Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations
ATC code: G03FA
The active ingredient, synthetic 17ß-estradiol, which is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.
The active ingredient is a nortestosterone derivative, with an in vitro affinity for the progesterone receptor 10-30 times less compared to other synthetic progestogens. In vivo data in animals demonstrated a strong progestational activity. Dienogest has no significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.
As estrogens promote the growth of the endometrium, unopposed estrogensincrease the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
After oral administration estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage.
Peak serum estradiol concentrations of 21 pg/ml are reached at about 6 hours after single administration of Estradiol Valerate 1 mg/Dienogest 2 mg.
Estradiol is bound non-specifically to serum albumin and specifically to SHBG. Only about 1-2% of the circulating estradiol is present as free steroid, 40-45% is bound to SHBG. The apparent volume of distribution of estradiol after single intravenous administration is about 1 l/kg.
Cleavage to estradiol and valeric acid gives rise to natural estradiol and its metabolites estrone and estriol. The valeric acid undergoes very fast metabolization. After oral administration some 3-6% of the dose is directly bioavailable as estradiol.
The plasma half-life of circulating estradiol is about 90 min. After oral administration, however, the situation differs. Because of the large circulating pool of estrogen sulfates and glucuronides, as well as enterohepatic recirculation, the terminal half-life of estradiol after oral administration represents a composite parameter which is dependent on all of these processes and is in the range of about 13-20 h Its metabolites are mostly excreted with the urine, only about 10% being excreted with the stool.
Following daily ingestion drug serum levels increase about 2.2 fold reaching steady-state conditions after 4-7 days of treatment. Trough, maximum and average estradiol serum concentrations at steady state are 21 pg/ml, 43 pg/ml and 33 pg/ml, respectively. Pharmacokinetics of estradiol are influenced by SHBG levels
Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 49 ng/ml are reached at about 1.5 hours after single ingestion of Estradiol Valerate 1 mg/Dienogest 2 mg. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1-8 mg.
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 concentrations are present as free steroid, 90% are non-specifically bound to albumin. The apparent volume of distribution (Vd/F) of dienogest is 51 l in postmenopausal women.
Dienogest is nearly completely metabolised by the known pathways of steroid metabolism (hydroxylation, conjugation), mainly by CYP3A4. The pharmacologically inactive metabolites are excreted rapidly resulting in dienogest as the major fraction in plasma accounting for approximately 50% of circulating dienogest derived compounds. The total clearance following the intravenous administration of 3Hdienogest was calculated as 5.1 l/h.
The terminal elimination half-life of DNG is 10.5 hours in postmenopausal women after administration of Estradiol Valerate 1 mg/Dienogest 2 mg. 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.
Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about 1.3 fold reaching steady-state conditions after 3-4 days of treatment. The pharmacokinetics of dienogest after repeated administration of Estradiol Valerate 1 mg/Dienogest 2 mg can be predicted from single dose pharmacokinetics. Trough, maximum and average DNG serum concentrations at steady state are about 10 ng/ml, 63 ng/ml and 25 ng/ml, respectively.
Pharmacokinetics of dienogest are not influenced by SHBG levels.
No pharmacokinetic information is available on estradiol valerate 1 mg/dienogest 2 mg in patients with renal or hepatic insufficiency.
The toxicity profile of estradiol is well known. There are no preclinical data of relevance to the prescriber that are additional to those already included in other sections of the SPC.
Preclinical data reveal no special hazard for humans based on conventionalstudies of safety pharmacology, single dose toxicity, repeated dose toxicity, genotoxicity, carcinogenic potential toxicity to reproduction and development.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
