Risk Summary

There are no randomized clinical studies of roflumilast in pregnant women. In animal reproductive toxicity studies, roflumilast administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest roflumilast dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Roflumilast induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice at doses corresponding to 49 times the MRHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Clinical Considerations 

Labor and delivery 

Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that roflumilast disrupted the labor and delivery process in mice.

Data 

Animal data 

In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day roflumilast (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m2 basis at a maternal oral dose of 0.2 mg/kg/day).

In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). Roflumilast did not cause fetal structural abnormalities at exposures up to approximately 29 times the MRHD (on an AUC basis at maternal oral doses up to 1.8 mg/kg/day).

In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day roflumilast during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m2 basis at maternal oral doses of 0.8 mg/kg/day).

In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, respectively). Roflumilast induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m2 basis at maternal doses > 2 mg/kg/day). Roflumilast decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m2 basis at a maternal dose of 12 mg/kg/day).