Risk Factor: CM
Class: Cardiovascular drugs/ Cardiac drugs
Fetal Risk Summary
Ibutilide is a cardiac antiarrhythmic agent with predominantly class III (cardiac action potential prolongation) properties (1). Other available class III antiarrhythmic agents are amiodarone, sotalol, and bretylium (2). Ibutilide is administered by IV injection only. It undergoes rapid and extensive hepatic metabolism to eight metabolites, only one of which is active. Ibutilide has an average elimination half-life of about 6 hours (range 212 hours) (1).
Dose-related teratogenic, embryocidal effects, and fetal toxicity were observed in rats given ibutilide orally on days 615 of gestation (1,3,4). The no-observed-adverse-effect level (NOAEL), corrected for the 3% oral bioavailability, was 5 mg/kg/day, approximately the same as the maximum recommended human dose on a mg/m2 basis (MRHD). Scoliosis was observed at a dose double the MRHD, but the incidence was not significantly different from controls (4). At four and eight times the MRHD, a significant dose-response effect was observed for adactyly, interventricular septal defects, scoliosis, and pharynx and palate malformations (4). A significant increase in embryo resorptions and fetal toxicity occurred at eight times the MRHD (4).
No reports describing the use of ibutilide in human pregnancy have been located. Similarly, human placental transfer of ibutilide has apparently not been studied. The molecular weight (about 443 for the fumarate salt), however, is low enough that passage to the fetus should be expected.
In summary, although the lack of human reports prevents an assessment of the risk to the fetus from ibutilide, the benefits of therapy appear to outweigh any fetal risk. This conclusion is based on several considerations. First, the teratogenic dose in rats was at least twice the MRHD, and in most cases much higher after dosing throughout organogenesis. Second, the indication for ibutilide (i.e., rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm) is indicative of severe maternal disease that would be, in itself, harmful to the fetus if not treated. Finally, treatment with ibutilide would most likely be short-term and occur in a hospital with the fetus under surveillance.
Breast Feeding Summary
No reports describing the use of ibutilide during lactation have been located. It is doubtful if such reports will occur because of the indication for this drug. In addition, its low oral bioavailability (about 3% in rats) probably indicates that little of the drug would be absorbed by a nursing infant.
- Product information. Corvert, Pharmacia & Upjohn, 2000.
- Granberry MC. Ibutilide: A new class III antiarrhythmic agent. Am J Health-Syst Pharm 1998;55:25560.
- Marks TA, Terry RD. Developmental toxicity of ibutilide fumarate in rats (abstract). Teratology 1995;49:406.
- Marks TA, Terry RD. Developmental toxicity of ibutilide fumarate in rats after oral administration. Teratology 1996;54:15764.