Diane-35 Mechanism of Action

Pharmacotherapeutic group: antiandrogens and estrogens. ATC code: G03HB.
Pharmacology: Pharmacodynamics: Hair follicles and sebaceous glands are androgen sensitive. Acne and seborrhea are due, in part, to a sebaceous gland dysfunction, caused by increased peripheral sensitivity or raised androgen plasma levels. Both active ingredients in Diane-35 have a positive therapeutic effect. Cyproterone acetate competitively displaces androgens in the effector organ, thus cancelling the androgenic effect. The plasma androgen concentration is then reduced by an antigonadotropic effect. Ethinyl estradiol intensifies this effect, which leads to an up-regulation of sex-hormone binding globulin (SHBG). Plasma free androgen levels are reduced. Acne efflorescences generally heal after 3 to 4 months when treated with Diane-35. Oiliness of the skin and hair disappears first. Androgen-dependent hair loss is also reduced. It has to be pointed out that the effect is slow when treating female hirsutism. It may take several months to show effects.
Cyproterone acetate is also a potent progestogen, which possesses a contraceptive effect when used in combination with ethinyl estradiol. It rests on the interaction of central and peripheral mechanisms, of which ovulation inhibition and changes to cervical secretion have to be considered the most important. Moreover, the morphological and enzymatic changes in the endometrium provide extremely unfavorable conditions for nidation.
Contraceptive protection begins with the first day of use.
Pharmacokinetics: Cyproterone acetate (CPA): Absorption: Following oral administration CPA is completely absorbed in a wide dose range. The ingestion of Diane-35 effects a maximum serum level of 15 ng of CPA/mL at 1.6 hours. The absolute bioavailability of CPA is 88 % of dose. The relative bioavailability of CPA from Diane-35 was 109%, when compared to an aqueous microcrystal suspension.
Distribution: CPA is present in serum almost exclusively in protein-bound form. About 3.5 - 4.0% of total CPA levels are present unbound and the remainder is bound to albumin. Since CPA binding to sex hormone binding globulin (SHBG) is non-specific, changes in SHBG levels caused by ethinyl estradiol do not affect the pharmacokinetics of CPA.
Metabolism: CPA is metabolized by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15β-hydroxy derivative.
Elimination: Drug serum levels decrease in two disposition phases characterised by half-lives of 0.8 hours and 2.3 days. The total clearance of CPA from serum is 3.6 mL/min^-1/kg^-1.
Some CPA dose parts are excreted unchanged with the bile fluid. Most of the dose is excreted in form of metabolites at a urinary to biliary ratio of 3:7 with a half-life of 1.9 days. Metabolites from plasma are eliminated at a similar rate (half-life of 1.7 days).
Steady-state conditions: That CPA accumulates during one treatment cycle is to be expected by virtue of the long half-life of the terminal disposition phase of CPA from serum and the daily intake. Mean maximum drug serum levels increase from 15 ng/mL (day 1) to 21 ng/mL and 24 ng/mL at the end of the treatment cycles 1 and 3 respectively. Steady-state conditions are reached after approximately 10 days. During long-term treatment, CPA accumulates over treatment cycles by about a factor of 2 to 2.5.
Smoking does not affect the pharmacokinetics of CPA.
Ethinyl estradiol (EE₂): Absorption: Orally administered EE₂ is absorbed rapidly and completely. After a single ingestion of Diane-35, maximum EE₂ serum levels of about 80 pg/mL are reached at 1.7 hours.
The relative bioavailability of EE₂ from Diane-35, with reference to an aqueous microcrystal suspension, was almost complete.
Distribution: An apparent distribution volume of approximately 5 L/kg was determined for EE₂.
EE₂ is highly but non-specifically bound to serum albumin. 2 % of the EE₂ levels are present unbound.
The bioavailability of EE₂ can be changed in both directions by other active substances. There is, however, no interaction with high doses of vitamin C. EE₂ induces the hepatic synthesis of SHBG and corticosteroid-binding globulin (CBG) during continuous use. The extent of SHBG induction is dependent, however, on the chemical structure and dose of the co-administered progestogen. During treatment with Diane-35, an increase was observed in the SHBG serum levels from approximately 100 nmol/L to 300 nmol/L and in the CBG serum levels from about 50 ug/mL to 95 pg/mL.
Metabolism: EE₂ is metabolized during absorption and the first liver passage resulting in a reduced absolute and variable oral bioavailability.
For EE₂, the metabolic clearance rate from plasma was determined to be about 5 mL/min/kg.
Elimination: The EE₂ plasma levels decrease in two phases characterised by half-lives of 1 - 2 hours and about 20 hours. For analytical reasons, these parameters can only be calculated for higher dosages.
Unchanged EE₂ is not eliminated. The metabolites of EE₂ are eliminated at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.
Steady-state conditions: According to the half-life of the terminal disposition phase of EE₂ from serum and the daily ingestion, steady state levels are reached after 3 - 4 days and are higher by 30 - 40 % as compared to a single dose.
Toxicology: Preclinical safety data: Ethinyl estradiol: The toxicity profile of ethinyl estradiol is well known. There are no preclinical safety data, which reveal relevant risks for humans and are not already included in other sections of the summary of product characteristics.
Cyproterone acetate: Systemic toxicity: Preclinical data reveal no specific risk for humans using Diane-35 based on conventional studies of repeated dose toxicity.
Reproductive toxicity, teratogenicity: The administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs causes signs of feminization in male fetuses after high doses. Observation of male neonates who had been exposed in utero to cyproterone acetate did not show any signs of feminization. Nevertheless, pregnancy is a contraindication for the use of Diane-35. Investigations into embryo-fetal development toxicity using the combination of both active ingredients showed no potential indicative of a teratogenic effect following treatment during organogenesis (end of treatment preceded the completed differentiation of the external genitalia) that exceeded the known effects on the differentiation of the male genital tract.
Genotoxicity, carcinogenicity: Recognized first-line tests of genotoxicity gave no indication of a mutagenic effect when conducted with cyproterone acetate. In further investigations, cyproterone acetate, however, was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats, monkeys and humans.
This DNA-adduct formation occurred at systemic 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 pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats.
The clinical significance of these findings is currently uncertain. Clinical experience to date would not support an increased incidence of hepatic tumors in man.
Investigations into the tumorigenicity of cyproterone acetate in rodents did not reveal any results that fundamentally differed from those obtained with other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissue and tumors.
On the whole, the available findings do not raise any objection to the use of Diane-35 in humans if used in accordance with the directions for the given indication and at the recommended doses.