tamsulosin hydrochloride capsules 0.8mg/day (steady-state) and furosemide 20mg intravenously (single dose) was eva luated in 10healthy volunteers (age range: 21to 40years). Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin Cmax and AUC, these changes are expected to be clinically insignificant and do not require dose adjustment for tamsulosin.
Calcium Channel Antagonists:Dutasteride: In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, n=6) and diltiazem (-44%, n=5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was coadministered with dutasteride (+7%, n=4). The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dosage adjustment is recommended.
Cholestyramine:Dutasteride: Administration of a single 5-mg dose of dutasteride followed 1hour later by 12g cholestyramine did not affect the relative bioavailability of dutasteride in 12normal volunteers.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No non-clinical studies have been conducted with JALYN. 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 500mg/kg/day for males and 3, 35, and 250mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250mg/kg/day (290-fold the MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3major 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 53mg/kg/day in males and 0.8, 6.3, and 15mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5mg/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 1to 3times the expected clinical exposure.
Tamsulosin: In a rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to 3times the MRHD of 0.8mg/day (based on AUC of animal doses up to 43mg/kg/day in males and up to 52mg/kg/day in females), with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4mg/kg or greater.
In a carcinogenicity assay, mice were administered up to 8times the MRHD of tamsulosin (oral doses up to 127mg/kg/day in males and 158mg/kg/day in females). There were no significant tumor findings in male mice. Female m |
