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Mice were administered doses up to 127 mg/ kg/ day in males and 158 mg/ kg/ day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/ kg/ day had statistically significant increases in the incidence of mammary gland fibroadenomas (P< 0.0001) and adenocarcinomas (P< 0.0075). The highest dose levels of tamsulosin HCI evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/ day. The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin HCI-induced hyperprolactinemia. It is not known if FLOMAX capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. Tamsulosin HCI produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. Text Continues Below
Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/ kg/ day of tamsulosin HCI (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/ kg/ day tamsulosin HCI (1/ 5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin HCI on sperm counts or sperm function have not been evaluated. Studies in females rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/ kg/ day of the R-isomer or racemic mixture of tamsulosin HCI, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/ kg/ day of the racemic mixture did not significantly alter fertility in female rats. Page: << Prev | 1 | 2 | 3
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