Ibutilide Fumarate 1 mg/10mL Injection, Solution — NDC 23155-326-31 (Billing 23155-0326-31)

WARNINGS Proarrhythmia Like other antiarrhythmic agents, ibutilide fumarate injection can induce or worsen ventricular arrhythmias in some patients. This may have potentially fatal consequences. Torsades de pointes, a polymorphic ventricular tachycardia that develops in the setting of a prolonged QT interval, may occur because of the effect ibutilide fumarate has on cardiac repolarization, but ibutilide fumarate can also cause polymorphic VT in the absence of excessive prolongation of the QT interval.

In general, with drugs that prolong the QT interval, the risk of torsades de pointes is thought to increase progressively as the QT interval is prolonged and may be worsened with bradycardia, a varying heart rate, and hypokalemia. In clinical trials conducted in patients with atrial fibrillation and atrial flutter, those with QTc intervals greater than 440 msec were not usually allowed to participate, and serum potassium had to be above 4 mEq/L. Although change in QTc was dose dependent for ibutilide, there was no clear relationship between risk of serious proarrhythmia and dose in clinical studies, possibly due to the small number of events.

In clinical trials of intravenous ibutilide, patients with a history of congestive heart failure (CHF) or low left ventricular ejection fraction appeared to have a higher incidence of sustained polymorphic ventricular tachycardia (VT), than those without such underlying conditions; for sustained polymorphic VT the rate was 5.4% in patients with a history of CHF and 0.8% without it. There was also a suggestion that women had a higher risk of proarrhythmia, but the sex difference was not observed in all studies and was most prominent for nonsustained ventricular tachycardia.

The incidence of sustained ventricular arrhythmias was similar in male (1.8%) and female (1.5%) patients, possibly due to the small number of events. Ibutilide fumarate is not recommended in patients who have previously demonstrated polymorphic ventricular tachycardia (eg, torsades de pointes). During registration trials, 1.7% of patients with atrial flutter or atrial fibrillation treated with Ibutilide fumarate developed sustained polymorphic ventricular tachycardia requiring cardioversion.

In these clinical trials, many initial episodes of polymorphic ventricular tachycardia occurred after the infusion of ibutilide fumarate was stopped but generally not more than 40 minutes after the start of the first infusion. There were, however, instances of recurrent polymorphic VT that occurred about 3 hours after the initial infusion. In two cases, the VT degenerated into ventricular fibrillation, requiring immediate defibrillation.

Other cases were managed with cardiac pacing and magnesium sulfate infusions. Nonsustained polymorphic ventricular tachycardia occurred in 2.7% of patients and nonsustained monomorphic ventricular tachycardias occurred in 4.9% of the patients (see ADVERSE REACTIONS ). Proarrhythmic events must be anticipated.

Skilled personnel and proper equipment, including cardiac monitoring equipment, intracardiac pacing facilities, a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during and after administration of ibutilide fumarate. Before treatment with ibutilide fumarate, hypokalemia and hypomagnesemia should be corrected to reduce the potential for proarrhythmia. 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. Management of polymorphic ventricular tachycardia includes discontinuation of ibutilide, correction of electrolyte abnormalities, especially potassium and magnesium, and overdrive cardiac pacing, electrical cardioversion, or defibrillation. Pharmacologic therapies include magnesium sulfate infusions.

Treatment with antiarrhythmics should ge… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS 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

5.1Nonsustained monomorphic VT 1 0.8 29

4.9 Nonsustained polymorphic VT — — 16

2.7Hypotension 2 1.6 12

2.0 Bundle branch block — — 11

1.9 Sustained polymorphic VT — — 10

1.7AV block 1 0.8 9

1.5 Hypertension — — 7

1.2 QT segment prolonged — — 7

1.2Bradycardia 1 0.8 7

1.2Palpitation 1 0.8 6

1.0Tachycardia 1 0.8 16

2.7GASTROINTESTINAL Nausea 1 0.8 11

1.9CENTRAL NERVOUS SYSTEM Headache 4 3.1 21

3.6In 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.

Drug Interactions 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.

Laboratory Test Interactions None known.

PRECAUTIONS General Antiarrhythmics Class Ia antiarrhythmic drugs (Vaughan Williams Classification), such as disopyramide, quinidine, and procainamide, and other class III drugs, such as amiodarone and sotalol, should not be given concomitantly with ibutilide fumarate injection or within 4 hours postinfusion because of their potential to prolong refractoriness. In the clinical trials, class I or other class III antiarrhythmic agents were withheld for at least 5 half-lives prior to ibutilide infusion and for 4 hours after dosing, but thereafter were allowed at the physician’s discretion.

Other drugs that prolong the QT interval The potential for proarrhythmia may increase with the administration of ibutilide fumarate injection to patients who are being treated with drugs that prolong the QT interval, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamine drugs (H 1 receptor antagonists). Heart block Of the nine (1.5%) ibutilide-treated patients with reports of reversible heart block, five had first degree, three had second degree, and one had complete heart block.

Laboratory Test Interactions None known. Drug Interactions 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. Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted to determine the carcinogenic potential of ibutilide fumarate; however, it was not genotoxic in a battery of assays, (Ames assay, mammalian cell forward gene mutation assay, unscheduled DNA synthesis assay, and mouse micronucleus assay). Similarly, no drug-related effects on fertility or mating were noted in a reproductive study in rats in which ibutilide was administered orally to both sexes up to doses of 20 mg/kg/day.

On a mg/m 2 basis, corrected for 3% bioavailability, the highest dose tested was approximately four times the maximum recommended human dose (MRHD). Pregnancy Ibutilide administered orally was teratogenic (abnormalities included adactyly, interventricular septal defects, and scoliosis) and embryocidal in reproduction studies in rats. On a mg/m 2 basis, corrected for the 3% oral bioavailability, the “no adverse effect dose” (5 mg/kg/day given orally) was approximately the same as the maximum recommended human dose (MRHD); the teratogenic dose (20 mg/kg/day given orally) was about four times the MRHD on a mg/m 2 basis, or 16 times the MRHD on a mg/kg basis.

Ibutilide fumarate should not be administered to a pregnant woman unless clinical benefit outweighs potential risk to the fetus. Nursing Mothers The excretion of ibutilide into breast milk has not been studied; accordingly, breastfeeding should be discouraged during therapy with ibutilide fumarate. Pediatric Use Clinical trials with ibutilide fumarate in patients with atrial fibrillation and atrial flutter did not include anyone under the age of 18.

Safety and effectiveness of ibutilide in pediatric patients has not been established. Geriatric Use Clinical studies of ibutilide fumarate (involving 586 patients) did not include sufficient numbers of subjects less than age 65 (45%) to determine whether they respond differently from older subjects. Other reported clinical experience has not identified… [Excerpted — this section continues on DailyMed.]