Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: progestogens, ATC code: G03DB08

Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately one third 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 oestradiol and thereby suppresses 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.
Data on efficacy:

Superiority of Visabelle over placebo was demonstrated in a 3-months study including 198 patients with endometriosis. Endometriosis-associated pelvic pain was measured on a Visual Analog Scale (0-100 mm). After 3 months of treatment with Visabelle a statistically significant difference compared to placebo (∆ = 12.3 mm; 95%CI: 6.4 – 18.1; p<0.0001) and a clinically meaningful reduction of pain compared to baseline (mean reduction = 27.4 mm ± 22.9) were demonstrated.

After 3 months of treatment, reduction of endometriosis-associated pelvic pain by 50% or more without relevant increase of concomitant pain medication was achieved in 37.3% of patients on Visabelle (placebo: 19.8%); a reduction of endometriosis-associated pelvic pain by 75% or more without relevant increase of concomitant pain medication was achieved in 18.6% of patients on Visabelle (placebo: 7.3%).
The open-label extension to this placebo-controlled study suggested a continued improvement of endometriosis-associated pelvic pain for a treatment duration of up to 15 months.

The placebo controlled results were supported by the results obtained in a 6 months active- controlled study versus a GnRH agonist including 252 patients with endometriosis.

Three studies including a total of 252 patients who received a daily dose of 2 mg dienogest demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.

In a small study (n=8 per dose group), a daily dose of 1 mg dienogest has been shown to induce an anovulatory state after 1 month of treatment. Visabelle has not been tested for contraceptive efficacy in larger studies.

Data on safety:

Endogenous estrogen levels are moderately suppressed during treatment with Visabelle.
Currently, long-term data on bone mineral density (BMD) and risk of fractures in users of Visabelle are not available. BMD was assessed in 21 adult patients before and after 6 months of treatment with Visabelle and there was no reduction of mean BMD. In 29 patients treated with leuprorelin acetate (LA), a mean reduction of 4.04% ± 4.84 was noted after the same period (∆ between groups = 4.29%; 95%CI: 1.93 – 6.66; p<0.0003).


No significant changes of the mean values of standard laboratory parameters (including haematology, blood chemistry, liver enzymes, lipids, and HbA1C) were observed during treatment with Visabelle for up to 15 months (n=168).

Safety in adolescents
The safety of Visabelle with respect to BMD was investigated in an uncontrolled clinical trial over 12 months in 111 adolescent women (12 to <18 years) with clinically suspected or confirmed endometriosis. The mean relative change in BMD of the lumbar spine (L2-L4) from baseline in the 103 patients with BMD measurement was -1.2 %. In a subset of the patients with decreased BMD a follow-up measurement was performed 6 months after end of treatment and showed an increase in BMD to -0.6%.

Long-term safety
A long-term post-approval observational active surveillance study was conducted to investigate the incidence of first-time occurrence or worsening of clinically relevant depression and occurrence of anemia. A total of 27,840 women with a newly prescribed hormonal therapy for endometriosis were enrolled in the study and followed up for up to 7 years.

A total of 3,023 women started with a prescription for dienogest 2 mg and 3,371 patients started with other approved endometriosis drugs. The overall adjusted hazard ratio for new occurrences of anemia comparing the dienogest patients with the patients on other approved endometriosis drugs was 1.1 (95% CI: 0.4 – 2.6). The adjusted hazard ratio for depression risk comparing dienogest and other approved endometriosis drugs was 1.8 (95% CI: 0.3-9.4). A slightly increased risk of depression in dienogest users compared with users of other approved endometriosis drugs could not be excluded.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

•     Absorption

Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/ml are reached at about 1.5 hours 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). 10 % of the total serum drug concentration is present as free steroid, 90 % is non-specifically bound to albumin.

The apparent volume of distribution (Vd/F) of dienogest is 40 l.

•     Biotransformation

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 two phases. The terminal disposition phase is characterized by a half-life of approximately 9-10 hours. Dienogest is excreted in form of metabolites which are excreted at a urinary to faecal ratio of about 3:1 after oral administration of 0.1 mg/kg. The half- life of urinary metabolites excretion is 14 hours. Following oral administration approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount excreted within the first 24 h, 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 Visabelle can be predicted from single dose pharmacokinetics.

•     Pharmacokinetics in Special Population

Visabelle has not been studied specifically in renally impaired subjects.
Visabelle has not been studied in subjects with hepatic impairment.