ctory resulting in fatal outcome (see adverse reactions , post-marketing reports). bradycardia and av stock drug-related bradycardia occurred in 90 (4.9%) of 1836 patients in clinical trials while they were receiving amiodarone hcl injection for life-threatening vt/vf; it was not dose-related. bradycardia should be treated by slowing the infusion rate or discontinuing amiodarone hcl injection. in some patients, inserting a pacemaker is required. despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. patients with a known predisposition to bradycardia or av block should be treated with amiodarone hcl injection in a setting where a temporary pacemaker is available. liver enzyme elevations elevations of blood hepatic enzyme values – alanine aminotransferase (alt), aspartate aminotransferase (ast), and gamma-glutamyl transferase (ggt) – are seen commonly in patients with immediately life-threatening vt/vf. interpreting elevated ast activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. approximately 54% of patients receiving amiodarone hcl injection in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. in 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. baseline abnormalities in hepatic enzymes are not a contraindication to treatment. acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of amiodarone hcl injection at a much higher loading dose concentration and much faster rate of infusion than recommended in dosage & administration . therefore, the initial concentration and rate of infusion should be monitored closely and should not exceed that prescribed in dosage & administration (see dosage & administration ). in patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of amiodarone hcl injection therapy, but patients receiving amiodarone hcl injection should be monitored carefully for evidence of progressive hepatic injury. consideration should be given to reducing the rate of administration or withdrawing amiodarone hcl injection in such cases. proarrhythmia like all antiarrhythmic agents, amiodarone hcl injection may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. proarrhythmia, primarily torsade de pointes (tdp), has been associated with prolongation by amiodarone hcl injection of the qtc interval to 500 ms or greater. although qtc prolongation occurred frequently in patients receiving amiodarone hcl injection, torsade de pointes or new-onset vf occurred infrequently (less than 2%). patients should be monitored for qtc prolongation during infusion with amiodarone hcl injection. combination of amiodarone with other antiarrhythmic therapy that prolongs the qtc should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. fluoroquinolones, macrolide antibiotics, and azoles are known to cause qtc prolongation. there have been reports of qtc prolongation, with or without tdp, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly (see drug interactions, other reported interactions with amiodarone). the need to coadminister amiodarone with any other drug known to prolong the qtc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. a careful assessment of the potential risks and benefits of administering amiodarone hcl injection must be made in patients with thyroid dysfunction due to the possibility of arrhythmia breakthrough or exacerbation of arrhythmia, which may result in death, in these patients. pulmonary disorders early-onset pulmonary toxicity there have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. findings have included pulmonary infiltrates and/or mass on x-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. some cases have progressed to respiratory failure and/or death. ards two percent (2%) of patients were reported to have adult respiratory distress syndrome (ards) during clinical studies involving 48 hours of therapy. ards is a disorder characterized by bilateral, diffuse pulmonary infiltrates with pulmonary edema and varying degrees of respiratory insufficiency. the clinical and radiographic picture can arise after a variety of lung injuries, such as those resulting from trauma, shock, prolonged cardiopulmonary resuscitation, and aspiration pneumonia, conditions present in many of the patients enrolled in the clinical studies. there have been postmarketing reports of ards in intravenous amiodarone patients. intravenous amiodarone may play a role in causing or exacerbating pulmonary disorders in those patients. postoperatively, occurrences of ards have been reported in patients receiving oral amiodarone 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. until further studies have been performed, it is recommended that fio 2 and the determinants of oxygen delivery to the tissues (e.g., sao 2, pao 2) be closely monitored in patients on amiodarone. pulmonary fibrosis only 1 of more than 1000 patients treated with amiodarone hcl injection in clinical studies developed pulmonary fibrosis. in that patient, the condition was diagnosed 3 months after treatment with amiodarone hcl injection, during which time she received oral amiodarone. pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see labeling for oral amiodarone). loss of vision cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. in some cases, visual impairment has progressed to permanent blindness. amiodarone hcl injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (vf) and hemodynamically unstable ventricular tachycardia (vt) in patients refractory to other therapy and can also be used to treat patients with vt/vf for whom oral amiodarone is indicated, but who are unable to take oral medication. optic neuropathy and/or neuritis may occur at any time following initiation of therapy. a causal relationship to the drug has not been clearly established. if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. appearance of optic neuropathy and/or neuritis calls for re-evaluation of amiodarone therapy. the risks and complications of antiarrhythmic therapy with amiodarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. regular ophthalmic examination, including fundoscopy and slit-lamp examination, is recommended during administrations of amiodarone (see adverse reactions ). long-term use see labeling for oral amiodarone. there has been limited experience in patients receiving amiodarone hcl injection for longer than 3 weeks. thyrotoxicosis amiodarone-induced hyperthyroidism may result in thyrotoxicosis and/or the possibility of arrhythmia breakthrough or aggravation. there have been reports of death associated with amiodarone-induced thyrotoxicosis. if any new signs of arrhythmia appear, the possibility of hyperthyroidism should be considered (see precautions , thyroid abnormalities). neonatal hypo- or hyperthyroidism although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with its oral administration. if amiodarone hcl injection is administered during pregnancy, the patient should be apprised of the potential hazard to the fetus.

