Dydrogesterone, Estradiol

Pharmacological properties

Pharmacodynamics

Estradiol. The active ingredient 17β-estradiol is chemically and biologically similar to the natural female sex hormone estradiol. It replaces the loss of the production of their own estrogen in women during the menopausal period and alleviates the symptoms of menopause.

Estrogens prevent bone loss after menopause or ovariectomy.

Dydrogesterone Dydrogesterone is an orally active progestogen whose action is comparable to that of parenteral progesterone. Due to the fact that estrogens stimulate endometrial growth, if progestogen is not used, they increase the risk of endometrial hyperplasia and carcinoma. Adding progestogen to therapy significantly reduces estrogen-induced risk in women with preserved uterus.

Femoston Conti, clinical trial data

Reducing the severity of symptoms of estrogen deficiency and improving the profile of bleeding.

A decrease in the severity of menopause symptoms was observed during the first few weeks of treatment.

Amenorrhea (without bleeding and spotting) was noted in 88% of women during the 10-12 months of treatment. Irregular bleeding and / or spotting appeared in 15% of women during the first 3 months of treatment and in 12% in the 10-12 months of treatment.

Prevention of osteoporosis. Estrogen deficiency after menopause is associated with an increase in bone resorption and a decrease in bone mass. The effect of estrogen on bone density is dose dependent. The protective effect of estrogen is valid only during their use. After discontinuation of hormone replacement therapy (HRT), the rate of decrease in bone mass is the same as in women who have not received this therapy.

The WHI (Women Health Initiative) study and a meta-analysis of other studies indicate that the use of HRT in predominantly healthy women in estrogen monotherapy or in combination with progestogen reduces the risk of hip, vertebral, and other fractures resulting from osteoporosis. HRT can also prevent fractures in women with low bone density and / or diagnosed osteoporosis, but data are limited.

After one year of drug treatment, bone density in the lumbar spine grew by about 4.0 ± 3.4% (mean ± standard deviation (SD)). In 90% of patients, bone density increased or remained unchanged during treatment.

Femoston Conti also influenced bone density in the femur. After one year of treatment with Femoston Conti, the bone density of the femoral neck was 1.5 ± 4.5% (mean ± SD), for the trochanter - 3.7 ± 6.0% (mean ± SD) and for the Wards triangle - 2.1 ± 7.2% (mean ± SD). The proportion of women who noted a preservation or increase in bone density in these three areas of the femur after treatment with Femoston Conti was 71; 66 and 81% respectively.

Femoston Conti mini, clinical trial data

Reducing the severity of symptoms of estrogen deficiency and improving the profile of bleeding.

A decrease in the severity of menopause symptoms was observed during the first few weeks of treatment.

When taking the drug Femoston Conti mini starting from the 4th week of treatment, a decrease in the severity of moderate and severe hot flushes was statistically significant compared with placebo. The number of moderate and severe hot flushes continued to decrease until the end of the treatment period in the 13th week. During two studies, amenorrhea (absence of bleeding or spotting) was noted in 91 and 88% of women, respectively, during the 10-12 months of treatment. Irregular bleeding or spotting occurred in 10 and 21% of women in the first 3 months of treatment and in 9 and 12% during the 10-12 months of treatment.

Pharmacokinetics

Estradiol

Suction. The absorption of estradiol depends on the particle size.Micronized estradiol is rapidly absorbed in the digestive tract.

The table below shows the average constant pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulfate (E1S) for each dose of micronized estradiol.

Data are presented as means (SD).

Distribution. Estrogens are determined in an unbound or bound state. About 98–99% of the dose of estradiol binds to blood plasma proteins, of which 30–52% - with albumin and about 46–69% - with sex hormone-binding globulin.

Biotransformation. After oral administration, estradiol is actively metabolized. The main unconjugated and conjugated metabolites are estrone and estrone sulfate. These metabolites may play a role in estrogenic activity directly or after conversion to estradiol. Estrone sulfate may pass through enterohepatic circulation.

In urine, the main compounds are estrone and estradiol glucuronides. T_½ is 10-16 hours. Estrogens pass into breast milk.

Dose and time dependent. With daily oral administration of the drug, the concentration of estradiol reaches an equilibrium state after about 5 days. In most cases, the concentration of the equilibrium state is achieved in the interval from the 8th to the 11th day of administration.

Dydrogesterone

Suction. After oral administration, dydrogesterone is rapidly absorbed with a time to reach C_max between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral dose of 20 mg compared with iv infusion of 7.8 mg) is 28%.

The following table presents the average constant established pharmacokinetic indicators of the dose of dydrogesterone (D) and dihydrohydrogesterone (DGD). Data are presented as means (SD).

Distribution. After iv administration of dydrogesterone, the equilibrium distribution volume is about 1400 liters. Dydrogesterone and DHD bind to plasma proteins by more than 90%.

Metabolism. After oral administration, dydrogesterone is rapidly metabolized with the formation of DGD. The level of the main active metabolite of 20α-DGD reaches a peak approximately 1.5 hours after the dose. The level of DHD in blood plasma is generally higher compared to the starting material. The ratio of AUC and C_max DGD and dydrogesterone are about 40 and 25, respectively. Medium End T_½ dydrogesterone and DGD fluctuates between 5–7 and 14–17 hours, respectively.

A common property of all metabolites is the preservation of the 4,6-dien-3-one configuration of the starting compound and the absence of 17α-hydroxylation. This explains the lack of estrogen and androgenic effects of dydrogesterone.

After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted in the urine. The total plasma clearance is 6.4 l / min. Complete excretion is carried out within 72 hours. DHD is determined in the urine mainly in the form of a conjugate with glucuronic acid.

Dose and time dependent. Pharmacokinetics with single and multiple use is linear in the range of oral doses from 2.5 to 10 mg. Comparison of the kinetics of single and multiple doses shows that the pharmacokinetics of dydrogesterone and DGD does not change as a result of repeated use. An equilibrium state was reached after 3 days of treatment.

Indications

Femoston Conti. HRT to eliminate the symptoms caused by estrogen deficiency in women