Pharmacotherapeutic Group: Genito urinary system and sex hormones, progestogens and oestrogens, sequential preparations. ATC Code: G03FB08.
Pharmacology: Pharmacodynamics: Estradiol: The active ingredient, 17β-estradiol, is chemically and biologically identical to endogenous human estradiol.
It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
Oestrogens prevent bone loss following menopause or ovariectomy.
Dydrogesterone: 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.
Clinical trial Information: Relief of oestrogen-deficiency symptoms and bleeding patterns.
Relief of menopausal symptoms was achieved during the first few weeks of treatment.
Regular withdrawal bleeding occurred in 76% of the women with a mean duration of 5 days.
Withdrawal bleeding usually started at mean day 28 of the cycle. Break through bleeding and/or spotting appeared in 23% of the women during the first three months of therapy and in 15% of the women during months 10-12 of treatment. Amenorrhoea (no bleeding or spotting) occurred in 21% of the cycles during the first year of treatment.
Prevention of osteoporosis.
Oestrogen deficiency at menopause is associated with increase in bone turnover and a decline in bone mass. The effect of oestrogens on the bone mineral density is dose dependent.
Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.
Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen - given to predominantly healthy women - reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.
For Femoston 1/10 the increase in lumbar spine BMD was 5.2% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 93.0%.
Femoston 1/10 also had an effect on hip BMD.
The increase after two years of treatment with Femoston 1/10 was 2.7% ± 4.2 % (mean ± SD) at femoral neck, 3.5% ± 5.0% (mean ± SD) at trochanter and 2.7%±6.7% (mean ± SD) at Wards triangle.
The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with Femoston 1/10 was 67-78%.
Pharmacokinetics: Estradiol: Absorption: Absorption of estradiol is dependent on the particle size, micronized estradiol is readily absorbed from the gastrointestinal tract.
The following table provides the mean single dose pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data is presented as mean (SD). (See Table 1.)
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Distribution: Oestrogens can be found either unbound or bound. About 98-99% of the estradiol dose binds to plasma proteins, from which about 30-52% on albumin and about 46-69% on the sex hormone-binding globulin (SHBG).
Metabolism: Following oral administration, estradiol 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 estradiol. Estrone sulphate may undergo enterohepatic circulation.
Elimination: In urine, the major compounds are the glucuronides of estrone and estradiol. The elimination half-life is between 10-16 h.
Oestrogens are secreted in the milk of nursing mothers.
Dose and time dependencies: Following daily oral administration of Femoston, estradiol concentrations reached a steady-state after about five days.
Generally, steady state concentrations appeared to be reached within 8 to 11 days of dosing.
Dydrogesterone: Absorption: Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20 mg dose versus 7.8 mg intravenous infusion) is 28 %.
The following table provides the mean steady state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD). Data is presented as mean (SD). (See Table 2.)
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Distribution: 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.
Metabolism: Following oral administration, dydrogesterone is rapidly metabolized 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.
Elimination: After oral administration of labeled 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.
Dose and time dependencies: The single and multiple dose pharmacokinetics are linear in the oral dose range 2.5 to 10 mg. 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.