APREMILAST (apremilast kit apremilast 20 mg tablet, film coated) Dailymed

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to apremilast during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. Risk Summary Available pharmacovigilance data with apremilast use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, but these data are extremely limited. Based on findings from animal reproduction studies, apremilast may increase the risk for fetal loss. In animal embryo-fetal development studies, the administration of apremilast to pregnant cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When administered to pregnant mice, during organogenesis there were no apremilast-induced malformations up to exposures 4.0-times the MRHD (see Data). Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1,000 mg/kg/day during the period of organogenesis (gestation Days 20 through 50). There was a dose-related increase in spontaneous abortions, with most abortions occurring during Weeks 3 to 4 of dosing in the first trimester, at doses approximately 2.1-times the MRHD and greater (on an area under the curve [AUC] basis at doses ≥ 50 mg/kg/day). No abortifacient effects were observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose of 20 mg/kg/day). Although, there was no evidence for a teratogenic effect at doses of 20 mg/kg/day and greater when examined at day 100, aborted fetuses were not examined. In an embryo-fetal development study in mice, apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams during organogenesis (gestation Day 6 through 15). In a combined fertility and embryo-fetal development study in mice, apremilast was administered at doses of 10, 20, 40, or 80 mg/kg/day starting 15 days before cohabitation and continuing through gestation Day 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in postimplantation loss at doses corresponding to a systemic exposure of 2.3-times the MRHD and greater (≥ 20 mg/kg/day). At doses of ≥ 20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day). Apremilast distributed across the placenta into the fetal compartment in mice and monkeys. In a pre- and postnatal study in mice, apremilast was administered to pregnant female mice at doses of 10, 80, or 300 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥ 4.0-times the MRHD (on an AUC basis at doses ≥ 80 mg/kg/day). No adverse effects occurred at a dose 1.3-times the MRHD (10 mg/kg/day). There was no evidence for functional impairment of physical development, behavior, learning ability, immune competence, or fertility in the offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300 mg/kg/day).

Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1,000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively). Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral blood lymphocytes, and the in vivo mouse micronucleus assay. In a fertility study of male mice, apremilast at oral doses up to approximately 3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥ 1.8-times the MRHD (≥ 20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had increased incidences of early postimplantation losses. There was no effect of apremilast approximately 1.0-times the MRHD (10 mg/kg/day).