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Pharmacology: Pharmacodynamics: Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately ⅓ of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.
Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppressing the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions. Additional properties, like immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.
Data on Efficacy: Superiority of Visanne over placebo with regard to reduction of endometriosis-associated pelvic pain (EAPP) and clinically meaningful reduction of pain compared to baseline were demonstrated in a 3-month study including 102 patients on Visanne.
The open-label extension to this placebo-controlled study showed a continued improvement of endometriosis-associated pelvic pain for a treatment duration of up to 15 months.
In addition, efficacy on endometriosis-associated pelvic pain was shown in a 6-month comparative trial of Visanne versus the gonadotropin-releasing hormone (GnRH) analogue leuprorelin acetate (LA) including 120 patients on Visanne. A clinically meaningful reduction of pain compared to baseline was observed in both treatment groups. Non-inferiority versus LA based on a predefined non-inferiority margin of 15 mm was demonstrated (p<0.0001).
Three (3) studies including a total of 252 patients who received a daily dose of dienogest 2 mg demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.
Data on Safety: Endogenous estrogen levels are only moderately suppressed during treatment with Visanne. Bone mineral density (BMD) was assessed in 21 patients before and after 6 months of treatment and there was no reduction in mean BMD.
No significant impact on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids, and lipids and hemoglobin A1C (HbA1C) was observed during treatment with Visanne for up to 15 months (n=168).
Pharmacokinetics: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/mL are reached at about 1.5 hrs after single ingestion. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1-8 mg.
Distribution: Dienogest is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Ten percent (10%) of the total serum drug concentrations are present as free steroid, 90% are nonspecifically bound to albumin.
The apparent volume of distribution (Vd/F) of dienogest is 40 L.
Metabolism: Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of endocrinologically mostly inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of dienogest. The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.
The metabolic clearance rate from serum (Cl/F) is 64 mL/min.
Elimination: Dienogest serum levels decrease in 2 phases. The terminal disposition phase is characterized by a half-life (t½) of approximately 9-10 hrs. Dienogest is excreted in form of metabolites which are excreted at a urinary to fecal ratio of about 3:1 after oral administration of 0.1 mg/kg. The t½ of urinary metabolites excretion is 14 hrs. Following oral administration approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount excreted within the first 24 hrs, mostly with the urine.
Steady-State Conditions: Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion, drug serum levels increase about 1.24-fold reaching steady-state conditions after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of Visanne can be predicted from single dose pharmacokinetics.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special risks for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
