Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
ATC code: G03F A01
Estradiol hemihydrate:
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.
Norethisterone:
As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen 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.
When starting Evorel Conti, bleeding episodes occur mostly during the first month of treatment, with a quick improvement of the bleeding profile. In first users of HRT, or after a hormone free period of at least 2 weeks, absence of bleeding was seen in 33 % of women during the first three months of treatment and 54 % were bleed-free during months 2 and 3. When Evorel Conti was started directly after a cycle of sequential HRT, only 7.5 % of the women were bleed- free during the first three months, 47 % reported no bleeding for months 2 and 3.
Over time, bleeding stops in the majority of women so that 63% of women from either group were bleed-free during the last 3 months of 12 months therapy with Evorel Conti. In women with well established menopause (mean 7 years since the last natural menstrual period), 56% were bleed-free during the first three months of treatment and 92% were bleed free during months 10-12.
Bleeding lasted five or less days in not more than 2 episodes per quarter year in >95% of subjects.
Starting Evorel Conti after a hormone free period may reduce the likelihood of uterine bleeding during the initial period of use of Evorel Conti.
In three clinical trials of one year duration, uterine bleeding episodes were reported as an adverse event by 53 of 344 (16%) women - the most frequently reported undesirable effect.
Prevention of osteoporosis
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. 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.
After one year of treatment with Evorel Conti, the increase in lumbar spine bone mineral density (BMD) was 2.94 ± 2.62 % (mean±SD). The percentage of women who maintained or gained BMD in the lumbar zone during treatment was 90%.
Evorel Conti also had an effect on hip BMD. The increase in BMD in the femoral neck was 2.42 ± 3.04 % and the percentage of women maintaining or gaining BMD in the femoral neck was 82%. In the total hip, the increase in BMD was 1.73 ± 2.55 % (mean±SD) with 74% women maintaining or gaining in BMD.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
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.
The estradiol / estrone ratio on use of Evorel Conti is close to one, similar to pre- menopausal women. Estradiol circulates in the blood bound to sex hormone binding globulin (35-45%) and albumin (60-65%).
Norethisterone acetate is cleaved immediately on resorption to yield norethisterone. Norethisterone distributes widely in the body and circulates bound to sex hormone binding globulin (about 36%) and albumin (about 61%).
It is metabolised mainly in the liver. Metabolites are conjugated with glucuronic or sulfuric acid. Conjugates are excreted in faeces and urine.
The hepatic metabolism of both estradiol and norethisterone is mediated primarily by the P450 enzyme system. (see Section 4.5, Interactions with other medicinal products and other forms of interaction).
Due to the transdermal administration, there is no noticeable first-pass effect.
Estradiol pharmacokinetics
Following first use of an Evorel Conti patch by post-menopausal women, serum estradiol levels rise within 23 hours (Tmax, single application) from, on average, ~ 18 pmol/L (~5 pg/ml) by an average of 150 pmol/L (41 pg/mL) (Cmax, single application). Levels decrease over 3.5 days to an average of 66 pmol/L (18 pg/mL). During continued use of Evorel Conti, estradiol levels rise over 21 hours from patch change (Tmax, multiple application) by an average of 121 pmol/L (33 pg/mL) (Cmax, multiple applications). The 95% confidence interval for Cmax ranges from 77 to 165 pmol/L (21 to 45 pg/mL). When patch use is discontinued, serum estradiol levels decrease with a half-life of 6.6 hours. After 24 hours, baseline levels are again observed.
Norethisterone pharmacokinetics
Following first use of Evorel Conti by post-menopausal women, serum norethisterone levels rise over 37 hours (Tmax, single application) to 706 pmol/L (240 pg/mL)(Cmax, single application) and then decrease to 420 pmol/L (143 pg/mL) at day 3.5. On patch change, levels rise again over 22 hours (Tmax, multiple applications) to 756 pmol/L (257 pg/mL)(Cmax, multiple applications).

When patch use is discontinued, norethisterone levels decrease with a half-life of ~15 hours.