Budesonide / Formoterol

[From component Formoterol] 8.1 Pregnancy Risk Summary There are limited available data with formoterol fumarate inhalation solution use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Beta-agonists may interfere with uterine contractility (see Clinical Considerations) . In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 730 to 29,000 times the MRHD on a mg/m 2 or AUC basis. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 300 times the MRHD (see Data) . The estimated background 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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Labor or delivery There are no adequate and well-controlled human studies that have studied the effects of formoterol fumarate inhalation solution during labor and delivery. Because of the potential for beta-agonists interference with uterine contractility, use of formoterol fumarate inhalation solution during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Data Animal Data In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species. However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 50 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 1,500 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6,000 mcg/kg and above). In a pre- and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 1,500 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6,000 mcg/kg and above). However, no effects were observed in this study at an exposure approximately 50 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 200 mcg/kg). In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species. Umbilical hernia, a malformation, was observed in rat fetuses at exposures approximately 730 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 3,000 mcg/kg/day and above). Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 3,600 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 15,000 mcg/kg/day). In another study with rats, no teratogenic effects were observed with exposures up to approximately 300 times the MRHD (on a mcg/m 2 basis with a maternal inhalation dose of 1,200 mcg/kg/day). Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 29,000 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed with exposures up to approximately 1,700 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 3,500 mcg/kg).

[Formoterol] 8.1 Pregnancy Risk Summary There are limited available data with formoterol fumarate inhalation solution use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Beta-agonists may interfere with uterine contractility (see Clinical Considerations) . In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 730 to 29,000 times the MRHD on a mg/m 2 or AUC basis. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 300 times the MRHD (see Data) . The estimated background 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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Labor or delivery There are no adequate and well-controlled human studies that have studied the effects of formoterol fumarate inhalation solution during labor and delivery. Because of the potential for beta-agonists interference with uterine contractility, use of formoterol fumarate inhalation solution during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Data Animal Data In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species. However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 50 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 1,500 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6,000 mcg/kg and above). In a pre- and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 1,500 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6,000 mcg/kg and above). However, no effects were observed in this study at an exposure approximately 50 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 200 mcg/kg). In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species. Umbilical hernia, a malformation, was observed in rat fetuses at exposures approximately 730 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 3,000 mcg/kg/day and above). Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 3,600 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 15,000 mcg/kg/day). In another study with rats, no teratogenic effects were observed with exposures up to approximately 300 times the MRHD (on a mcg/m 2 basis with a maternal inhalation dose of 1,200 mcg/kg/day). Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 29,000 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed with exposures up to approximately 1,700 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 3,500 mcg/kg). 8.2 Lactation Risk Summary There are no well-controlled human studies of the use of formoterol fumarate inhalation solution in nursing mothers. It is not known whether formoterol fumarate is excreted in human milk, or whether there are effects on the breastfed infant or on the milk production. In reproductive studies in rats formoterol was excreted in the milk (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother`s clinical need for formoterol fumarate inhalation solution and any potential adverse effects on the breastfed child from formoterol fumarate inhalation solution or from the underlying maternal condition. Data In a pharmacokinetic study in rats formoterol was excreted in the milk. The amount of radioactive labelled 3 H-formoterol fumarate was less than 2% of that in the maternal plasma. 8.4 Pediatric Use Formoterol fumarate inhalation solution is not indicated for use in children. The safety and effectiveness of formoterol fumarate inhalation solution in pediatric patients have not been established. The pharmacokinetics of formoterol fumarate has not been studied in pediatric patients. 8.5 Geriatric Use Of the 586 subjects who received formoterol fumarate inhalation solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received formoterol fumarate inhalation solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetics of formoterol fumarate inhalation solution has not been studied in elderly subjects.