DOFETILIDE

Fetal Risk Summary

Dofetilide is an antiarrhythmic agent with Class III (cardiac action potential duration prolongation) properties that is indicated for the maintenance of normal sinus rhythm in patients with atrial fibrillation/flutter. Only about 20% of the drug is metabolized.

In reproduction studies in mice and rats, oral doses of dofetilide equal to or greater than 4 and 2 times, respectively, the maximum likely human exposure (based on the 24-hour area under the plasma concentration curve) (MHE), caused sternebral and vertebral anomalies in both species (1). In addition, an increased incidence of unossified calcaneum was noted in mice. In rats given doses approximately equal to the MHE, an increased incidence of unossified metacarpal and the occurrence of hydroureter and hydronephroses were observed. When the dose was doubled (2 times the MHE) in rats, additional defects noted were cleft palate, adactyly, levocardia, and dilation of cerebral ventricles. The no effect adverse effect dose in mice was approximately equal to the MHE, whereas in rats it was about one-half the MHE (1).

Dofetilide had no effect on mating and fertility in rats at doses up to 3 times the MHE (1). It was also not mutagenic in in vitro and in vivo tests, nor was it carcinogenic in tests with mice and rats. Chronic administration of dofetilide did cause testicular atrophy, decreased testicular weight, and/or epididymal oligospermia in mice, rats, and dogs at doses greater than 3, 4, and 1.3 times, respectively, the MHE (1).

In a 1996 study, the embryo toxicity and teratogenicity of dofetilide in rats were shown to be gestational-age related and resulted from dose-dependent bradycardia in in vitro (rat embryo culture) and in vivo (pregnant rat) experiments (2). In the embryo cultures, the minimum effective concentration for significant bradycardia (22 ng/mL) was about 6 times the human peak plasma concentration achieved after an oral dose of 12 µg/kg (3.5 ng/mL) (2). An embryo culture dose twice the minimum effective dose caused an almost complete cessation of the heartbeat. In pregnant rats, single oral doses of various concentrations were given on different gestational days. On gestational day (GD) 10, a high incidence of resorptions occurred, but no malformations except one fetus with a short tail. Defects and/or toxicity seen on other days included GD 11 (right-sided cleft lip), GD 12 (small number of defects; 100% lethality at highest dose), and GD 13 (most sensitive day; hind limb defects; resorptions at higher doses). The defects were preceded by hemorrhage, but the investigators could not determine if the hemorrhage caused the defect or if the hemorrhage and defect were caused by the bradycardia-induced hypoxia (2).

It is not known if dofetilide crosses the human placenta. The molecular weight (about 442) is low enough that transfer to the fetus should be expected.

No reports describing the use of dofetilide during human pregnancy have been located. Although the antiarrhythmic is teratogenic and toxic in animals at exposures slightly above those expected in humans, the lack of human data prevents an assessment of the potential embryo/fetal risk. However, if dofetilide therapy is required in a pregnant woman, the benefits appear to outweigh the unknown risk.

Breast Feeding Summary

No reports describing the use of dofetilide in human lactation have been located. The molecular weight (about 442) is low enough that excretion in breast milk should be expected. The effects of this exposure on a nursing infant are unknown. Until the pharmacokinetics of dofetilide in milk have been determined, and until the effects on a nursing infant from exposure to the drug in milk have been clarified, women receiving this agent should probably not breast feed.

References

1. Product information. Tikosyn. Pfizer, 2001.
2. Webster WS, Brown-Woodman PDC, Snow MD, Danielsson BRG. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 1996;53:168–75.