Rydapt Use In Pregnancy & Lactation

Pregnancy: Risk summary: Rydapt can cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies in pregnant women. Reproductive studies in rats and rabbits demonstrated that midostaurin induced fetotoxicity. An increase in number of late resorptions, a reduction in fetal weight and reduced skeletal ossification were observed in rats and rabbits following prenatal exposure to midostaurin at concentrations over 50-fold below the exposure in humans at the recommended doses of 50 and 100 mg twice daily based on AUC. Pregnant women should be advised of the potential risk to the fetus.
Animal data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of midostaurin at 3, 10, and 30 mg/kg/day and at 2, 10 and 20 mg/kg/day, respectively, during the period of organogenesis. An increase in number of late resorptions was observed at all dose levels and a reduction in fetal weight and skeletal ossification was observed in rats at the high dose of 30 mg/kg/day; no maternal toxicity was observed. In rabbits, maternal toxicity was observed at all dose levels. Mortality in dams, reduced fetal weight and delayed ossification was observed at 10 and 20 mg/kg/day. The concentrations at which maternal and fetal toxicity occurred in both species are over 50-fold below the human therapeutic exposures at the recommended doses of 50 and 100 mg twice daily based on AUC comparisons across species. In a pre- and post-natal developmental study, rats were given oral doses of 5, 15, and 30 mg/kg/day during gestation through lactation up to weaning. Maternal toxicity including signs of dystocia and reduced litter size were observed at 30 mg/kg/day. Lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted in the rat pups (F1 generation) exposed to midostaurin at 30 mg/kg/day. Maternal systemic exposure at 30 mg/kg (based on AUC) was 17 to 20-fold below the human therapeutic exposures at the human doses of 50 and 100 mg twice daily.
Lactation: It is unknown whether midostaurin or its active metabolites are transferred in human milk. There are no data on the effects of Rydapt on the breastfed child or the effects of Rydapt on milk production. Studies show that orally administered midostaurin and its active metabolites pass into the milk of lactating rats. Because many drugs are transferred in human milk and because of the potential for serious adverse reactions in nursing infants from Rydapt, a nursing woman should be advised on the potential risks to the child and breast-feeding should be discontinued during treatment with Rydapt and for at least 4 months after stopping treatment.
Females and males of reproductive potential: Pregnancy testing: Sexually-active females of reproductive potential are advised to have a pregnancy test within seven days prior to starting treatment with Rydapt.
Contraception: Females of reproductive potential should be advised that animal studies show Rydapt to be harmful to the developing fetus. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using Rydapt and for at least 4 months after stopping treatment with Rydapt.
Sexually-active males taking Rydapt should use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment with Rydapt to avoid conception or embryo-fetal harm.
Infertility: Based on findings in animals, Rydapt may impair fertility in humans. It is not known whether these effects on fertility are reversible. Oral administration of midostaurin at 10, 30 and 60 mg/kg/day was associated with reproductive toxicity in male and female rats at 60 mg/kg/day. In males, testicular degeneration and atrophy, alterations in sperm motility, a decrease in sperm counts, and a decrease in reproductive organ weights were observed. In females, increased resorptions, decreased pregnancy rate, number of implants and live embryos were observed at 60 mg/kg/day. Inhibition of spermatogenesis was seen in dogs at doses ≥3 mg/kg/day. The concentrations in rats at 60 mg/kg/day and dogs at 3 mg/kg/day are 8- and 100-fold below the human therapeutic exposures at the recommended doses of 50 or 100 mg twice daily based on AUC.