n embryo/fetal development study with pregnantrats that received the combination of subcutaneous administration of fluticasone propionate andoral administration of salmeterol at doses of 0/1000, 30/0, 10/100, 30/1000, and 100/10,000mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findingswere generally consistent with the individual monoproducts and there was no exacerbation ofexpected fetal effects. Omphalocele, increased embryo/fetal deaths, decreased body weight, andskeletal variations were observed in rat fetuses, in the presence of maternal toxicity, when
combining fluticasone propionate at a dose approximately 2 times the MRHDID (on a mcg/m2basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol atapproximately 3500 times the MRHDID (on a mcg/m2basis at a maternal oral dose of 10,000 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed when combining
fluticasone propionate at a dose 0.6 times the MRHDID (on a mcg/m2 basis at a maternalsubcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at approximately 350 times theMRHDID (on a mcg/m2 basis at a maternal oral dose of 1000 mcg/kg/day).
In an embryo/fetal development study with pregnant mice that received the combination ofsubcutaneous administration of fluticasone propionate and oral administration of salmeterol atdoses of 0/1400, 40/0, 10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasonepropionate/salmeterol) during the period of organogenesis, findings were generally consistentwith the individual monoproducts and there was no exacerbation of expected fetal effects. Cleftpalate, fetal death, increased implantation loss, and delayed ossification were observed in mousefetuses when combining fluticasone propionate at a dose approximately 1.4 times the MRHDID(on a mcg/m2basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a doseapproximately 1470 times the MRHDID (on a mcg/m2basis at a maternal oral dose of 10,000mcg/kg/day). No developmental toxicity was observed at combination doses of fluticasonepropionate up to approximately 0.8 times the MRHDID (on a mcg/m2basis at a maternalsubcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 420 times theMRHDID (on a mcg/m2basis at a maternal oral dose of 1400 mcg/kg).
Fluticasone Propionate: In embryo/fetal development studies with pregnant rats and mice dosedby the subcutaneous route throughout the period of organogenesis, fluticasone propionate wasteratogenic in both species. Omphalocele, decreased body weight, and skeletal variations wereobserved in rat fetuses, in the presence of maternal toxicity, at a dose approximately 2 times theMRHDID (on a mcg/m2basis with a maternal subcutaneous dose of 100 mcg/kg/day). The ratNOAEL was observed at approximately 0.6 times the MRHDID (on a mcg/m2basis with amaternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations wereobserved in mouse fetuses at a dose approximately 0.5 times the MRHDID (on a mcg/m2basiswith a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a
dose approximately 0.16 times the MRHDID (on a mcg/m2basis with a maternal subcutaneousdose of 15 mcg/kg/day).
In an embryo/fetal development study with pregnant rats dosed by the inhalation routethroughout the period of organogenesis, fluticasone propionate produced decreased fetal bodyweights and skeleta |
