Dienille Mechanism of Action

Pharmacotherapeutic group: progestogens and estrogens, fixed combination. ATC code: G03AA.
Pharmacology: Pharmacodynamics: Dienille is a combined oral contraceptive with anti-androgenic effect; its estrogen component is ethinylestradiol and its gestogenic component is dienogest.
The contraceptive property of Dienille is based on several factors. The primary mechanism of action is inhibition of ovulation and alterations to the cervical mucus.
Based on a large-scale surveillance study the unadjusted Pearl- index is 0.14 whereas the adjusted value is 0.09.
The anti-androgenic effect of the combination of ethinylestradiol and dienogest is based among others on the reduction of serum androgen levels. In a multicenter study including 1040 female patients between 16 and 40 years, with mild to moderate acne papulopustulosa, dienogest 2 mg / ethinylestradiol 0.03 mg film- coated tablets was found to be no inferior to a reference triphasic COC containing ethinylestradiol and norgestimate concerning improvement of total lesions counts and of inflammatory lesions counts after 6 cycles of treatment.
Dienogest is a nortestosterone derivate. In vitro it binds to progesterone receptors with 10-30 times lower affinity compared to other synthetic gestogens. In vivo dienogest does not have any significant androgenic, mineralocorticoid or glucocorticoid effect.
Dienogest inhibits ovulation on its own in a daily dose of 1 mg.
Contraceptives with higher-dose of ethinylestradiol (e. g. 50 μg) offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer). It is not known whether lower-dose combined oral contraceptives have this advantage too.
Pharmacokinetics: Ethinylestradiol: Absorption: Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of Dienille maximum drug serum levels of about 67 pg/ml are reached at 1.5 - 4 hours. After absorption and the "first-pass-effect" ethinylestradiol is metabolized to a great extent, thus average oral bioavailability is about 44%.
Distribution: Ethinylestradiol is highly, but non-specifically bound to serum albumin (approximately 98%) and raises serum levels of steroid hormone binding globulin (SHBG). Ethinylestradiol has an apparent volume of distribution of about 2.8-8.6 l/kg.
Metabolism: Ethinylestradiol is conjugated both in the mucosa of the small intestine and in the liver. Ethinylestradiol is metabolized via aromatic hydroxylation, however a whole range of hydroxilated and methylated derivates is generated, which are present as free or glucuronide or sulfate metabolites. A metabolic clearance rate of about 2.3-7 ml/min/kg was determined.
Elimination: Ethinylestradiol serum levels decrease in two phases characterized by 1 hour and 10-20 hours half lives. Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.
Steady-state-status: Steady-state is reached at the second half of the treatment period when serum level is twice as much as the one after a single dose.
Dienogest: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Following ingestion of Dienille maximum drug serum levels of cca. 51 pg/ml are reached at 2.5 hours. In combination with ethinylestradiol its average bioavailability is about 96%.
Distribution: Dienogest binds to serum albumin, but it does not bind to SHBG or to corticosteroid-binding globulin (CBG). 10% of the drug levels are present unbound, while 90% is non-specifically bound to albumin. Dienogest has an apparent volume of distribution of about 37-45 l.
Metabolism: Dienogest is metabolized mainly via hydroxylation; however conjugation also plays an important role to create endocrinologically inactive metabolites. Those metabolites are eliminated from the plasma fast, thus besides the unchanged dienogest, no significant amount of its metabolites can be detected in the human plasma. After a single dose it has a total clearance (Cl/F) of 3.6 l/hour.
Elimination: Dienogest has a half-life of 8.5-10.8 hours. Only negligible amounts of dienogest are excreted via the kidneys in unchanged form. After 0.1 mg/kg dose, proportion of the renal and faecal excretion was 3:1. After oral application 86% of the dose is eliminated within 6 days; a big proportion of this is excreted in the first 24 hours, mainly with the urine.
Steady-state status: Pharmacokinetics of dienogest is not influenced by serum level of SHBG proteins. When applied daily, serum level of dienogest is increased to one and a half, and steady-state status is reached after 4 days.
Toxicology: Preclinical safety data: In animal studies effect of ethinylestradiol and dienogest is limited to pharmacological properties of the active ingredients.
Reproduction toxicology tests with dienogest have shown gestogenic effects: increase in abnormality of pre- and post-implantation, elongation of the gestational period, increase in the newborn mortality of pupils. If high dose dienogest is given to animals in the late phase of pregnancy and lactation, impaired fertility of the descendants could be observed.
Ethinylestradiol is the estrogen component in most of the combined oral contraceptive products. In high dose it was embriotoxic and it had detrimental effect on the differentiation of the urogenital organs.
There are no preclinical toxicity data obtained via conventional studies saying that repeated application of the product might be a special risk factor for genotoxicity and carcinogenicity, besides the facts usually related to the use of combined oral contraceptives, as previously mentioned.
It should be retained though that sex hormones may favour the growth of the specific hormone-dependent tissues and tumours.