Ibutilide Fumarate (Page 3 of 4)

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. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.

Calcium channel blocking agents

Coadministration 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

Coadministration 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 injection; 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/m2 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/m2 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/m2 basis, or 16 times the MRHD on a mg/kg basis. Ibutilide fumarate injection 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 injection.

Pediatric Use

Clinical trials with ibutilide fumarate injection 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 differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in Patients With Hepatic or Renal Dysfunction

The safety, effectiveness, and pharmacokinetics of ibutilide fumarate injection have not been established in patients with hepatic or renal dysfunction. However, it is unlikely that dosing adjustments would be necessary in patients with compromised renal or hepatic function based on the following considerations: (1) ibutilide fumarate injection is indicated for rapid intravenous therapy (duration ≤ 30 minutes) and is dosed to a known, well-defined pharmacologic action (termination of arrhythmia) or to a maximum of two 10-minute infusions; (2) less than 10% of the dose of ibutilide fumarate injection is excreted unchanged in the urine; and (3) drug distribution appears to be one of the primary mechanisms responsible for termination of the pharmacologic effect. Nonetheless, patients with abnormal liver function should be monitored by telemetry for more than the 4-hour period generally recommended.

In 285 patients with atrial fibrillation or atrial flutter who were treated with ibutilide fumarate injection, the clearance of ibutilide was independent of renal function, as assessed by creatinine clearance (range 21 to 140 mL/min).

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 injection 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 injection 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 (2.0%), 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 injection than in the placebo group.

Another adverse reaction that may be associated with the administration of ibutilide fumarate injection 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.

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