Drugs in Pregnancy and Lactation: Tenth Edition

RUFINAMIDE

Anticonvulsant

PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk

BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity

PREGNANCY SUMMARY

No reports describing the use of rufinamide in human pregnancy have been located. The drug caused embryo–fetal toxicity in two animal species at systemic exposures less than the human exposure. If a pregnant woman is exposed to this drug, she should be informed of the absence of human pregnancy experience and the potential for embryo–fetal risk.

FETAL RISK SUMMARY

Rufinamide is an oral triazole derivative that is unrelated to other anticonvulsants. It is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children ≥4 years of age and adults. Rufinamide is extensively metabolized to inactive metabolites. Only 34% of the drug is bound to plasma proteins, mostly to albumin, and the plasma half-life is about 6–10 hours (1).

Reproduction studies have been conducted in rats and rabbits. In rats, daily oral doses during organogenesis resulting in plasma exposures (AUC) that were 2 times the plasma exposure (AUC) from the maximum recommended human dose of 3200 mg/day (MRHD) caused decreased fetal weights and increased incidences of skeletal abnormalities, but maternal toxicity also was evident. In rabbits, daily oral doses during organogenesis resulting in exposures that were >0.2 times the MRHD resulted in embryo–fetal death, decreased fetal body weights, and increased incidences of visceral and skeletal abnormalities. A dose 2 times the MRHD caused abortions. In both species, the no-observed-effect-level (NOEL) for adverse effects on embryo–fetal development was 0.2 times the MRHD. In prenatal and postnatal studies with rats, daily oral doses given from implantation through weaning resulting plasma exposures that were <0.1–1.5 times the MRHD caused decreased offspring growth and survival at all doses. A NOEL was not established in these studies (1).

Long-term exposures to rufinamide in mice and rats were carcinogenic, but the drug was not mutagenic or clastogenic in multiple assays. In male and female rats daily doses that were ≥0.2 times than the MRHD before and throughout mating, and continued in females up to gestational day 6, were associated with impaired fertility including decreased sperm count and motility, decreased conception rates, mating, and fertility indices, decreased numbers of corpora lutea, implantations, and live embryos, and increased preimplantation loss. A NOEL for impaired fertility was not established (1).

It is not known if rufinamide crosses the human placenta. The low molecular weight (about 238), lipophilic nature, and long plasma half-life suggest that exposure of the embryo–fetus will occur. However, the extensive metabolism to inactive compounds might limit the exposure.

BREASTFEEDING SUMMARY

No reports describing the use of rufinamide during human lactation have been located. The low molecular weight (about 238), lipophilic nature, and long plasma half-life suggest that the drug will be excreted into breast milk, but the extensive metabolism should limit the amount. The effect of this exposure on a nursing infant is unknown. If mother chooses to nurse her infant while taking rufinamide, the infant should be closely observed for changes in behavior and other signs of toxicity. Somnolence, vomiting, and headache were the three most frequent adverse reactions observed in pediatric patients treated with the drug (1).

Reference

1.Product information. Banzel. Eisai, 2008.



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