Neutropenia/Infections: Neutropenia has occurred in patients receiving RYDAPT as monotherapy and in combination with chemotherapy (see Adverse Reactions). Severe neutropenia (ANC less than 0.5 x 109/L) was generally reversible by withholding RYDAPT until recovery or discontinuation in the Advanced SM studies. White blood cells (WBCs) should be monitored regularly, especially at treatment initiation.
In patients who develop unexplained severe neutropenia, treatment with RYDAPT should be interrupted until ANC is greater than or equal to 1.0 x 109/L in patients with AML or 1.5 x 109/L in patients with Advanced SM, as recommended in Tables 4 and 5. RYDAPT should be discontinued in patients who develop recurrent or prolonged severe neutropenia that is suspected to be related to RYDAPT (see Dosage & Administration).
Any active serious infections should be under control prior to starting treatment with RYDAPT monotherapy. Patients should be monitored for signs and symptoms of infection and if a diagnosis of infection is made, appropriate treatment should be instituted promptly, including as needed, the discontinuation of RYDAPT.
Cardiac dysfunction: In the Advanced SM studies with RYDAPT, cardiac dysfunction such as congestive heart failure (CHF), some of which were fatal, and transient decreases in left ventricular ejection fraction (LVEF) occurred. Fatal cardiac failure was reported in patients in the Advanced SM studies while no difference in CHF or LVEF dysfunction was observed between the RYDAPT + chemotherapy and placebo + chemotherapy arms in the randomized AML study. In patients at risk, RYDAPT should be used with caution and patients should be closely monitored (at baseline and during treatment).
Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis, some of which have been fatal, have occurred in patients treated with RYDAPT monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis and RYDAPT should be discontinued in patients who experience pulmonary symptoms indicative of ILD/pneumonitis which are ≥Grade 3 (NCI CTCAE).
Embryo-fetal toxicity and lactation: Based on findings from animal studies, RYDAPT can cause fetal harm when administered to pregnant women. Administration of midostaurin to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity. Pregnant women should be advised of the potential risk to a fetus; Females of reproductive potential should be advised to use effective contraception during treatment with Rydapt and for at least 4 months after stopping treatment.
Because of the potential for serious adverse effects in nursing infants from Rydapt, nursing women should be advised to discontinue breastfeeding during treatment with Rydapt and for at least 4 months after stopping treatment (see Use in Pregnancy & Lactation).
Females and males of reproductive potential: Pregnancy testing: Sexually-active females of reproductive potential are advised to have a pregnancy test 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: RYDAPT may impair fertility in humans. 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.