Central Nervous System (Miscellaneous)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although the animal data suggest risk, the very limited human pregnancy experience does not allow an accurate assessment of the human embryo–fetal risk. Nevertheless, amyotrophic lateral sclerosis (ALS) is a severe progressive disease with marked morbidity resulting in eventual death. Consequently, the maternal benefit appears to be much greater than the unknown embryo–fetal risk.
FETAL RISK SUMMARY
Riluzole is indicated for the treatment of patients with ALS to extend survival and/or time to tracheostomy. It is a member of the benzothiazole class. The agent is extensively metabolized and some of the metabolites are pharmacologically active. Riluzole is 96% bound to plasma proteins, mainly to albumin and lipoproteins. The mean elimination half-life is 12 hours (1).
Reproduction studies have been conducted in rats and rabbits. In these species, doses that were 2.6 and 11.5 times, respectively, the maximum recommended daily dose based on BSA (MRDD) caused embryotoxicity. Maternal toxicity also was observed at these doses. When rats received a dose that was 1.5 times the MRDD before and during mating (males and females) and throughout pregnancy and lactation, decreased implantations, increased intrauterine death, and adverse effects in offspring viability and growth were observed (1).
Riluzole was not carcinogenic in mice and rats, and there was no evidence of mutagenic or clastogenic potential in multiple assays. The major active metabolite, N-hydroxyriluzole, did cause chromosomal damage in two tests, but negative results were observed in other assays. As discussed above, Riluzole impaired fertility when administered to male and female rats (1).
It is not known if riluzole or its metabolites cross the human placenta. The molecular weight of the parent drug (about 234) and long elimination half-life suggest that riluzole and its metabolite will cross to the embryo–fetus.
The first report of riluzole use in human pregnancy appeared in 2009 (2). A 28-year-old woman was diagnosed with ALS and treated with riluzole (dose not specified). When her pregnancy was discovered at 9 weeks’ gestation, riluzole was discontinued. She had a normal pregnancy and gave birth vaginally at 40 weeks’ to a healthy male infant. No other information about the infant was given other than that he was in good health at the time of this report. The woman eventually had a second pregnancy, apparently without riluzole (2).
A 2010 case report described the pregnancy outcome of a 34-year-old primigravida Japanese woman with ALS (3). The woman had been taking riluzole (100 mg/day) for 2 years. Her pregnancy was diagnosed at 30 weeks’ gestation and riluzole was continued. She gave birth vaginally at 38 weeks’ to a 2280-g growth-restricted female infant with Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. The growth restriction may have been wholly or partially due to cigarette smoking. The infant was developing normally at 1 year of age. In addition to this case, the authors reviewed the pregnancy outcomes of 11 women with ALS (all occurring before the availability of riluzole) (3).
BREASTFEEDING SUMMARY
No reports describing the use of riluzole during human lactation have been located. The molecular weight (about 234) and long elimination half-life (12 hours) suggest that the drug, and possibly its metabolites, will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, the drug caused marked toxicity in adults with about 14% of patients in clinical trials discontinuing riluzole because of adverse effects (1).
References
1.Product information. Rilutek. Sanofi-Aventis, 2009.
2.Sarafov S, Doitchinova M, Karagiozova Z, Slancheva B, Dengler R, Petri S, Kollewe K. Two consecutive pregnancies in early and late stage of amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009;10:483–6.
3.Kawamichi Y, Makino Y, Matsuda Y, Miyazaki K, Uchiyama S, Ohta H. Riluzole use during pregnancy in a patient with amyotrophic lateral sclerosis: a case report. J Int Med Res 2010;38:720–6.