Pharmacotherapeutic Group: Progestogens. ATC Code: G03D.
Pharmacology: Pharmacodynamics: Visanne is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately 1/3 of that of cyproterone acetate. Visanne 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, Visanne has a strong progestogenic effect in vivo. Visanne has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.
Visanne 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, Visanne leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.
Data on Efficacy: Superiority of Visanne over placebo was demonstrated in a 3-month 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 Visanne 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% without relevant increase of concomitant pain medication was achieved in 37.3% of patients on Visanne (placebo: 19.8%); a reduction of endometriosis-associated pelvic pain by ≥75% relevant increase of concomitant pain medication was achieved in 18.6% of patients on Visanne (placebo: 7.3%).
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.
The placebo controlled results were supported by the results obtained in a 6-month active-controlled study versus a GnRH agonist including 252 patients with endometriosis.
Three (3) studies including a total of 252 patients who received a daily dose of Visanne 2 mg 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 Visanne 1 mg has been shown to induce an anovulatory state after 1 month of treatment. Visanne has not been tested for contraceptive efficacy in larger studies.
Data on Safety: Endogenous estrogen levels are only moderately suppressed during treatment with Visanne.
Currently, long-term data on bone mineral density (BMD) and risk of fractures in users of Visanne are not available. BMD was assessed in 21 patients before and after 6 months of treatment with Visanne 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 impact on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids and HbA1C was observed during treatment with Visanne for up to 15 months (n=168).
Orally administered Visanne 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 Visanne are dose-proportional within the dose range of 1-8 mg.
Distribution: Visanne 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 Visanne is 40 L.
Metabolism: Visanne 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 Visanne. The metabolites are excreted very quickly, so that in plasma unchanged Visanne is the dominating fraction.
The metabolic clearance rate from serum (Cl/F) is 64 mL/min.
Elimination: Visanne serum levels decrease in 2 phases. The terminal disposition phase is characterized by a half-life of approximately 9-10 hrs. Visanne 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 half-life 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 Visanne 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 Visanne after repeated administration of Visanne can be predicted from single dose pharmacokinetics.
Special Population: Visanne has not been studied specifically in renally impaired subjects.
Visanne has not been studied in subjects with hepatic impairment.
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.
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Information checked by Dr. Sachin Kumar, MD Pharmacology