l variations, in the presence of maternal toxicity, at a dose approximately 0.5times the MRHDID (on a mcg/m2basis with a maternal inhalation dose of 25.7 mcg/kg/day);however, there was no evidence of teratogenicity. The NOAEL was observed with a doseapproximately 0.1 times the MRHDID (on a mcg/m2
basis with a maternal inhalation dose of 5.5mcg/kg/day).
In an embryo/fetal development study in pregnant rabbits that were dosed by the subcutaneousroute throughout organogenesis, fluticasone propionate produced reductions of fetal bodyweights, in the presence of maternal toxicity at doses approximately 0.02 times the MRHDIDand higher (on a mcg/m2basis 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 doseapproximately 0.2 times the MRHDID (on a mcg/m2basis with a maternal subcutaneous dose of4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.004times the MRHDID (on a mcg/m2basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).
In a pre- and post-natal development study in pregnant rats dosed by the subcutaneous routefrom 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 effectson developmental landmarks, learning, memory, reflexes, or fertility at doses up to approximateequivalence to the MRHDID (on a mcg/m2basis with maternal subcutaneous doses up to 50mcg/kg/day).
Fluticasone propionate crossed the placenta following subcutaneous administration to mice andrats and oral administration to rabbits.
Salmeterol: In three embryo/fetal development studies, pregnant rabbits received oraladministration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the periodof organogenesis. In pregnant Dutch rabbits administered salmeterol doses approximately700 times the MRHDID (on a mcg/m2basis at maternal oral doses of 1000 mcg/kg/day andhigher), fetal toxic effects were observed characteristically resulting from beta-adrenoceptorstimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb andpaw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at asalmeterol dose approximately 420 times the MRHDID (on a mcg/m2basis at a maternal oraldose of 600 mcg/kg/day). New Zealand White rabbits were less sensitive since only delayed
ossification of the frontal cranial bones was seen at a salmeterol dose approximately 7,000 timesthe MRHDID (on a mcg/m2basis at a maternal oral dose of 10,000 mcg/kg/day).
In two embryo/fetal development studies, pregnant rats received salmeterol by oraladministration at doses ranging from 100 to 10,000 mcg/kg/day during the period of
organogenesis. Salmeterol produced no maternal toxicity or embryo/fetal effects at doses up to3500 times the MRHDID (on a mcg/m2basis at maternal oral doses up to 10,000 mcg/kg/day).
In a peri-and post-natal development study in pregnant rats dosed by the oral route from lategestation through delivery and lactation, salmeterol at a dose 3500 times the MRHDID (onmcg/m2basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased thefertility of survivors.
Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.
8.2 Lactation
Risk Summary
There are no available data on the p |
