IBUTILIDE FUMARATE

Ibutilide Fumarate Injection is an antiarrhythmic drug with predominantly class III (cardiac action potential prolongation) properties according to the Vaughan Williams Classification. Each milliliter of Ibutilide Fumarate Injection contains 0.1 mg of ibutilide fumarate, USP (equivalent to 0.087 mg ibutilide free base), 0.189 mg sodium acetate trihydrate, USP, 8.90 mg sodium chloride, USP, hydrochloric acid NF and/or sodium hydroxide NF to adjust pH to approximately 4.6, and Water for Injection, USP. Ibutilide Fumarate Injection is an isotonic, clear, colorless, sterile aqueous solution. Ibutilide fumarate has one chiral center, and exists as a racemate of the (+) and (−) enantiomers. The chemical name for ibutilide fumarate is Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1-hydroxybutyl} phenyl}, (+) (−), (E)-2-butenedioate (1:0.5) (hemifumarate salt) Its molecular formula is C 22 H 38 N 2 O 5 S, and its molecular weight is 442.62. Ibutilide fumarate is a white to off-white powder with an aqueous solubility of over 100 mg/mL at pH 7 or lower. The structural formula is represented below: structure

Ibutilide fumarate injection is indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. Patients with atrial arrhythmias of longer duration are less likely to respond to ibutilide fumarate. The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration. LIFE-THREATENING ARRHYTHMIAS—APPROPRIATE TREATMENT ENVIRONMENT Ibutilide fumarate can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, usually in association with QT prolongation (torsades de pointes), but sometimes without documented QT prolongation. In registration studies, these arrhythmias, which require cardioversion, occurred in 1.7% of treated patients during, or within a number of hours of, use of Ibutilide fumarate. These arrhythmias can be reversed if treated promptly (see WARNINGS, Proarrhythmia ). It is essential that Ibutilide fumarate be administered in a setting of continuous ECG monitoring and by personnel trained in identification and treatment of acute ventricular arrhythmias, particularly polymorphic ventricular tachycardia. Patients with atrial fibrillation of more than 2 to 3 days’ duration must be adequately anticoagulated, generally for at least 2 weeks. CHOICE OF PATIENTS Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm (see CLINICAL STUDIES ) and treatments to maintain sinus rhythm carry risks. Patients to be treated with Ibutilide fumarate , therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of Ibutilide fumarate , and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.

The recommended dose based on controlled trials (see CLINICAL STUDIES ) is outlined in the Table below. Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked prolongation of QT or QTc. Recommended Dose of Ibutilide Fumarate Injection Patient Weight Initial Infusion (over 10 minutes) Second Infusion 60 kg (132 lb) or more One vial (1 mg ibutilide fumarate) If the arrhythmia does not terminate within 10 minutes after the end of the initial infusion, a second 10-minute infusion of equal strength may be administered 10 minutes after completion of the first infusion. Less than 60 kg (132 lb) 0.1 mL/kg (0.01 mg/kg ibutilide fumarate) In a trial comparing ibutilide and sotalol (see CLINICAL STUDIES ), 2 mg ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg was also effective in terminating atrial fibrillation or atrial flutter. In the post-cardiac surgery study (see CLINICAL STUDIES ), one or two intravenous infusions of 0.5 mg (0.005 mg/kg per dose for patients weighing less than 60 kg) was effective in terminating atrial fibrillation or atrial flutter. Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Skilled personnel and proper equipment (see WARNINGS, Proarrhythmia ), such as a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during administration of ibutilide fumarate and subsequent monitoring of the patient. Dilution Ibutilide fumarate injection may be administered undiluted or diluted in 50 mL of diluent. Ibutilide fumarate may be added to 0.9% Sodium Chloride Injection or 5% Dextrose Injection before infusion. The contents of one 10 mL vial (0.1 mg/mL) may be added to a 50 mL infusion bag to form an admixture of approximately 0.017 mg/mL ibutilide fumarate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Compatibility and Stability The following diluents are compatible with ibutilide fumarate injection (0.1 mg/mL): 5% Dextrose Injection 0.9% Sodium Chloride Injection The following intravenous solution containers are compatible with admixtures of ibutilide fumarate injection (0.1 mg/mL): polyvinyl chloride plastic bags polyolefin bags Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15° to 30° C or 59° to 86° F) and for 48 hours at refrigerated temperatures (2° to 8°C or 36° to 46°F). Strict adherence to the use of aseptic technique during the preparation of the admixture is recommended in order to maintain sterility.

Ibutilide fumarate injection is contraindicated in patients who have previously demonstrated hypersensitivity to ibutilide fumarate or any of the other product components.

Ibutilide fumarate injection was generally well tolerated in clinical trials. Of the 586 patients with atrial fibrillation or atrial flutter who received ibutilide fumarate in phase II/III studies, 149 (25%) reported medical events related to the cardiovascular system, including sustained polymorphic ventricular tachycardia (1.7%) and nonsustained polymorphic ventricular tachycardia (2.7%). Other clinically important adverse events with an uncertain relationship to ibutilide fumarate include the following (0.2% represents one patient): sustained monomorphic ventricular tachycardia (0.2%), nonsustained monomorphic ventricular tachycardia (4.9%), AV block (1.5%), bundle branch block (1.9%), ventricular extrasystoles (5.1%), supraventricular extrasystoles (0.9%), hypotension/postural hypotension (2%), bradycardia/sinus bradycardia (1.2%), nodal arrhythmia (0.7%), congestive heart failure (0.5%), tachycardia/sinus tachycardia/supraventricular tachycardia (2.7%), idioventricular rhythm (0.2%), syncope (0.3%), and renal failure (0.3%). The incidence of these events, except for syncope, was greater in the group treated with ibutilide fumarate than in the placebo group. Another adverse reaction that may be associated with the administration of ibutilide fumarate was nausea, which occurred with a frequency greater than 1% more in ibutilide-treated patients than those treated with placebo. The medical events reported for more than 1% of the placebo- and ibutilide-treated patients are shown in the following Table. Treatment-Emergent Medical Events With Frequency of More Than 1% and Higher Than That of Placebo Event Placebo N=127 All Ibutilide N=586 Patients Patients n % n % CARDIOVASCULAR Ventricular extrasystoles 1 0.8 30 5.1 Nonsustained monomorphic VT 1 0.8 29 4.9 Nonsustained polymorphic VT — — 16 2.7 Hypotension 2 1.6 12 2.0 Bundle branch block — — 11 1.9 Sustained polymorphic VT — — 10 1.7 AV block 1 0.8 9 1.5 Hypertension — — 7 1.2 QT segment prolonged — — 7 1.2 Bradycardia 1 0.8 7 1.2 Palpitation 1 0.8 6 1.0 Tachycardia 1 0.8 16 2.7 GASTROINTESTINAL Nausea 1 0.8 11 1.9 CENTRAL NERVOUS SYSTEM Headache 4 3.1 21 3.6 In the post-cardiac surgery study (see CLINICAL STUDIES ), similar types of medical events were reported. In the 1 mg ibutilide fumarate treatment group (N=70), 2 patients (2.9%) developed sustained polymorphic ventricular tachycardia and 2 other patients (2.9%) developed nonsustained polymorphic ventricular tachycardia. Polymorphic ventricular tachycardia was not reported in the 73 patients in the 0.5 mg dose group or in the 75 patients in the 0.25 mg dose group.

No specific pharmacokinetic or other formal drug interaction studies were conducted. Digoxin Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Co-administration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials. Calcium channel blocking agents Co-administration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials. Beta-adrenergic blocking agents Co-administration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.