Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Theramex HQ UK LTD, Sloane Square House, 1 Holbein Place, London SW1W 8NS UK
ATC code: G03CA03
The active ingredient, synthetic 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.
Relief of menopausal symptoms was achieved to a similar degree during the first few weeks of treatment with Evorel 50 and Evorel 100.
Oestrogen deficiency at menopause is associated with increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density (BMD) is dose-dependent; the relationship is not linear, however. Protection appears to be effective 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.
In a clinical trial of two years duration comparing Evorel 50 and 100 to placebo, the increase in lumbar spine bone mineral density (BMD) with Evorel 50 was 4.46 ± 4.04 % (mean±SD). With Evorel 100, the gain in lumbar spine bone density was 5.93 ± 4.34 %.
The percentage of women who maintained or gained BMD in the lumbar spine with Evorel 50 was 84% and with Evorel 100, 92.5%.
Evorel also had an effect on hip BMD. The increase in BMD in the femoral neck with Evorel 50 was 1.26 ± 2.86 % and with Evorel 100, 1.61±0.53 %. The percentage of women maintaining or gaining BMD in the femoral neck was 65 and 63.5 %, respectively. In the total hip, the increase in BMD was 2.17 ± 2.33 % with Evorel 50 and 2.82±0.51 % with Evorel 100. The percentage of women maintaining or gaining BMD in the total hip was 93 and 82.5 %, respectively.
The estradiol hemihydrate of the patch is taken up through the skin as estradiol. Estradiol is metabolised primarily in the liver to estrone, which has weak estrogenic activity. Estrone is either conjugated with glucuronic or sulphuric acid or reconverted to estradiol. Conjugates are excreted mainly by the kidneys. In contrast to oral preparations, the estradiol/estrone ratio on use of Evorel is in the physiological range below 2, similar to that in pre-menopausal women. Estradiol circulates in the blood bound to sex hormone binding globulin (35-45%) and albumin (60-65%).
Estradiol is metabolised mainly in the liver by the P450 enzyme system. (see Section 4.5 Interactions).
Due to the transdermal administration, there is no noticeable first-pass effect.
Pharmacokinetic parameters for the four sizes of Evorel patches are shown in the following table.
| Evorel 25 | Evorel 50 | Evorel 75 | Evorel 100 | |||||
|---|---|---|---|---|---|---|---|---|
| Serum estradiol (pmol/L; mean+/-SD) | ||||||||
| Cmax | 151± | 69 | 277± | 121 | 473± | 286 | 655± | 447 |
| C96h | 64± | 27 | 113± | 47 | 176± | 112 | 226± | 125 |
| Cavg | 96± | 35 | 173± | 68 | 271± | 161 | 382± | 232 |
Preclinical effects were observed at exposures considered sufficiently in excess of the maximum human exposure, or were related to an exaggerated pharmacological effect, or were related to differences between species regarding hormonal regulation/metabolism and indicate little relevance to clinical use.
Subchronic skin irritation studies in rabbits and dermal sensitisation tests in guinea pigs have been performed. The studies show that the estradiol transdermal patch is an irritant and that estradiol contributes to the irritancy. It is recognised that test studies on rabbits over-predict skin irritation which occurs in humans.
The dermal sensitisation test shows that Evorel is not a skin sensitiser.
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