ed to achieve effective arrhythmia suppression. the first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2100 mg were associated with an increased risk of hypotension. the initial infusion rate should not exceed 30 mg/min. based on the experience from clinical studies of amiodarone hcl injection, a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient's age, renal function, or left ventricular function. there has been limited experience in patients receiving amiodarone hcl injection for longer than 3 weeks. the surface properties of solutions containing injectable amiodarone are altered such that the drop size may be reduced. this reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used. amiodarone hcl injection must be delivered by a volumetric infusion pump. amiodarone hcl injection should, whenever possible, be administered through a central venous catheter dedicated to that purpose. an in-line filter should be used during administration. amiodarone hcl injection loading infusions at much higher concentrations and rates of infusion much faster than recommended have resulted in hepatocellular necrosis and acute renal failure, leading to death (see precautions , liver enzyme elevations). amiodarone hcl injection concentrations greater than 3 mg/ml in d 5w have been associated with a high incidence of peripheral vein phlebitis; however, concentrations of 2.5 mg/ml or less appear to be less irritating. therefore, for infusions longer than 1 hour, amiodarone hcl injection concentrations should not exceed 2 mg/ml unless a central venous catheter is used (see adverse reactions , postmarketing reports). amiodarone hcl injection infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing d 5w. use of evacuated glass containers for admixing amiodarone hcl injection is not recommended as incompatibility with a buffer in the container may cause precipitation. it is well known that amiodarone adsorbs to polyvinyl chloride (pvc) tubing and the clinical trial dose administration schedule was designed to account for this adsorption. all of the clinical trials were conducted using pvc tubing and its use is therefore recommended. the concentrations and rates of infusion provided in dosage & administration reflect doses identified in these studies. amiodarone hcl injection has been found to leach out plasticizers, including dehp [di-(2-ethylhexyl)phthalate] from intravenous tubing (including pvc tubing). the degree of leaching increases when infusing amiodarone hcl injection at higher concentrations and lower flow rates than provided in dosage & administration . in addition, polysorbate 80, a component of amiodarone hcl injection, is also known to leach dehp from pvc (see description ). therefore, it is important that the recommendations in dosage & administration be followed closely. amiodarone hcl injection does not need to be protected from light during administration. note: parenteral drug products should be inspected visually for particulate matter, whenever solution and container permit. admixture incompatibility amiodarone hcl injection in d 5w is incompatible with the drugs shown below. intravenous to oral transition patients whose arrhythmias have been suppressed by amiodarone hcl injection may be switched to oral amiodarone. the optimal dose for changing from intravenous to oral administration of amiodarone will depend on the dose of amiodarone hcl injection already administered, as well as the bioavailability of oral amiodarone. when changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients. since there are some differences between the safety and efficacy profiles of the intravenous and oral formulations, the prescriber is advised to review the package insert for oral amiodarone when switching from intravenous to oral amiodarone therapy. since grapefruit juice is known to inhibit cyp3a4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see precautions , drug interactions). the following table provides suggested doses of oral amiodarone to be initiated after varying durations of amiodarone hcl injection administration. these recommendations are made on the basis of a comparable total body amount of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability of oral amiodarone. dosage 1 dosage 2 dosage 3 dosage 4

t common (incidence ≥ 2%) treatment-emergent adverse events during amiodarone hcl injection therapy considered at least possibly drug-related. these data were collected in clinical trials involving 1836 patients with life-threatening vt/vf. data from all assigned treatment groups are pooled because none of the adverse events appeared to be dose-related. summary tabulation of treatment-emergent drug-related study events in patients receiving amiodarone hcl injection in controlled and open-label studies (≥ 2% incidence) other treatment-emergent possibly drug-related adverse events reported in less than 2% of patients receiving amiodarone hcl injection in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased alt, increased ast, lung edema, nodal arrhythmia, prolonged qt interval, respiratory disorder, shock, sinus bradycardia, stevens-johnson syndrome, thrombocytopenia, vf, and vomiting. postmarketing reports in postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ards), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pleuritis, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (siadh), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, stevens-johnson syndrome, exfoliative dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence also have been reported with amiodarone therapy. also, in patients receiving recommended dosages of amiodarone hcl injection, there have been postmarketing reports of the following injection site reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing (see dosage & administration ). adverse

