Risk Summary

Rare pregnancy outcomes reported postmarketing and from clinical trials, with very limited use of ARCALYST in pregnant women, are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the mother and fetus associated with Cryopyrin Associated Periodic Syndromes (CAPS) (see Clinical Considerations). In an animal reproduction study, subcutaneous administration of rilonacept to pregnant monkeys during the period of organogenesis was complicated by losses of drug exposure as the study progressed, due to anti-drug antibody formation at all doses, but a dose-related increase in exposure was still evident. There were no treatment-related effects on fetal survival or development of malformations with doses up to 11 times the maximum recommended human dose (MRHD). Increased incidences of lumbar ribs, a skeletal variation, were observed in fetuses at doses approximately 2 times the MRHD and higher that slightly exceeded incidences in both control animals and the historical control database (see Data). There were findings of multiple fusion and absence of the ribs and thoracic vertebral bodies and arches in one fetus of the only pregnant monkey with exposure to rilonacept during the later period of gestation associated with a dose approximately 6 times the MRHD (see Data). The relationship of these findings in a single fetus to drug treatment was unclear, as these findings were not evident in fetuses from pregnant monkeys that had higher exposures to rilonacept during the period of organogenesis associated with a dose approximately 11 times the MRHD.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and of miscarriage is 15%–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that increased maternal levels of interleukin (IL)-1β, which induces inflammation that occurs in CAPS, may be associated with pre-term birth.

Data

Animal Data

In an embryo-fetal development study, pregnant cynomolgus monkeys received rilonacept at subcutaneous doses of 0, 5, 15 or 30 mg/kg given twice a week from gestation days 20 to 48. The study was complicated by losses of drug exposure as the study progressed, due to anti-drug antibody formation at all doses, but a dose-related increase in exposure was still evident. There were no treatment-related effects on fetal survival or development of malformations with doses up to 11 times the MRHD (on a mg/kg basis with maternal subcutaneous doses up to 30 mg/kg). Increased incidences of lumbar ribs, a skeletal variation, were observed in fetuses at doses approximately 2 times the MRHD and higher (on a mg/kg basis with maternal subcutaneous doses of 5 mg/kg and higher) that slightly exceeded incidences in both control animals and the historical control database. There were findings of multiple fusion and absence of the ribs and thoracic vertebral bodies and arches in one fetus of the only pregnant monkey with exposure to rilonacept during the later period of gestation associated with a dose 6 times the MRHD (on a mg/kg basis with a maternal subcutaneous dose of 15 mg/kg). The relationship of these findings in a single fetus to drug treatment was unclear, as these findings were not evident in fetuses from pregnant monkeys that had higher exposures to rilonacept during the period of organogenesis associated with a dose approximately 11 times the MRHD (on a mg/kg basis with a maternal subcutaneous dose of 30 mg/kg). All doses of rilonacept reduced maternal serum levels of estradiol up to 64% compared to controls. In pre- and postnatal development studies in the mouse model using a murine analog of rilonacept (subcutaneous doses of 0, 20, 100 or 200 mg/kg), there was a small increase in the number of stillbirths in dams treated with 200 mg/kg three times per week.