AMIODARONE HCI

INDICATIONS & USAGE Amiodarone HCl injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. Amiodarone HCl injection also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with amiodarone HCl injection, patients may be transferred to oral amiodarone therapy (see DOSAGE & ADMINISTRATION ). Amiodarone HCl injection should be used for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but amiodarone HCl injection may be safely administered for longer periods if necessary.

DOSAGE & ADMINISTRATION Amiodarone shows considerable interindividual variation in response. Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose as needed is essential. The recommended starting dose of amiodarone HCl injection is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen: After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should be continued utilizing a concentration of 1 to 6 mg/mL (Amiodarone HCl Injection concentrations greater than 2 mg/mL should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, 150 mg supplemental infusions of amiodarone HCl injection mixed in 100 mL of D 5W may be administered. Such infusions should be administered over 10 minutes to minimize the potential for hypotension. The rate of the maintenance infusion may be increased 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

CONTRAINDICATIONS Amiodarone HCl injection is contraindicated in patients with known hypersensitivity to any of the components of amiodarone HCl injection, including iodine, or in patients with cardiogenic shock, marked sinus bradycardia, and second- or third-degree AV block unless a functioning pacemaker is available.

WARNINGS Hypotension Hypotension is the most common adverse effect seen with Amiodarone HCl injection. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with amiodarone HCl injection. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose-related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in amiodarone HCl injection therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Hypotension should be treated initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. The initial rate of infusion should be monitored closely and should not exceed that prescribed in DOSAGE & ADMINISTRATION . In some cases, hypotension may be refractory 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.

ADVERSE REACTIONS In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received amiodarone HCl injection for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days. The most important treatment-emergent adverse effects were hypotension, asystole/cardiac arrest/ electromechanical dissociation (EMD), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse effects. The most common adverse effects leading to discontinuation of amiodarone HCl injection therapy were hypotension (1.6%), asystole/cardiac arrest/EMD (1.2%), VT (1.1%), and cardiogenic shock (1%). The following table lists the most 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