Nexterone

1 INDICATIONS AND USAGE NEXTERONE 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. NEXTERONE is an antiarrhythmic agent indicated for treatment and prophylaxis of ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. (1)

2 DOSAGE AND ADMINISTRATION • The recommended starting dosing regimen is: (2) o Initial Load: 150 mg in 100 mL infused over 10 minutes o Followed by: 1 mg/min for 6 hours o Followed by: 0.5 mg/min thereafter • For breakthrough episodes of VF or hemodynamically unstable VT, repeat the Initial Load (2) 2.1 General Considerations Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit, solution should be clear. Visually inspect the container. If the administration port protector is damaged, detached or not present, discard the container as the solution path sterility may be compromised. Check for minute leaks prior to use by squeezing the bag firmly. If leaks are detected, discard solution as sterility may be impaired. Protect from light until ready to use. NEXTERONE Premixed Injection is available in GALAXY containers as a single-use, ready-to-use, iso-osmotic solution in dextrose for intravenous administration. No further dilution is required. Discard any unused portion after use. Administer NEXTERONE, whenever possible, through a central venous catheter dedicated to that purpose. Use an in-line filter during administration. 2.2 Recommended Dosage NEXTERONE response can vary. Monitor patient response and adjust dose accordingly. In controlled clinical trials, mean daily doses above 2100 mg were associated with an increased risk of hypotension. Table 1: NEXTERONE Dosage Recommendations Loading Infusion First Rapid 150 mg over the FIRST 10 minutes (15 mg/min). Directly infuse NEXTERONE Premixed Injection (150 mg/100 mL; 1.5 mg/mL) at a rate of 10 mL/min. Followed by Slow 360 mg over the NEXT 6 hours (1 mg/min). Directly infuse NEXTERONE Premixed Injection (360 mg/200 mL; 1.8 mg/mL) at a rate of 0.556 mL/min. 540 mg over the REMAINING 18 hours (0.5 mg/min ) Decrease the rate to 0.278 mL/min. Maintenance Infusion After the first 24 hours, continue the maintenance infusion 720 mg per 24 hour period (0.5 mg/min) Directly infuse NEXTERONE Premixed Injection (360 mg/200 mL; 1.8 mg/mL) at a rate of 0.278 mL/min). Breakthrough VF or Hemodynamically Unstable VT 150 mg supplemental infusion over 10 minutes (15 mg/min). Directly infuse NEXTERONE Premixed Injection (150 mg/100mL; 1.5 mg/mL) at a rate of 10 mL/min. Admixture Incompatibility Amiodarone in D 5 W Injection forms precipitates with the drugs shown in Table 2 . If co-administration of the following drugs is necessary, use separate intravenous administration lines. Table 2: Y-SITE INJECTION INCOMPATIBILITY D5W = Dextrose 5% in Sterile Water, NS = Normal Saline Drug Vehicle Amiodarone Concentration Aminophylline D5W; NS 4 mg/mL Amoxicillin Sodium-Clavulanic Acid unknown 12.5 mg/mL Ampicillin Sodium-Sulbactam Sodium NS 6 mg/mL Argatroban D 5 W 1.8 mg/mL Bivalirudin D 5 W 4 mg/mL Cefamandole Nafate D 5 W 4 mg/mL Cefazolin Sodium D 5 W 4 mg/mL Ceftazidime D 5 W 6 mg/mL Digoxin D 5 W 6 mg/mL Furosemide (10 mg/mL) D 5 W 6 mg/mL Mezlocillin Sodium D 5 W 4 mg/mL Heparin Sodium D 5 W -- Imipenem-Cilastin Sodium D 5 W 6 mg/mL Magnesium Sulfate (500 mg/mL) D 5 W 6 mg/mL Micafungin NS 4 mg/mL Piperacillin Sodium –Tazobactam Sodium D 5 W 6 mg/mL Potassium Phosphates D 5 W 6 mg/mL Sodium Bicarbonate D 5 W 3 mg/mL Sodium Nitroprusside D 5 W 1.5, 6 and 15 mg/mL Sodium Phosphates D 5 W 6 mg/mL 2.3 Transition From Intravenous Amiodarone to Oral Amiodarone Table 3 provides suggested doses of oral amiodarone to be initiated after varying durations of NEXTERONE infusion. Table 3: RECOMMENDATIONS FOR ORAL DOSAGE AFTER INTRAVENOUS INFUSION Duration of Amiodarone Infusion Assuming a 720 mg/day infusion (0.5 mg/min). Initial Daily Dose of Oral Amiodarone Less than 1 week 800 to 1600 mg 1 to 3 weeks 600 to 800 mg More than 3 weeks Intravenous amiodarone is not intended for maintenance treatment. 400 mg

3 DOSAGE FORMS AND STRENGTHS Injection, 1.5 mg/mL (150 mg/100 mL) Premixed in Dextrose Injection, 1.8 mg/mL (360 mg/200 mL) Premixed in Dextrose Injection, 1.5 mg/mL (150 mg/100 mL) Premixed in Dextrose (3) Injection, 1.8 mg/mL (360 mg/200 mL) Premixed in Dextrose (3)

