-barrier creams or protective clothing. During long-term treatment, 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 AgentsPatients on amiodarone hydrochloride therapy may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.