Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/ kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/ m 2 ). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/ or malignant transitional cell neoplasms were observed in male rats at 4 mg/ kg/ day and above (approximately equal to the maximum recommended human oral dose based on mg/ m 2 ). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/ kg/ day (approximately 11 times the maximum recommended human oral dose based on mg/ m 2 ). No drug-induced tumors were observed in any organ. During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors were identified. Occasionally, abnormal urinary cytology results indicating possi-ble malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies, includ-ing the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/ HPRT and AS52/ XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA syn-thesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/ kg pioglitazone HCl daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/ m 2 ). Animal Toxicology Heart enlargement has been observed in mice (100 mg/ kg), rats (4 mg/ kg and above) and dogs (3 mg/ kg) treated orally with pioglitazone HCl (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/ m 2 ). In a one-year rat study, drug-related early death due to apparent heart dysfunc-tion occurred at an oral dose of 160 mg/ kg/ day (approximately 35 times the maximum rec-ommended human oral dose based on mg/ m 2 ). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/ kg and above (approximately 4 times the max-imum recommended human oral dose based on mg/ m 2 ), but not in a 52-week study at oral doses up to 32 mg/ kg (approximately 13 times the maximum recommended human oral dose based on mg/ m 2 ). | ||||
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