Flutamide, a potent nonsteroidal
antiandrogen, was administered orally to male beagle dogs for 2, 3, or 4 years at doses of 10, 20, or 40 mg/kg/day. At each study interval, the results of clinical pathology examinations, organ weight determinations, necropsy, and histopathologic examinations generally were similar and included
atrophy of the prostate gland, testicular interstitial cell
hyperplasia, and seminiferous tubular
atrophy and degeneration. After 3 years of
drug exposure, there were 3 dogs with testicular interstitial cell
adenomas and a few dogs with 1 or more enlarged mammary gland nipples. Based upon the pharmacologic activity of
flutamide, these findings were expected and considered the consequence of long-term blocking of
testosterone receptors and an exaggerated compensatory response to increased secretion of
luteinizing hormone. The findings of this study were consistent with other examples of dysregulated
hormone stimulation of target tissues noted during the nonclinical safety assessment of
flutamide. In consideration of the clinical indication of
flutamide for advanced prostatic
carcinoma and based upon reports of minimal
flutamide-related adverse clinical responses, the findings of this study pose no concern for human risk assessment.