PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
No reports describing the use of ezogabine in human pregnancy have been located. The animal data in two species suggest risk but the absence of human pregnancy experience prevents a better assessment. If a woman becomes pregnant while taking the drug or is prescribed the drug during pregnancy, she should be advised of the absence of human data and the potential risk to her embryo and/or fetus. Pregnant women taking ezogabine are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll-free number 1-800-233-2334.
FETAL RISK SUMMARY
Ezogabine is a potassium channel opener that is available as oral tablets. It is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older. Ezogabine is metabolized to an N-acetyl metabolite (NAMR) that has antiepileptic activity but less than the parent drug, as well as inactive metabolites. Plasma protein binding of ezogabine and NAMR are about 80% and 45%, respectively, whereas the elimination half-lives are 7–11 hours for both molecules (1).
Reproductive studies have been conducted in rats and rabbits. In rats given ezogabine during organogenesis, fetal skeletal variations were observed. When the drug was given throughout pregnancy and lactation, increased prenatal and postnatal mortality, decreased body weight gain, and delayed reflex development in the offspring were observed. The no-effect dose for embryo–fetal toxicity in both of these periods produced maternal plasma exposures (AUC) of ezogabine and NAMR that were less than those in humans at the maximum recommended human dose (MRHD). In rabbits, exposure throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal skeletal variations. The no-effect dose for embryo–fetal toxicity was associated with plasma levels of ezogabine and NAMR that were less than those in humans at the MRHD. In both rats and rabbits, the maximum doses evaluated were by maternal toxicity (acute neurotoxicity) (1).
In a 1-year study, a dose-related increased in the frequency of lung neoplasms was noted in male mice. No evidence of carcinogenicity was observed in a 2-year study in rats. In studies for mutagenicity with ezogabine, three assays were negative and one was positive. For assays with NAMR, one was negative and one was positive. In male and female rats, ezogabine had no effect on fertility, reproductive performance, or early embryonic development at doses producing a plasma ezogabine exposure (AUC) less than that in humans at the MRHD (1).
It is not known if ezogabine or its active metabolite NAMR crosses the placenta. The molecular weight of ezogabine (about 303), and the moderate plasma protein binding and long elimination half-lives of the parent drug and active metabolite suggest that both will cross to the embryo–fetus.
No reports describing the use of ezogabine during human lactation have been located. The molecular weight of ezogabine (about 303) and the moderate plasma protein binding (80% for ezogabine; 45% for the active metabolite [NAMR]) and long elimination half-lives (7–11 hours for both) suggest that ezogabine and NAMR will be excreted into breast milk. Although the systemic absorption in infants is unknown, the parent drug is well absorbed in adults. The drug is best avoided during breastfeeding because of the concern for clinically significant toxicity in a nursing infant.
1.Product information. Potiga. GlaxoSmithKline, 2012.