Amiodarone Hydrochloride

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 )

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

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/thyroid cancer. Nervous System Disorders: intracranial pressure increased, pseudotumor cerebri, tremor, dizziness and hypoesthesia. Psychiatric Disorders: confusional state, hallucination, disorientation, and delirium. Renal and Urinary Disorders: acute renal failure (sometimes fatal), renal impairment, renal insufficiency, and blood creatinine increased. Reproductive Disorders and Breast Disorders: Epididymitis Respiratory, Thoracic and Mediastinal Disorders: interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia (possibly fatal), pulmonary alveolar hemorrhage, pulmonary phospholipidoisis, pleural effusion, bronchospasm, dyspnea, cough, hemoptysis, wheezing, and hypoxia. Skin and Subcutaneous Tissue Disorders: toxic epidermal necrolysis (sometimes fatal), Stevens-Johnson syndrome, exfoliative dermatitis, erythema multiforme, skin cancer, pruritus, angioedema, and urticaria. Vascular Disorders: vasculitis and flushing.