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CPK Levels: During required laboratory testing in clinical trials, sporadic, transient eleva-tions in creatine phosphokinase levels (CPK) were observed. A single, isolated elevation to greater than 10 times the upper limit of normal (values of 2150 to 8610) was noted in 7 patients. Five of these patients continued to receive ACTOS and the other two patients had completed receiving study medication at the time of the elevated value. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. Drug Interactions Text Continues Below
Oral Contraceptives: Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. The pharma-cokinetics of coadministration of ACTOS and oral contraceptives have not been evaluated in patients receiving ACTOS and an oral contraceptive. Therefore, additional caution regarding contraception should be exercised in patients receiving ACTOS and an oral contraceptive. In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). 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%). Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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