4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine [ see Warnings and Precautions (5.8) ]. • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrioventricular (AV) block unless a functioning pacemaker is available. NEXTERONE is contraindicated in patients with (4) : • Known hypersensitivity to any of the components of NEXTERONE, including iodine • Cardiogenic shock • Marked sinus bradycardia • Second- or third-degree atrio-ventricular (AV) block unless a pacemaker is available.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in labeling: • Hypotension [ see Warnings and Precautions (5.2) ] • Hepatic injury [ see Warnings and Precautions (5.4) ] • Proarrhythmia [ see Warnings and Precautions (5.5) ] • Pulmonary injury [ see Warnings and Precautions (5.6) ] • Thyroid injury [ see Warnings and Precautions (5.8) ] • Hypersensitivity [ see Warnings and Precautions (5.10) ] • The most common adverse reactions (1-2%) leading to discontinuation of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock. (6) • Other important adverse reactions are torsade de pointes, congestive heart failure, and liver function test abnormalities. (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone 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. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days. The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), 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 reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%). Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, diarrhea, shock, sinus bradycardia, Stevens-Johnson syndrome, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been reported in the post-marketing experience during or in close temporal relationship to intravenous amiodarone administration. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, and granulocytosis. Cardiac Disorders: sinus node dysfunction (sinus arrest, sinoatrial block), intraventricular conduction disorders including bundle branch block and infra-HIS block, bradycardia (sometimes fatal), ventricular extrasystoles, and antegrade conduction via an accessory pathway. Endocrine Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH). Eye Disorders: visual field defect and blurred vision. Gastrointestinal Disorders: pancreatitis. General Disorders and Administration Site Conditions: infusion site reactions, including thombosis, phlebitis, thrombophlebitis, cellulitis, pain, induration, edema, inflammation, urticaria, pruritus, erythema, pigment changes, hypoesthesia, skin sloughing, extravasation possibly leading to venous/infusion site necrosis, and granuloma. Hepatobiliary Disorders: cholestasis, cirrhosis, jaundice, alkaline phosphatase and blood lactate dehydrogenase increase. Musculoskeletal and Connective Tissue Disorders: myopathy, muscle weakness, rhabdomyolysis, muscle spasms, and back pain. Neoplasms benign, malignant and unspecified (incl cysts and polyps) Disorders: thyroid nodules/thyr …

7 DRUG INTERACTIONS Drug interactions with amiodarone are described in Table 5 below. Table 5: Amiodarone Drug Interactions Concomitant Drug Class/Name Examples Clinical Comment QT Prolonging Drugs class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents Increased risk of Torsade de Pointes. Avoid concomitant use. Negative Chronotropes digoxin, beta blockers, verapamil, diltiazem, clonidine, ivabradine Potentiates the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest and AV block. Monitor heart rate. CYP450 Inhibitors Grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine Increased exposure of amiodarone. Avoid concomitant use. CYP450 Inducers St. John’s Wort Reduced amiodarone serum levels Cyclosporine Increased plasma levels of cyclosporine have been reported resulting in elevated creatinine, despite reduction of cyclosporine dose. Monitor cyclosporine drug levels and renal function with concomitant use. Cholestyramine Reduced amiodarone serum levels Antiarrhythmics quinidine, procainamide, flecainide Reserve concomitant use for patients who are unresponsive to a single agent. Antiarrhythmic metabolism inhibited by amiodarone. Initiate antiarrhythmic at a lower than usual dose and monitor patient carefully. Reduce dose levels of previously administered antiarrhythmic by 30 to 50% for several days after transitioning to oral amiodarone. Evaluate continued need for antiarrhythmic. Digoxin Increased digoxin concentration. Reduce digoxin by half or discontinue. If continued, monitor for evidence of toxicity. HMG-CoA Reductase Inhibitors simvastatin, lovastatin, atorvastatin Increased plasma concentration of HMG-CoA 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 INR by 100% after 3 to 4 days. Reduce warfarin dose by one-third to one-half and monitor INR. Phenytoin Increased steady state levels of phenytoin. Monitor phenytoin levels. Hepatitis C direct acting antiviral Sofosbuvir Cases of symptomatic bradyarrhythmia requiring pacemaker insertion have been reported in patients on oral maintenance amiodarone who initiated therapy with Sofosbuvir. • Amiodarone is a substrate for CYP3A and CYP2C8, so inhibitors and inducers affect amiodarone exposure ( 7 ) • Amiodarone inhibits p-glycoprotein and CYP1A2, CYP2C9, CYP2D6, and CYP3A, increasing exposure to other drugs ( 7 )

