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Pharmacology: Pharmacodynamics: Estradiol: The active ingredient, 17β-estradiol, is chemically and biologically identical to the endogenous human estradiol.
It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
Femoston Conti 1/5 and Femoston 1/10 oestrogens prevent bone loss following menopause.
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.
Femoston Conti 1/5: Amenorrhoea was seen in 88% of the women during months 10-12 treatment. Irregular bleeding and/or spotting appeared in 15% of the women during the first 3 months of treatment and in 12% during months 10-12 of treatment.
Femoston 1/10: 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. Breakthrough 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. Amenorrhea (no bleeding or spotting) occurred in 21% of the cycles during the first year of treatment.
Femoston 2/10: Regular withdrawal bleeding occurred in 89% of the women with a mean duration of 5 days. Withdrawal bleeding usually started at mean day 28 of the cycle. Breakthrough bleeding and/or spotting appeared in 22% of the women during the first three months of therapy and in 19% of the women during months 10-12 of treatment. Amenorrhoea (no bleeding or spotting) occurred in 12% of the cycles during the first year of treatment.
Femoston Conti 1/5, Femoston 1/10 and Femoston 2/10: Relief of climacteric complaints was achieved during the first weeks of treatment.
Femoston Conti 1/5 and Femoston 1/10: Prevention of osteoporosis: Oestrogen deficiency at menopause is associated with an 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.
Femoston Conti 1/5: After one year of treatment the bone mineral density in the lumbar vertebrae increased about 4.0% ± 3.4% (mean ± SD). In 90% of the subjects the bone mineral density increased or stayed the same during treatment. Femoston 1/5 also had an effect on hip BMD.
The increase after one year of treatment with Femoston Conti 1/5 was 1.5% ± 4.5% (mean ± SD) at femoral neck, 3.7% ± 6% (mean ± SD) at trochanter and 2.1% ± 7.2% (mean ± SD) at Wards triangle.
The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with Femoston Conti 1/5 was 71%, 66% and 81% respectively.
Femoston 1/10: 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% (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%.
Femoston 2/10: After two years of treatment with Femoston 2/10, the increase in lumbar spine bone mineral density (BMD) was 6.7% ± 3.9% (mean ± SD). For Femoston 2/10 the percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%. Femoston 2/10 also had an effect on hip BMD.
The increase after two years of treatment with Femoston 2/10 was 2.6% ± 5.0% (mean ± SD) at femoral neck; 4.6% ± 5.0% (mean ± SD) at trochanter and 4.1% ± 7.4% (mean ± SD) at Wards triangle.
The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with Femoston 2/10 was 71-88%.
Pharmacokinetics: Estradiol: Absorption: Absorption of estradiol is dependent on the particle size, micronized estradiol is readily absorbed from the gastrointestinal tract.
The following tables provide the mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data is presented as mean (SD). (See Tables 2 and 3.)
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Click on icon to see table/diagram/imageDistribution: 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 hormones-binding globulin (SHBG).
Metabolism: Following oral administration, estradiol is extensively metabolized. 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 to 16 hours.
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 for within 8 to 11 days of dosing.
Dydrogesterone: Absorption: Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 1.5 hours.
The following tables provide the mean pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD) after single dose (5 mg dydrogesterone) and at steady state (10 mg dydrogesterone). Data is presented as mean (SD). (See Tables 4 and 5.)
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Click on icon to see table/diagram/imageAfter a single dose, food delays the peak plasma concentration of dydrogesterone with approximately 1 hour, resulting in approximately 20% lower dydrogesterone peak plasma concentrations without affecting the extent of exposure to dydrogesterone and DHD.
Distribution: After oral administration of dydrogesterone, the apparent volume of distribution is large, being approximately 22000 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.
Metabolism: Following oral administration, dydrogesterone is rapidly metabolized to 20 α-dihydrodydrogesterone (DHD). The levels of the main active metabolite DHD peak at similar times as dydrogesterone. The plasma concentrations of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are approximately 25 and 20, respectively. The mean terminal half-lives of dydrogesterone and DHD is about 15 hours. A common feature of all metabolites characterized 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.
Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible.
Elimination: After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. The apparent total body clearance of dydrogesterone from plasma is high at approximately 20 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 20 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 conditions are generally reached after 3 days of treatment.
Toxicology: Preclinical safety data: 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 monograph.
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