Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: No Human Data—Contraindicated
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
No reports describing the use of fingolimod in human pregnancy have been located. The receptor affected by fingolimod is involved in angiogenesis and vascular formation during embryogenesis. An increase in malformations has been noted in rats given doses similar to the recommended human dose based on BSA (RHD). Reduced pre- and postnatal survival and an increase in learning deficits have also been seen. In rabbits, an increase in embryo–fetal death and growth restriction has been noted, with the no-effect-dose-level approximately 20 times the RHD. On the basis of the termination half-life of the drug, the manufacturer suggests that fingolimod be discontinued at least 2 months before attempting conception.
FETAL RISK SUMMARY
Fingolimod is an orally administered drug that modulates sphingosine 1-phosphate receptors. Its active metabolite, fingolimod-phosphate, binds with high affinity to sphingosine 1-phosphate receptors and blocks capacity of lymphocytes to egress from the lymph nodes. It is indicated for the treatment of patients with relapsing forms of multiple sclerosis to delay the frequency of clinical exacerbations and to delay the accumulation of physical disability. Both fingolimod and its active metabolite are highly (99.7%) plasma protein bound. The terminal elimination half-life for both is 6–9 days. The receptor affected by fingolimod affects angiogenesis and is known to be involved in vascular formation during embryogenesis (1,2).
Reproduction studies have been conducted in rats and rabbits. In rats, at oral doses of 0.03–10 mg/kg/day, increased incidences of malformations and embryo–fetal deaths were observed at all but the lowest dose. The lowest end of the dosing range in these studies is less than the RHD. The most common malformations reported in rats were persistent truncus arteriosus and ventricular septal defects. In addition, in rats administered fingolimod during pregnancy and lactation at 0.05–0.5 mg/kg/day, pup survival was decreased at all doses and learning deficits were seen at the highest dose. The lowest dose administered is similar to the RHD. In rabbits, increased incidences of embryo–fetal mortality and growth restriction were seen at doses of 1.5 and 5 mg/kg/day. The no-effect dose in rabbits was about 20 times the RHD (1).
The carcinogenic potential of fingolimod was evaluated in mice and rats. In mice at oral doses of 0.025–2.5 mg/kg/day for up to 2 years, the incidence of malignant lymphoma was increased at the mid and high doses. However, in rats at doses up to 50 times the RHD, no increase in tumors was seen. Both in vitro and in vivo assays for fingolimod were negative for mutagenicity.
No effects on male and female fertility in rats were noted at the highest dose tested, which is approximately 200 times the RHD (1).
It is not known if fingolimod or its active metabolite crosses the human placenta. The relatively low molecular weight (about 307) and the long terminal half-life suggest that the drug will cross, but the high plasma protein binding may limit the exposure of the embryo–fetus (1,3).
No reports describing the use of fingolimod during human lactation have been located. The molecular weight (about 307) and the long terminal half-life (6–9 days) suggest that the drug and its active metabolite will be excreted into breast milk, but the high plasma protein binding (99.7%) may limit the amount (1,3). The effect of this exposure on a nursing infant is unknown.
1.Product information. Gilenya. Novartis, 2011.
2.Schmid G, Guba M, Ischenko I, Papyan A, Joka M, Schrepfer S, Bruns CJ, Jauch KW, Heeschen C, Graeb C. The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1-phosphate receptor 1. J Cell Biochem 2007;101:259–70.
3.Chun J, Hartung H-P. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010;33:91–101.