Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mylan Products Ltd., 20 Station Close, Potters Bar, Herts, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain
ATC code: G03CA03
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.
Combined therapy with progestogens is also recommended in hysterectomised women with a history of endometriosis as cancer development in extra-uterine endometriotic implants in women on oestrogen-only therapy has been reported (see section 4.4 Special warnings and precautions).
Relief of menopausal symptoms was achieved during the first few weeks of treatment.
Hot flushes have been shown to be significantly reduced with 1 mg and 2 mg 17 beta estradiol at 4 weeks.
Regular withdrawal bleeding in women treated with Zumenon 1mg daily for 28 days and Dydrogesterone 10mg daily for the last 12-14 days of a 28 day cycle, occurred in approximately 75-80% of women with a mean duration of 5 days. 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 occurred in 21-25% of the women for months 10 to 12 of treatment.
In women treated with Zumenon 2mg daily for 28 days and Dydrogesterone 10mg daily for the last 12-14 days of a 28 day cycle, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Zumenon 1mg, amenorrhoea (no bleeding or spotting) occurred in 7-11% of the women for months 10 to 12 of treatment.
Oestrogen deficiency at menopause is associated with an increasing bone turnover and 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.
After two years of treatment with Zumenon 2mg, the increase in lumbar spine bone mineral density (BMD) was 6.7% ± 3.9% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%.
Zumenon 2mg also had an effect on hip BMD. The increase after two years of treatment with 2mg oestradiol 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 2mg oestradiol was 71-88%.
After 18 months treatment spinal trabecular bone density increased (annual increases of 2.5% in the women taking 2.0 mg micronized 17 betaestradiol).
Estradiol, estra-1,3,5(10)-triene-3,17β-diol is identical to human ovarian estradiol.
Absorption of estradiol is dependent on the particle size: micronized estradiol is rapidly absorbed from the gastrointestinal tract with arithmetic mean Tmax values at steady-state of 5.8 hours.
The following table provides the arithmetic mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for 2 mg dose of micronized estradiol. Data is presented as arithmetic mean (standard deviation).
| Estradiol 2 mg | ||||
|---|---|---|---|---|
| Parameters | E2 | E1 | Parameters | E1S* |
| Cmax (pg/mL) | 89 (16) | 591 (178) | Cmax (ng/mL) | 25.9 (16.4) |
| Cmin (pg/mL) | 35.0 (13.4) | 208 (102) | Cmin (ng/mL) | 5.7 (5.9) |
| Cav (pg/mL) | 62.9 (15.6) | 392 (142) | Cav (ng/mL) | 13.1 (9.4) |
| AUC0-24 (pg.h/mL) | 1486 (374) | 9275 (3389) | AUC0-24 (ng.h/mL) | 307.3 (224.1) |
* E1S: data is taken from oral dosing of estradiol 2 mg + dydrogesterone 20 mg (no clinically relevant effects of dydrogesterone on estradiol kinetics are reported).
Oestrogens can be found either unbound or bound. About 98-99% of the estradiol dose binds to plasma proteins, from which about 30-52% to albumin and about 46-69% to the sex hormonebinding globulin (SHBG).
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.
In urine, the major compounds are the glucuronides of estrone and estradiol. The elimination half-life of estradiol and its main metabolites is between 10-16 h.
Oestrogens are secreted in the milk of nursing mothers.
The mean estradiol exposure at steady-state after oral daily dosing of 2 mg micronized estradiol is approximately 2-fold greater than that after daily dosing of 1 mg micronized estradiol. Based on the elimination half-life of the micronized estradiol, it can be estimated that estradiol concentrations reach steady-state approximately within one week following oral daily administration.
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.
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