Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Mylan Products Ltd., 20 Station Close, Potters Bar, Herts, EN6 1TL, United Kingdom
The ATC code is G03FB08. (Oestrogens: urogenital system and sex hormones)
Sequential hormone replacement therapy (combined oestradiol and dydrogesterone).
The active ingredient, synthetic 17β-oestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.
Dydrogesterone is an orally-active progestogen having an activity comparable to parenterally administered progesterone. As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Relief of oestrogen-deficiency symptoms and bleeding patterns.
Withdrawal bleeding usually started on the day of the last pill of the progestogen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea (no bleeding or spotting) occurred in 21-25% of the women for months 10 to 12 of treatment.
Prevention of osteoporosis:
Absorption of oestradiol is dependent on the particle size: micronized oestradiol is readily absorbed from the gastrointestinal tract.
The following table provides the mean steady state pharmacokinetic parameters of oestradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized oestradiol. Data is presented as mean (SD).
| Oestradiol 1mg | ||||
|---|---|---|---|---|
| Parameters | E2 | E1 | Parameters | E1S |
| Cmax (pg/mL) | 71 (36) | 310 (99) | Cmax (ng/mL) | 9.3 (3.9) |
| Cmin (pg/mL) | 18.6 (9.4) | 114 (50) | Cmin (ng/mL) | 2.099 (1.340) |
| Cav (pg/mL) | 30.1 (11.0) | 194 (72) | Cav (ng/mL) | 4.695 (2.350) |
| AUC0-24 (pg.h/mL) | 725 (270) | 4767 (1857) | AUC0-24 (ng.h/mL) | 112.7 (55.1) |
Oestrogens can be found either unbound or bound. About 98-99% of the oestradiol dose binds to plasma proteins, from which about 30-52% to albumin and about 46-69% to the sex hormone-binding globulin (SHBG).
Following oral administration, oestradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the oestrogen activity, either directly or after conversion to oestradiol. Estrone sulphate may undergo enterohepatic circulation.
In urine, the major compounds are the glucuronides of estrone and oestradiol. The elimination half-life is between 10-16 h.
Oestrogens are secreted in the milk of nursing mothers.
Following daily oral administration of Femoston, oestradiol concentrations reached a steady-state after about five days.
Generally, steady state concentrations appeared to be reached for within 8 to 11 days of dosing.
Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20mg dose versus 7.8mg intravenous infusion) is 28%.
The following table provide the mean steady state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD). Data is presented as mean (SD).
| Dydrogesterone 10mg | ||
|---|---|---|
| Parameters | D | DHD |
| Cmax (ng/mL) | 2.54 (1.80) | 62.50 (33.10) |
| Cmin (ng/mL) | 0.13 (0.07) | 3.70 (1.67) |
| Cav (ng/mL) | 0.42 (0.25) | 13.04 (4.77) |
| AUC0-t (ng.h/mL) | 9.14 (6.43) | 311.17 (114.35) |
After intravenous administration of dydrogesterone the steady-state volume of distribution is approximately 1400 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.
Following oral administration, dydrogesterone is rapidly metabolised to DHD. The levels of the main active metabolite 20 α-dihydrodydrogesterone (DHD) peak about 1.5 hours post dose. The plasma levels of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Mean terminal half-lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α- hydroxylation. This explains the lack of oestrogenic and androgenic effects of dydrogesterone.
After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Total plasma clearance is 6.4 L/min. Within 72 hours excretion is complete. DHD is present in the urine predominantly as the glucuronic acid conjugate.
The single and multiple dose pharmacokinetics are linear in the oral dose range 2.5 to 10mg. Comparison of the single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD are not changed as a result of repeated dosing. Steady state was reached after 3 days of treatment.
There are no preclinical safety data of relevance to the prescriber in the target population that are additional to those already included in other sections of the Summary of Product Characteristics (SmPC).
This medicinal product may pose a risk to the aquatic environment. Medicines no longer required should not be disposed of via wastewater or household waste. Any unused product or waste material should be disposed of in accordance with local requirements or returned to the pharmacy.
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