|
Pressor agents — Because of possible effects on blood pressure, STRATTERA should be used cautiously with pressor agents. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis — Atomoxetine HCl was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/ kg/ day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/ m 2 basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/ m 2 basis. Mutagenesis — Atomoxetine HCl was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration). The metabolite N-desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test. Impairment of fertility — Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to 57 mg/ kg/ day, which is approximately 6 times the maximum human dose on a mg/ m 2 basis. Pregnancy Pregnancy Category C — Pregnant rabbits were treated with up to 100 mg/ kg/ day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/ kg/ day. The 100-mg/ kg dose is approximately 23 times the maximum human dose on a mg/ m 2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose. Text Continues Below
Rats were treated with up to approximately 50 mg/ kg/ day of atomoxetine (approximately 6 times the maximum human dose on a mg/ m 2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/ kg (but not at 13 mg/ kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/ kg/ day (approximately 5 times the maximum human dose on a mg/ m 2 basis) but not at 20 mg/ kg/ day. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/ kg/ day (approximately 17 times the maximum human dose on a mg/ m 2 basis) by gavage throughout the period of organogenesis. No adequate and well-controlled studies have been conducted in pregnant women. STRATTERA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Labor and Delivery Parturition in rats was not affected by atomoxetine. The effect of STRATTERA on labor and delivery in humans is unknown. Nursing Mothers Atomoxetine and/ or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if STRATTERA is administered to a nursing woman.
Pediatric Use
The safety and efficacy of STRATTERA in pediatric patients less than 6 years of age have not been established. The efficacy of STRATTERA beyond 9 weeks and safety of STRATTERA beyond 1 year of treatment have not been systematically evaluated. A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/ kg/ day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/ m 2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood.
Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/ kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/ kg), and a slight decrease in corpora lutea (50 mg/ kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/ kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/ kg and females at 50 mg/ kg) and on Day 30 (females at 50 mg/ kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown. Geriatric Use The safety and efficacy of STRATTERA in geriatric patients have not been established. Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
