No non-clinical studies have been conducted with dutasteride and tamsulosin hydrochloride capsules. The following information is based on studies performed with dutasteride or tamsulosin. 

Carcinogenesis 

Dutasteride: A 2 year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of a 0.5 mg daily dose) in female mice only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known. 

In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5- alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5-alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure. 

Tamsulosin: In a rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to 3 times the MRHD of 0.8 mg/day (based on AUC of animal doses up to 43 mg/kg/day in males and up to 52 mg/kg/day in females), with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4 mg/kg or greater. 

In a carcinogenicity assay, mice were administered up to 8 times the MRHD of tamsulosin (oral 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 2 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. 

The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin-induced hyperprolactinemia. It is not known if tamsulosin elevates prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. 

Mutagenesis

Dutasteride: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test. 

Tamsulosin: Tamsulosin 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 CHO cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. 

Impairment of Fertility 

Dutasteride: Treatment of sexually mature male rats with dutasteride at 0.1 times the MRHD (animal doses of 0.05 mg/kg/day or greater for up to 31 weeks) based on mean serum concentration resulted in dose- and time-dependent decreases in fertility at all doses; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes (cytoplasmic vacuolation of tubular epithelium in the epididymides and/or decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles) in the reproductive organs at all doses in the absence of paternal toxicity. The fertility effects were reversed by Recovery Week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The microscopic changes were no longer present at Recovery Week 14 at 0.1 times the MRHD and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to treated males (10 to 500 mg/kg/day for 29 to 30 weeks) which are 16 to 110 times the MRHD based on mean serum concentration. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats. 

In a fertility study in female rats with dosing 4 weeks prior to mating through early gestation, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size due to increased resorptions and in feminization of male fetuses (decreased anogenital distance) at 2 to 10 times the MRHD (animal doses of 2.5 mg/kg/day or greater) based on mean serum concentration, in the presence of maternal toxicity (decreased body weight gain). Fetal body weights were also reduced at approximately 0.02 times the MRHD (rat dose of 0.05 mg/kg/day or greater) based on mean serum concentration, with no no-effect level, in the absence of maternal toxicity. 

Tamsulosin: Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (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 daily dosing. Effects on fertility in males were completely reversed within 9 weeks after discontinuation of multiple daily dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin on sperm counts or sperm function have not been evaluated. 

Studies in female rats revealed significant reductions in fertility after single or multiple daily doses of 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple daily doses of 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.