) node. its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption. amiodarone hcl injection administration prolongs intranodal conduction (atrial-his, ah) and refractoriness of the atrioventricular node (erp avn), but has little or no effect on sinus cycle length (scl), refractoriness of the right atrium and right ventricle (erp ra and erp rv), repolarization (qtc), intraventricular conduction (qrs), and infranodal conduction (his-ventricular, hv). a comparison of the electrophysiologic effects of amiodarone hcl injection and oral amiodarone is shown in the table below. effects of intravenous and oral amiodarone on electrophysiologic parameters ⇔no change at higher doses (>10 mg/kg) of amiodarone hcl injection, prolongation of the erp rv and modest prolongation of the qrs have been seen. these differences between oral and iv administration suggest that the initial acute effects of amiodarone hcl injection may be predominantly focused on the av node, causing an intranodal conduction delay and increased nodal refractoriness due to slow channel blockade (class iv activity) and noncompetitive adrenergic antagonism (class ii activity). pharmacokinetics and metabolism amiodarone exhibits complex disposition characteristics after intravenous administration. peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/l. peak concentrations after 10-minute infusions of 150 mg amiodarone hcl injection in patients with ventricular fibrillation (vf) or hemodynamically unstable ventricular tachycardia (vt) range between 7 and 26 mg/l. due to rapid distribution, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. in clinical trials, after 48 hours of continued infusions (125, 500 or 1000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4 mg/l were observed (n=260). n-desethylamiodarone (dea) is the major active metabolite of amiodarone in humans. dea serum concentrations above 0.05 mg/l are not usually seen until after several days of continuous infusion but with prolonged therapy reach approximately the same concentration as amiodarone. amiodarone is metabolized to desethylamiodarone by the cytochrome p450 (cyp450) enzyme group, specifically cytochrome p450 3a4 (cyp3a4) and cyp2c8. the cyp3a4 isoenzyme is present in both the liver and intestines. the highly variable systemic availability of oral amiodarone may be attributed potentially to large interindividual variability in cyp3a4 activity. amiodarone 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. amiodarone and dea cross the placenta and both appear in breast milk. 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. dea’s 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 administration in humans correlates more closely with dea accumulation over time than with amiodarone accumulation. on the other hand (see clinical trials), after amiodarone hcl injection administration, there is evidence of activity well before significant concentrations of dea are attained. the following table summarizes the mean ranges of pharmacokinetic parameters of amiodarone reported in single dose iv (5 mg/kg over 15 min) studies of healthy subjects. pharmacokinetic profile after amiodarone hcl injection administration notes: v c and v ss denote the central and steady-state volumes of distribution from iv studies. “—” denotes not available. desethylamiodarone clearance and volume involve an unknown biotransformation factor. the systemic availability of oral amiodarone in healthy subjects ranges between 33% and 65%. from in vitro studies, the protein binding of amiodarone is >96%. in clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with vt and vf ranged between 220 and 440 ml/h/kg. age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or dea. renal impairment does not influence the pharmacokinetics of amiodarone. after a single dose of amiodarone hcl injection in cirrhotic patients, significantly lower c max and average concentration values are seen for dea, but mean amiodarone levels are unchanged. normal subjects over 65 years of age show lower clearances (about 100 ml/h/kg) than younger subjects (about 150 ml/h/kg) and an increase in t½ from about 20 to 47 days. in patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition t½ 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. there is no established relationship between drug concentration and therapeutic response for short-term intravenous use. steady-state amiodarone concentrations of 1 to 2.5 mg/l have been associated with antiarrhythmic effects and acceptable toxicity following chronic oral amiodarone therapy. pharmacodynamics amiodarone hcl injection has been reported to produce negative inotropic and vasodilatory effects in animals and humans. in clinical studies of patients with refractory vf or hemodynamically unstable vt, treatment-emergent, drug related hypotension occurred in 288 of 1836 patients (16%) treated with amiodarone hcl injection. no correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of amiodarone hcl injection. clinical trials apart from studies in patients with vt or vf, described below, there are two other studies of amiodarone showing an antiarrhythmic effect before significant levels of dea could have accumulated. a placebo-controlled study of iv amiodarone (300 mg over 2 hours followed by 1200 mg/day) in post-coronary artery bypass graft patients with supraventricular and 2- to 3-consecutive-beat ventricular arrhythmias showed a reduction in arrhythmias from 12 hours on. a baseline-controlled study using a similar iv regimen in patients with recurrent, refractory vt/vf also showed rapid onset of antiarrhythmic activity; amiodarone therapy reduced episodes of vt by 85% compared to baseline. the acute effectiveness of amiodarone hcl injection in suppressing recurrent vf or hemodynamically unstable vt is supported by two randomized, parallel, dose-response studies of approximately 300 patients each. in these studies, patients with at least two episodes of vf or hemodynamically unstable vt in the preceding 24 hours were randomly assigned to receive doses of approximately 125 or 1000 mg over the first 24 hours, an 8-fold difference. in one study, a middle dose of approximately 500 mg was evaluated. the dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. the maintenance infusion was continued up to hour 48. additional 10-minute infusions of 150 mg amiodarone hcl injection were given for “breakthrough” vt/vf more frequently to the 125 mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the two studies. the prospectively defined primary efficacy end point was the rate of vt/vf episodes per hour. for both studies, the median rate was 0.02 episodes per hour in patients receiving the high dose and 0.07 episodes per hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes per day (p=0.07, 2-sided, in both studies). in one study, the time to first episode of vt/vf was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14 hours in patients receiving the high dose). in both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including amiodarone hcl injection) was deemed necessary. clinical clinical 2