Source: Υπουργείο Υγείας (CY) Revision Year: 2015 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Hormone antagonists and related agents, Anti-androgens
ATC Code: L02BB01
Flutamide is an anilide, nonsteroidal oral antiandrogen. In animal studies flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding in target tissues. When flutamide is given in combination with surgical or medical castration, suppression of both testicular and adrenal androgen activity is achieved.
Flutamide is well absorbed following oral ingestion. Studies with radiolabelled flutamide show rapid and extensive conversion to its metabolites which are detectable in plasma up to 8 hours post dosing. Approximately 45% of the administered dose is excreted in urine and 2% in faeces during the first two days. Metabolism removes the radiolabel resulting in apparent slowing of excretion due to retention of the label as tritiated water. Thus excretion and metabolism is essentially complete within two days.
Animal studies to determine tolerance after repeated administration have been performed in monkeys for up to 6 weeks, in rats for up to 52 weeks and in dogs for up to 78 weeks. The daily administered oral doses were up to 90mg/kg in monkeys, up to 40mg/kg in dogs and up to 180mg/kg in rats, corresponding to 1.5 to 18 fold of the dose used in humans. In addition to weight loss and anorexia which occurred in all animal species, vomiting was observed in dogs and monkeys. All other clinical findings showed no abnormalities. The autopsy finding revealed a reduced size of the prostate, testicles and seminal vesicles with suppressed spermatogenesis which corresponded to the antiandrogenic effect of flutamide. In addition, an increase in the organ weight of the liver in rats and dogs, and increased transaminase levels in dogs were observed without corresponding morphological changes. In rats only, the occurrence of drug-related (but not dose-dependent) adenomas of testicular interstitial cells was observed. This effect is related to the mechanism of action of flutamide and is species-specific. In a long-term study in rats, dose-related increases in mammary gland adenomas or carcinomas were observed.
In a range of screening tests flutamide did not show any mutagenic potential.
The influence of flutamide on fertility and the development of the progeny have been studied in rats; additional teratogenicity studies have been performed in rabbits. The effects were related to the antiandrogenic actions of flutamide. These effects are not relevant to the clinical use of flutamide in prostate cancer.
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