Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, ISANDO, 1609
Pharmacotherapeutic group: antiandrogens and estrogens
ATC code: G03HB
The substance cyproterone acetate contained In DIANE-35 blocks the effect of endogenously produced and exogenously administered androgens at the target organs by means of competitive inhibition. The stimulating effect of male sex hormones on androgen-dependent structures and functions is weakened or abolished by cyproterone acetate.
Excessive sebaceous gland function is decreased.
Apart from the described anti-androgen effect, cyproterone acetate also has a progestational action. The ethinylestradiol in the combination inhibits ovulation and changes the cervical mucus and the endometrium rendering them unfavourable for sperm penetration and nidation of a fertilised ovum, respectively.
Orally administered cyproterone acetate is rapidly and completely absorbed. Peak serum concentrations of 15 ng/ml are reached at about 1,6 hours after single ingestion. Bioavailability is about 88%.
Cyproterone acetate is almost exclusively bound to serum albumin. Only 3,5-4,0% of the total serum concentrations are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of cyproterone acetate. The apparent volume of distribution of cyproterone acetate is about 986 ± 437 l.
Cyproterone acetate is almost completely metabolised. The main metabolite in plasma was identified as 15β-OH-CPA which is formed via the cytochrome P450 enzyme CYP3A4. The clearance rate from serum is about 3,6 ml/min/kg.
Cyproterone acetate serum levels decrease in two phases which are characterised by half-lives of about 0,8 h and about 2,3-3,3 days.Cyproterone acetate is partly excreted in unchanged form.Its metabolites are excreted at a urinary to biliary ratio of about 1:2. The half-life of metabolite excretion is about 1,8 days.
Cyproterone acetate pharmacokinetics are not influenced by SHBG levels. Following daily ingestion serum levels increase about 2,5-fold reaching steady-state conditions during the second half of a treatment cycle.
Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 71 pg/ml are reached at 1,6 hours. During absorption and first-liver passage, ethinylestradiol is metabolised extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%.
Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2,8-8,6 l/kg was determined.
Ethinylestradiol is subject to pre-systemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to be about 2,3-7 ml/min/kg.
Ethinylestradiol serum levels decrease in two disposition phases characterised by half-lives of about 1 hour and 10-20 hours, respectively. Unchanged ethinylestradiol is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.
Steady-state conditions are reached during the second half of a treatment cycle when serum levels are higher by 60% as compared to single dose.
Administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs (after approximately day 45 of gravidity) could lead to signs of feminisation in male foetuses following higher doses. Observation of male newborn children who had been exposed in utero to cyproterone acetate did not show any signs of feminisation. However, pregnancy is a contra-indication for the use of DIANE-35.
Recognised first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, there is some evidence of genotoxicity as 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. 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 pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats.
The clinical relevance of these findings and how these findings relate to the risk of developing benign and malignant liver tumours in humans is presently unknown. Clinical experience to date would not support an increased incidence of hepatic tumours in humans. Nor did investigations into the tumorigenicity of cyproterone acetate in rodents reveal any indication of a specific tumorigenic potential. However, it must be borne in mind that sexual steroids such as the substances contained in DIANE-35 can promote the growth of certain hormone-dependent tissues and tumours.
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