8.1Pregnancy Risk Summary
There are insufficient data on the use of fluticasone propionate in pregnant women to inform a drug-associated risk. In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, were observed in rats, mice, and rabbits with subcutaneously administered maternal toxic doses of fluticasone propionate 5 times, equivalent to, and less than the maximum recommended human daily intranasal dose (MRHDID) on a mcg/m 2 basis, respectively.
( See Animal Data .) However, fluticasone propionate administered via nose-only inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose equivalent to the MRHDID on a mcg/m 2 basis. ( See Animal Data .) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data : Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery. Animal Data : In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species.
Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 5 times the MRHDID of 200 mcg/day (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed at approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).
Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.3 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the nose-only inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal nose-only inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.
The NOAEL was observed with a dose approximately 0.25 times the MRHDID (on a mcg/m 2 basis with a maternal nose-only inhalation dose of 5.5 mcg/ kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.06 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).
Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose 0.39 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.01 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/ day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.
In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).
