luded 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 m |
