Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with tolterodine immediate release were conducted in mice and rats. At the maximum tolerated dose in mice (30 mg/ kg/ day), female rats (20 mg/ kg/ day), and male rats (30 mg/ kg/ day), AUC values obtained for toltero-dine were 355, 291, and 462 µg° h/ L, respectively. In comparison, the human AUC value for a 2-mg dose administered twice daily is estimated at 34 µg° h/ L. Thus, tolterodine exposure in the carcinogenicity studies was 9-to 14-fold higher than expected in humans. No increase in tumors was found in either mice or rats. No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including bacterial mutation assays (Ames test) in 4 strains of Salmonella typhimurium and in 2 strains of Escherichia coli, a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human lymphocytes. Tolterodine was also negative in vivo in the bone marrow micronu-cleus test in the mouse. In female mice treated for 2 weeks before mating and during gestation with 20 mg/ kg/ day (corresponding to AUC value of about 500 µg° h/ L), neither effects on reproductive performance or fertility were seen. Based on AUC values, the systemic exposure was about 15-fold higher in animals than in humans. In male mice, a dose of 30 mg/ kg/ day did not induce any adverse effects on fertility. Pregnancy Pregnancy Category C. At oral doses of 20 mg/ kg/ day (approximately 14 times the human exposure), no anomalies or malformations were observed in mice. When given at doses of 30 to 40 mg/ kg/ day, tolterodine has been shown to be embryolethal and reduce fetal weight, and increase the incidence of fetal abnor-malities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and vari-ous skeletal abnormalities, primarily reduced ossification) in mice. At these doses, the AUC values were about 20-to 25-fold higher than in humans. | ||||
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