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Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60-mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in male mice given 41 or 210 mg/ kg (4.7 or 24 times the AUC in humans), and prostatic leiomyoblastoma in male mice given 210 mg/ kg. In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/ theca cell origin was observed in female rats given 279 mg/ kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation. Mutagenesis — Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice. Text Continues Below
Impairment of Fertility — When male and female rats were given daily doses 5 mg/ kg ( 0.8 times the human dose based on surface area, mg/ m 2 ) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/ kg (16 times the human dose based on surface area, mg/ m 2 ) for at least 2 weeks did not affect sperm production or quality, or reproductive performance. In female rats, at doses of 0.1 to 10 mg/ kg/ day (0.02 to 1.6 times the human dose based on surface area, mg/ m 2 ), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses 0.1 mg/ kg ( 0.02 times the human dose based on surface area, mg/ m 2 ), raloxifene delayed and disrupted embryo implantation resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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