Endocrine/Metabolic Agent (Gaucher Disease)
PREGNANCY RECOMMENDATION: No Human Data—Contraindicated
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of miglustat in human pregnancy have been located. The animal data suggest risk for embryotoxicity and decreased fetal weight at exposure levels comparable to human systemic exposure.
FETAL RISK SUMMARY
Miglustat is an oral medication that inhibits the enzyme glucosylceramide synthase and is used for the treatment of type I Gaucher disease in individuals for whom enzyme replacement therapy is not an option. Miglustat does not bind to plasma proteins. The effective elimination half-life is 6–7 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats, miglustat was given by oral gavage at doses up to ≥2 times the human therapeutic systemic exposure based on BSA (HTSE) beginning 14 days before mating and continuing through day 17 (organogenesis). At the mid-to-high doses that were ≥2 times the HTSE, decreased fetal survival, including complete litter loss, and decreased fetal weights were observed. Delayed parturition and dystocia were observed in another rat study that used the same mid-to-high doses and route of administration from gestation day 6 through lactation. In addition, decreased survival and reduced fetal weights were seen at doses comparable to or below the HTSE. In rabbits, doses that were less than the HTSE during gestation days 6–18 resulted in maternal toxicity and death (1).
In 2-year carcinogenicity studies conducted in mice, mucinous adenocarcinomas of the large intestine were observed in male and female mice given oral doses that were 3 and 6 times the recommended human dose (RHD), respectively. In rats, an increased incidence of interstitial cell adenomas of the testis was observed in males at doses equivalent to the RHD. Miglustat was not mutagenic or clastogenic in multiple in vitro and in vivo assays. Fertility studies in rats demonstrated decreased spermatogenesis in males who were treated 14 days prior to mating and at doses below the HTSE. In females, decreased corpora lutea were noted, as well as increased postimplantation loss at the lowest dose (1). However, in a study conducted in seven normal human males who were administered 100 mg of miglustat twice a day for 6 weeks, no effects on sperm concentration, motility, and morphology were seen (2).
It is not known if miglustat crosses the human placenta. The molecular weight (about 200), lack of plasma protein binding, and prolonged elimination half-life suggest that the drug will cross the placenta throughout gestation.
No reports of human pregnancy exposure to miglustat have been located. Because the drug is contraindicated in pregnancy, pregnancy exposures should be rare. One pharmacovigilance study in Europe followed 122 type I Gaucher disease patients for 5 years and identified 1 woman who discontinued the drug for a planned pregnancy (3).
BREASTFEEDING SUMMARY
No reports describing the use miglustat during human lactation have been located. The molecular weight (about 200), lack of plasma protein binding, and relatively long elimination half-life (6–7 hours) suggest that the drug will be excreted into breast milk.
References
1.Product information. Zavesca. Actelion Pharmaceuticals, 2010.
2.Amory JK, Muller CH, Page ST, Leifke E, Pagel ER, Bhandari A, Subramanyam B, Bone W, Radlmaier A, Bremner WJ. Miglustat has no apparent effect on spermatogenesis in normal men. Hum Reprod 2007;22:702–7.
3.Hollak CE, Hughes D, van Schaik IN, Schwierin B, Bembi B. Miglustat (Zavesca) in type I Gaucher disease: 5-year results of a post-authorisation safety surveillance programme. Pharmacoepidemiol Drug Saf 2009;18:770–7.