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Use NEXTERONE during pregnancy only if the potential benefit to the mother justifies the risk to the fetus (8.1) . • Nursing mothers: Advise mothers to discontinue breast feeding (8.2) . 8.1 Pregnancy Risk Summary Available data from postmarketing reports and published case series indicate that amiodarone use in pregnant women may increase the risk for fetal adverse effects including neonatal hypo- and hyperthyroidism, neonatal bradycardia, neurodevelopmental abnormalities, preterm birth and fetal growth restriction. Amiodarone and its metabolite, desethylamiodarone (DEA), cross the placenta. Untreated underlying arrhythmias, including ventricular arrhythmias, during pregnancy pose a risk to the mother and fetus (see Clinical Considerations). In animal studies, administration of amiodarone to rabbits, rats, and mice during organogenesis resulted in embryo-fetal toxicity at doses less than the maximum recommended human maintenance dose (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%‐20%, respectively. Clinical Considerations Disease-associated maternal and or embryo/fetal Risk The incidence of ventricular tachycardia is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may therefore, increase during pregnancy due to the increased propensity to ectopic activity. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state. Fetal/Neonatal adverse reactions Amiodarone and its metabolite have been shown to cross the placenta. Adverse fetal effects associated with maternal amiodarone use during pregnancy may include neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles, neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure, neonatal hyperthyroxinemia, neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia, jerk nystagmus with synchronous head titubation, fetal growth restriction, and premature birth. Monitor the newborn for signs and symptoms of thyroid disorder and cardiac arrhythmias. Labor and Delivery Risk of arrhythmias may increase during labor and delivery. Data Animal Data In pregnant rats and rabbits during the period of organogenesis, an amiodarone HCl dose 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 (approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose*). Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg …

12.1 Mechanism of Action Amiodarone is considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, amiodarone exerts a noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a 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. Intravenous amiodarone 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 infra-nodal conduction (His-ventricular, HV). A comparison of the electrophysiologic effects of intravenous amiodarone and oral amiodarone is shown in the table below. Table 5: EFFECTS OF INTRAVENOUS AND ORAL AMIODARONE ON ELECTROPHYSIOLOGIC PARAMETERS Formulation SCL QRS QTc AH HV ERP RA ERP RV ERP AVN Intravenous ↔ ↔ ↔ ↑ ↔ ↔ ↔ ↑ Oral ↑ ↔ ↑ ↑ ↔ ↑ ↑ ↑ ↔No change At higher doses (>10 mg/kg) of intravenous amiodarone, 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 intravenous amiodarone may be predominately 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).

11 DESCRIPTION NEXTERONE contains amiodarone HCl (C 25 H 29 I 2 NO 3 •HCl), a class III antiarrhythmic drug. Amiodarone HCl is (2-butyl-3-benzo-furanyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride. Amiodarone HCl has the following structural formula: Amiodarone HCl is a white to slightly yellow crystalline powder and is very slightly soluble in water. It has a molecular weight of 681.78 and contains 37.3% iodine by weight. NEXTERONE Premixed Injection is a sterile clear, colorless to slightly yellow solution visually free from particulates. NEXTERONE Premixed Injection is available as a ready-to-use, nonpyrogenic, iso-osmotic solution for intravenous administration in 100-mL GALAXY containers with 150 mg of amiodarone HCl, USP (1.5 mg/mL) in dextrose, and 200-mL GALAXY containers with 360 mg of amiodarone HCl, USP (1.8 mg/mL) in dextrose. NEXTERONE Premixed Injection (150 mg/100 mL, 1.5 mg/mL): Each mL contains 1.5 mg of amiodarone HCl, USP, 15 mg Betadex Sulfobutyl Ether Sodium, NF, 0.362 mg citric acid anhydrous, 0.183 mg sodium citrate dihydrate and 42.1 mg dextrose anhydrous in water for injection. Sodium hydroxide or hydrochloric acid may have been added to adjust pH. NEXTERONE Premixed Injection (360 mg/200 mL, 1.8 mg/mL): Each mL contains 1.8 mg of amiodarone HCl, USP, 18 mg Betadex Sulfobutyl Ether Sodium, NF, 0.362 mg citric acid anhydrous, 0.183 mg sodium citrate dihydrate and 41.4 mg dextrose anhydrous in water for injection. Sodium hydroxide or hydrochloric acid may have been added to adjust pH. NEXTERONE does not contain polysorbate 80 or benzyl alcohol. The GALAXY container is fabricated from a specially designed multilayered plastic. Solutions are in contact with the polyethylene layer of the container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability and safety of the plastic have been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies. Amiodarone HCl Structural Formula

10 OVERDOSAGE There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of intravenous amiodarone include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Treat hypotension and cardiogenic shock by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Monitor hepatic enzyme concentrations closely. Neither amiodarone nor DEA is dialyzable.

16 HOW SUPPLIED/STORAGE AND HANDLING NEXTERONE (amiodarone HCl) Premixed Injection is supplied as a ready-to-use, sterile, nonpyrogenic, iso-osmotic solution in 100 mL and 200 mL single-dose GALAXY containers packaged in individual cartons as follows: 150 mg/100 mL NDC 43066 – 150 – 10 2G3451 360 mg/200 mL NDC 43066 – 360 – 20 2G3450 Do not add supplementary medication to NEXTERONE Premixed Injection. Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). See USP Controlled Room Temperature. Protect from light and excessive heat. Protect from freezing. Use carton to protect contents from light until used.