Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
Pharmacotherapeutic group: sex hormones and modulators of the genital system, antiandrogens, plain
ATC code: G03HA01
Prostatic carcinoma and its metastases are in general androgen-dependent. Cyproterone acetate exerts a direct anti-androgen action on the tumour and its metastases. It also has progestogenic activity, which exerts a negative feedback effect on the hypothalamic receptors, so leading to a reduction in gonadotrophin release, and hence to diminished production of testicular androgens. Sexual drive and potency are reduced and gonadal function is inhibited.
The antigonadotropic effect of cyproterone acetate is also exerted when administered with LHRH analogues. The initial increase of testosterone caused by this class of substances is reduced by cyproterone acetate.
An occasional tendency for the prolactin levels to increase slightly has been observed under higher doses of cyproterone acetate.
Based on results from a French epidemiological cohort study, a cumulative dose-dependent association between cyproterone acetate (CPA) 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 CPA tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose CPA (cumulative dose ≥3 g) and women who were slightly exposed to CPA (cumulative dose <3 g). A cumulative dose-response relationship was demonstrated.
Incidence and risk of meningioma with different cumulative doses of CPA:
| Cumulative dose of cyproterone acetate | Incidence rate (in patient-years) | HRadj (95% CI)a |
|---|---|---|
| Slightly exposed (<3 g) | 4.5/100,000 | Ref. |
| Exposed to ≥3 g | 23.8/100,000 | 6.6 [4.0-11.1] |
| 12 to 36 g | 26/100,000 | 6.4 [3.6-11.5] |
| 36 to 60g | 54.4/100,000 | 11.3 [5.8-22.2] |
| more than 60 g | 129.1/100,000 | 21.7 [10.8-43.5] |
a Adjusted based on age as a time-dependent variable and oestrogen at inclusion
A cumulative dose of 12 g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.
Following oral administration, cyproterone acetate is completely absorbed over a wide dose range. The ingestion of two cyproterone acetate 50 mg tablets gives maximum serum levels of about 285 ng/ml at about 3 hours. Thereafter, drug serum levels declined during a time interval of typically 24 to 120 h, with a terminal half-life of 43.9 ± 12.8 h.. The total clearance of cyproterone acetate from serum is 3.5 ± 1.5 ml/min/kg. Cyproterone acetate is metabolised by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15β-hydroxy derivative.
Some drug is excreted unchanged with bile fluid. Most of the dose is excreted in the form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion proceeds with a half-life of 1.9 days. Metabolites from plasma are eliminated at a similar rate (half-life of 1.7 days).
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.
The absolute bioavailability of cyproterone acetate is almost complete (88% of dose).
Preclinical data reveal 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).
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. In vivo consequences of cyproterone acetate treatment were 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.
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.
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