Gale Mechanism of Action

ATC code: G03HA01.
Pharmacology: Pharmacodynamics: Prostatic carcinoma and its metastases are generally dependent on androgens. Cyproterone acetate is a progestational steroid with strong anti-androgen activities, and in addition cyproterone acetate exerts a negative feedback on the hypothalamic receptors; therefore suppressing gonadotrophin release, and hence secretion of testosterone (and other androgens) is reduced.
Meningioma: Based on results from a French epidemiological cohort study, a cumulative dose dependent association between cyproterone acetate and meningioma has been observed. This study was based on data from the French Health insurance (CNAM) and included a population of 253,777 women using 50-100 mg cyproterone tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose ≥3 g) and women who were slightly exposed to cyproterone acetate (cumulative dose <3 g). A cumulative dose-response relationship was demonstrated. (See table.)

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A cumulative dose of 12 g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.
Pharmacokinetics: Following oral administration of tablets, cyproterone acetate is quickly and completely absorbed over a wide dosage range. The absolute bioavailability of cyproterone acetate is almost complete. The maximal plasma levels after a single dose are achieved after about 3 hours. After oral administration of 100 mg daily the steady state plasma concentration is 260±50 ng/ml. The mean plasma half life is about 2 days.
Cyproterone acetate is metabolised by hydrolysis to free cyproterone, and then to 15 β-hydroxycyproterone. Excretion occurs via the bile (70%) and urine (30%). Only small amounts of unchanged drug are found in the bile, most is excreted in the form of metabolites.
Cyproterone acetate is almost exclusively bound to plasma albumin. About 3.5-4% of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.
Toxicology: Preclinical safety data: Systemic toxicity: Preclinical data revealed no specific risk for humans based on conventional studies of repeated dose toxicity beyond those discussed in other sections of the SPC.
Experimental investigations produced corticoid-like effects on the adrenal glands in rats and dogs following higher dosages, which could indicate similar effects in humans at the highest given dose (300 mg/day).
Genotoxicity and carcinogenicity: Recognised first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes, the DNA-adduct level in the dog liver cells was extremely low.
This DNA-adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. One in vivo consequence of cyproterone acetate treatment was the increased incidence of focal, possibly preneoplastic, liver lesions in which cellular enzymes were altered in female rats and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutation. The clinical relevance of these findings is presently uncertain. Clinical experience to date would not support an increased incidence of hepatic tumours in man.
In long-term carcinogenicity studies in rats cyproterone acetate increased the incidence of liver tumours including carcinomas at high doses which concomitantly caused liver toxicity and exceeded the maximum human dose. Further investigations into rodents at lower, non-hepatotoxic doses revealed benign liver proliferations similar to effects described for other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumours.