NEXTERONE (AMIODARONE HCI)

1 INDICATIONS & 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 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 NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration ( 2 )]. Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

2 DOSAGE & ADMINISTRATION Amiodarone shows considerable interindividual variation in response. Although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose is essential. The recommended starting dose of NEXTERONE is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen: After the first 24 hours, continue the maintenance infusion rate of 0.5 mg/min (720 mg per 24 hours) by directly infusing NEXTERONE Premixed Injection (360 mg/200 mL; 1.8 mg/mL) at a rate of 0.278 mL/min. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression. In the event of breakthrough episodes of VF or hemodynamically unstable VT, use 150 mg supplemental infusions of NEXTERONE (infused over 10 minutes to minimize the potential for hypotension). 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. Do not exceed an initial infusion rate of 30 mg/min. Based on the experience from clinical studies of intravenous amiodarone, a maintenance infusion of up to 0.5 mg/min can be 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 intravenous amiodarone for longer than 3 weeks. Administer NEXTERONE, whenever possible, through a central venous catheter dedicated to that purpose. Use an in-line filter during administration. Intravenous amiodarone 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 Warnings and Precautions ( 5- 5.3)]. Intravenous amiodarone concentrations greater than 3 mg/mL 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, do not exceed NEXTERONE concentrations of 2 mg/mL, unless a central venous catheter is used [see Adverse Reactions ( 6- 6.2)]. 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. NEXTERONE Premixed Injection should not be combined with any product in the same intravenous line or premixed container. Do not add supplemental medication. Protect from light until ready to use. NEXTERONE does not need to be protected from light during administration. Since the premixed container is for single-use only, any unused portion should be discarded. NOTE: 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. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. Preparation of NEXTERONE Premixed Injection for administration: 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Admixture Incompatibility Amiodarone in D5W Injection forms precipitates with the drugs shown in Table 2. If co-administration of the following drugs is necessary, use separate intravenous administration lines. Intravenous to Oral Transition Patients whos …

3 DOSAGE FORMS & 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

4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), uritcaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available.

6 ADVERSE REACTIONS The following adverse reactions are described in Warnings and Precautions: hypotension, rhythm disturbances, hepatic injury, pulmonary injury, thyroid injury, hypersensitivity. 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, 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 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%). Table 4 lists the most common (incidence ≥2%) adverse reactions during intravenous amiodarone 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 reactions appeared to be dose-related. Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone 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, atrioventricular block, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, 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, intravascular amiodarone deposition/mass (developed in the superior vena cava around acentral venous catheter after long – term [28 days] amiodarone therapy administered through a central line), 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 beni …

