DRUG INTERACTIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC exposure approximately 450 times human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the maximum recommended daily inhalation dose). This finding was not observed in the drinking water study, nor was it seen in mice (see below).
In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 590 times human exposure at the maximum recommended daily inhalation dose) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC exposure approximately 60 times human exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human exposure at the maximum recommended daily inhalation dose). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.
Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats.
Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1000 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis).
Pregnancy, Teratogenic Effects, Pregnancy Category C
Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis) and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg (approximately 70 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis). When given to rats throughout organogenesis, oral doses of 0.2 mg/kg and above delayed ossification of the fetus, and doses of 6 mg/kg and above decreased fetal weight. Formoterol fumarate did not cause malformations in rats or rabbits following oral administration. Because there are no adequate and well-controlled studies in pregnant women, FORADIL AEROLIZER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in Labor and Delivery
Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis) and above in rats receiving the drug for several days at the end of pregnancy. These effects were not produced at a dose of 0.2 mg/kg (approximately 70 times the maximum recommended daily inhalation dose in humans on a mg/m2 basis). There are no adequate and well-controlled human studies that have investigated the effects of FORADIL AEROLIZER during labor and delivery.
Because beta-agonists may potentially interfere with uterine contractility, FORADIL AEROLIZER should be used during labor only if the potential benefit justifies the potential risk.
Nursing Mothers
In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if FORADIL AEROLIZER is administered to nursing women. There are no well-controlled human studies of the use of FORADIL AEROLIZER in nursing mothers.
Pediatric Use
Asthma
A total of 776 children 5 years of age and older with asthma were studied in three multiple-dose controlled clinical trials. Of the 512 children who received formoterol, 508 were 5-12 years of age, and approximately one third were 5-8 years of age.
Exercise-Induced Bronchospasm
A total of 25 pediatric patients, 4-11 years of age, were studied in two well-controlled single-dose clinical trials.
The safety and effectiveness of FORADIL AEROLIZER in pediatric patients below 5 years of age has not been established. (See CLINICAL TRIALS, Pediatric Asthma Trial, and ADVERSE REACTIONS, Experience in Pediatric, Adolescent and Adult Patients.)
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