ts and rabbits and teratogenicity in rats. Increased incidences of post-implantationloss and fetal abnormalities (external, urogenital and skeletal) in rat and of embryo-fetal deaths, abortions and fetalvariations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2times the exposure in humans at the highest recommended dose of 2 mg/day.
In the US general population, the estimated background risk of major birth defects and miscarriage in clinicallyrecognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects andmiscarriage for the indicated population is unknown.
Data
Animal Data
When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, postimplantation loss and fetal malformations (visceral and skeletal) were increased at the lowest dose tested, the only dosewith fetuses available for eva luation. A no-effect dose for adverse effects on embryo-fetal development in rats was notidentified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at therecommended human dose (RHD) of 2 mg/day.
When siponimod (0, 0.1, 1, or 5 mg/kg) was orally administered to pregnant rabbits during the period of organogenesis,embryolethality and increased incidences of fetal skeletal variations were observed at all but the lowest dose tested.
Plasma exposure (AUC) at the no-effect dose (0.1 mg/kg) for adverse effects on embryo-fetal development in rabbits is
less that than in humans at the RHD.
When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally administered to female rats throughout pregnancy and lactation,increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring at all but thelowest dose tested. An increase in malformations was observed at all doses. A no-effect dose for adverse effects on preandpostnatal development in rats was not identified. The lowest dose tested (0.05 mg/kg) is less than the RHD, on amg/m2 basis.
8.2 Lactation
Risk Summary
There are no data on the presence of siponimod in human milk, the effects of MAYZENT on the breastfed infant, or theeffects of the drug on milk production. A study in lactating rats has shown excretion of siponimod and/or its metabolitesin milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinicalneed for MAYZENT and any potential adverse effects on the breastfed infant from MAYZENT or from the underlyingmaternal condition.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Before initiation of MAYZENT treatment, women of childbearing potential should be counselled on the potential for aserious risk to the fetus and the need for effective contraception during treatment with MAYZENT [see Use in SpecificPopulations (8.1)]. Since it takes approximately 10 days to eliminate the compound from the body after stoppingtreatment, the potential risk to the fetus may persist and women should use effective contraception during this period [seeWarnings and Precautions (5.7)].
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of MAYZENT did not include sufficient numbers of subjects aged 65 and over to determine whether theyrespond differently from younger subjects. Other reported clinical exper |
