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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. Text Continues Below
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. Rabbits treated subcutaneously at a dose of 0.8 mg/ kg/ day achieved an AUC of 100 µg° h/ L, which is about 3-fold higher than that resulting from the human dose. This dose did not result in any embryotoxicity or teratogenicity. There are no studies of tolterodine in pregnant women. Therefore, DETROL LA should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. Nursing Mothers Tolterodine immediate release is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20 mg/ kg/ day during the lactation period had slightly reduced bodyweight gain. The offspring regained the weight during the maturation phase. It is not known whether tolterodine is excreted in human milk; therefore, DETROL LA should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue DETROL LA in nursing mothers. Pediatric Use The safety and effectiveness of tolterodine in pediatric patients has not been established. Geriatric Use No overall differences in safety were observed between the older and younger patients treated with tolterodine (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).
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