7 DRUG INTERACTIONS 7.1 Pharmacodynamic Interactions Drugs prolonging the QT interval: Co-administration of drugs prolonging the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents) increases the risk of Torsade de Pointes. In general, avoid concomitant use of drugs that prolong the QT interval [see Warnings and Precautions ( 5- 5.4)]. Drugs that slow heart rate: Concomitant use of drugs with depressant effects on the sinus and AV node (e.g., digoxin, beta blockers, verapamil, diltiazem, ivabradine, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate. 7.2 Pharmacokinetic Interactions Effect of other drugs on amiodarone Amiodarone is metabolized to the active metabolite desethylamiodarone (DEA) by the cytochrome P450 (CYP450) enzyme group, specifically CYP3A and CYP2C8. Amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP450 enzymes (e.g., inhibitors such as protease inhibitors, grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals and inducers such as St. John’s Wort) or P-glycoprotein. In view of the long and variable half-life of amiodarone, potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone [see Clinical Pharmacology ( 12- 12.3)]. Patients should avoid grapefruit juice beverages while taking amiodarone because exposure to amiodarone is significantly increased [see Clinical Pharmacology ( 12- 12.3)]. Effect of amiodarone on other drugs Amiodarone and DEA are inhibitors of P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6 and CYP3A [see Clinical Pharmacology ( 12- 12.3)]. Antiarrhythmics: The metabolism of quinidine, procainamide, flecainide can be inhibited by amiodarone. In general, initiate any added antiarrhythmic drug at a lower than usual dose and monitor the patient carefully. During transfer to oral amiodarone, reduce the dose levels of previously administered agents by 30 to 50% several days after the addition of oral amiodarone. Review the continued need for the other antiarrhythmic agent after the effects of amiodarone have been established, and attempt discontinuation [see Clinical Pharmacology ( 12- 12.3)]. Digoxin: In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in serum digoxin concentration. Reduce dose of digoxin by half or discontinue digoxin. If digitalis treatment is continued, monitor serum levels closely and observe patients for clinical evidence of toxicity [see Clinical Pharmacology ( 12- 12.3)]. HMG-CoA Reductase Inhibitors: Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs. Anticoagulants: Potentiation of warfarin-type (CYP2C9 and CYP3A substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the INR by 100% after 3 to 4 days, reduce the dose of the anticoagulant by one-third to one-half, and monitor INR closely. Cyclosporine (CYP3A substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. Monitor cyclosporine drug levels and renal function in …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions ( 5- 5.8)]. Teratogenic Effects Amiodarone and desethylamiodarone cross the placenta. Reported risks 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 retardation • premature birth Amiodarone has caused a variety of adverse effects in animals. Amiodarone was given intravenously to rabbits at dosages of 5, 10, or 25 mg/kg per day (about 0.1, 0.3, and 0.7 times human intravenous maintenance dose of 0.5 mg/min on a body surface area basis), during gestation days 8 to 16 (organogenesis). The incidence of maternal deaths increased with increasing dose and occurred in all treated groups and controls. Mean fetal weights were significantly decreased in the low and middle dose groups and embryotoxicity (as manifested by fewer full-term fetuses and increased resorptions) occurred at dosages of 10 mg/kg and above. There were no significant differences in the number of minor fetal abnormalities and no major fetal abnormalities were observed. Amiodarone was administered by continuous intravenous infusion to rats at dosages of 25, 50, or 100 mg/kg per day (about 0.3, 0.7 and 1.3 times the human intravenous maintenance dose of 0.5 mg/min on a body surface area basis) during gestation days 8 to 16 (organogenesis). Maternal toxicity (manifest as reduced weight gain and food consumption) and embryotoxicity (manifest as increased resorptions, decreased live litter size and fetal body weights, and delayed sternal and metacarpal ossification) were observed in the 100 mg/kg group. The delayed ossification was reversible and related to decreased fetal weight. Fetal thyroid tissues appeared normal in all groups. Nonteratogenic Effects Very high concentrations of amiodarone and desethylamiodarone may be found in testes. An elevated follicle-stimulating hormone and luteinizing hormone levels, suggestive of testicular dysfunction, have been reported in men on long-term amiodarone treatment. While planning pregnancy after discontinuation of amiodarone treatment, consider the long half-life of amiodarone and its metabolite DEA. 8.2 Labor and Delivery It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition. 8.3 Nursing Mothers Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and transient reduced body weight gains. The risk of exposing the infant to amiodarone and DEA must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing. 8.4 Pediatric Use The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended. In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and AV block (15%) were common dose-related adverse reactions and were severe or life-threatening in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients receiving intravenous amiodarone through a peripheral vein irrespective of dose regimen. 8.5 Geriatric Use Clinical studies of amiodarone did not include sufficient numb …

11 DESCRIPTION NEXTERONE contains amiodarone HCl (C25H29I2NO3•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 (PL 2501). 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. STRUCTURE

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 HCI) PREMIXED INJECTION is supplied in the following dosage forms. NDC 51662-4180-1 NEXTERONE (AMIODARONE HCI) PREMIXED INJECTION 150mg/100mL (1.5mg/mL) 100mL BAG NDC 51662-4181-1 NEXTERONE (AMIODARONE HCI) PREMIXED INJECTION 360mg/200mL (1.8mg/mL) 200mL BAG HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms 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 (PL 2501 plastic) packaged in individual cartons as follows: 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. HOW SUPPLIED