Femoston film-coated tablets 1 mg+1 mg/10 mg No. 28

Instructions for Femoston film-coated tablets 1 mg + 1 mg / 10 mg No. 28

Composition

estradiol tablet:

active ingredient: estradiol;

1 tablet contains micronized estradiol hemihydrate, equivalent to 1 mg estradiol;

excipients: lactose monohydrate; hypromellose (HPMC 2910), corn starch, colloidal anhydrous silica, magnesium stearate;

film coating: Opadry Y-1-7000 white (hypromellose (HPMC 2910), polyethylene glycol 400, titanium dioxide (E 171)) – for tablets containing 1 mg of estradiol.

estradiol and dydrogesterone tablet:

active ingredients: estradiol; dydrogesterone;

1 tablet contains micronized estradiol hemihydrate, equivalent to estradiol 1 mg; micronized dydrogesterone 10 mg;

excipients: lactose monohydrate; hypromellose (HPMC 2910), corn starch, colloidal anhydrous silica, magnesium stearate;

film coating: Opadry II gray 85F27664 (polyethylene glycol 3350, talc (E 553b), polyvinyl alcohol, black iron oxide (E 172), titanium dioxide (E 171)) – for tablets containing 1 mg of estradiol and 10 mg of dydrogesterone.

Dosage form

Film-coated tablets.

Main physicochemical properties:

tablet containing 1 mg of estradiol: round, biconvex, film-coated, white tablet marked "379" on one side; diameter 7 mm and tablet weight approximately 144 mg;

tablet containing 1 mg of estradiol and 10 mg of dydrogesterone: round, biconvex, film-coated, grey tablet marked "379" on one side; diameter 7 mm and tablet weight approximately 144 mg.

Pharmacotherapeutic group

Preparations for the treatment of diseases of the genitourinary system and sex hormones. Combined preparations containing progestogens and estrogens for sequential use. ATX code G03F B08.

Pharmacological properties

Pharmacodynamics

Estradiol

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

Estrogens prevent bone loss after menopause or oophorectomy.

Dydrogesterone

Dydrogesterone is an orally active progestogen whose effects are comparable to those of parenterally administered progesterone.

Because estrogens stimulate endometrial growth, if not used with a progestogen, they increase the risk of endometrial hyperplasia and carcinoma. The addition of a progestogen to therapy significantly reduces the estrogen-induced risk in women with an intact uterus.

Clinical trial data

Reducing symptoms of estrogen deficiency and improving the bleeding profile.

A reduction in menopausal symptoms was observed during the first few weeks of treatment.

Regular withdrawal bleeding lasting an average of 5 days when using Femoston, estradiol 1 mg + estradiol/dydrogesterone 1 mg/10 mg, was observed in 76% of women. Withdrawal bleeding usually began on the last day of the progestogen phase (on average on day 28 of the cycle). Breakthrough uterine bleeding or spotting was recorded in approximately 23% of women in the first 3 months of treatment and in 15% of women during the 10th-12th months of treatment. Amenorrhea (absence of bleeding or spotting) was observed in 21% of cycles during the first year of treatment.

Osteoporosis prevention

Estrogen deficiency after menopause is associated with increased bone resorption and decreased bone mass. The effect of estrogens on bone density is dose-dependent. The protective effect is only effective during their use. After discontinuation of hormone replacement therapy (HRT), the rate of bone loss is the same as in women who did not receive the therapy.

Data from the Women's Health Initiative (WHI) trial and meta-analyses of other studies suggest that the use of HRT in predominantly healthy women, either as estrogen monotherapy or in combination with a progestogen, reduces the risk of hip, vertebral, and other types of fractures due to osteoporosis. HRT may also prevent fractures in women with low bone density and/or known osteoporosis, but the data on this are limited.

In women taking Femoston, estradiol 1 mg + estradiol/dydrogesterone 1 mg/10 mg, bone density in the lumbar spine increased by 5.2 + 3.8% (mean ± standard deviation). Bone density in the lumbar spine increased or remained unchanged in 93.0% of women.

Femoston also affected the GCT of the femur.

After two years of therapy with Femoston, estradiol 1 mg + estradiol/dydrogesterone 1 mg/10 mg, the GCT in the femoral neck increased by 2.7 ± 4.2% (mean ± standard deviation), in the trochanteric zone by 3.5 ± 5.0% (mean ± standard deviation) and in the triangle of Ward by 2.7 ± 6.7% (mean ± standard deviation). GCT in the three femoral zones increased or remained unchanged after treatment with Femoston, estradiol 1 mg + estradiol/dydrogesterone 1 mg/10 mg, in 67-78% of women.

Pharmacokinetics

Estradiol

The absorption of estradiol depends on the particle size of the particles: micronized estradiol is rapidly absorbed from the gastrointestinal tract.

The following Table 1 presents the mean steady-state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulfate (E1S) for each dose of micronized estradiol.

Data are presented as mean (SD).

Distribution

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

Biotransformation

After oral administration, estradiol is extensively metabolized. The major unconjugated and conjugated metabolites are estrone and estrone sulfate. These metabolites may contribute to estrogenic activity directly or after conversion to estradiol. Estrone sulfate may undergo enterohepatic circulation.

Breeding

In urine, the main compounds are glucuronides of estrone and estradiol. The half-life is from 10 to 16 hours. Estrogens are secreted into breast milk.

Dose and time dependence

With daily oral administration of Femoston, estradiol concentrations reach steady state after approximately five days. In most cases, steady state concentrations are reached between the 8th and 11th day of administration.

Dydrogesterone

Absorption

After oral administration, dydrogesterone is rapidly absorbed with a Tmax of 0.5-2.5 hours. The absolute bioavailability of dydrogesterone (oral dose of 20 mg compared to intravenous infusion of 7.8 mg) is 28%.

Table 2 presents the mean steady-state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DH).

Data are presented as mean (SD).

Distribution

After intravenous administration of dydrogesterone, the equilibrium volume of distribution is approximately 1400 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.

Biotransformation

After oral administration, dydrogesterone is rapidly metabolized to DHD. Levels of the main active metabolite, 20α-dihydrodydrogesterone (DHD), peak approximately 1.5 hours after dosing. Plasma levels of DHD are generally higher than those of the parent drug. The AUC and Cmax ratios of DHD and dydrogesterone are approximately 40 and 25, respectively. The mean terminal half-lives of dydrogesterone and DHD range from 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 parent compound and the absence of 17α-hydroxylation. This explains the lack of estrogenic and androgenic effects of dydrogesterone.

Breeding

After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted in the urine. Total plasma clearance is 6.4 l/min. Complete elimination occurs within 72 hours. DHD is present in the urine mainly as a glucuronic acid conjugate.

Dose and time dependence

The pharmacokinetics of single and multiple doses are linear in the oral dose range of 2.5 to 10 mg. Comparison of single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD do not change with repeated administration. Steady state was achieved after 3 days of treatment.

Indication

Hormone replacement therapy (HRT) to eliminate symptoms caused by estrogen deficiency in menopausal women no earlier than 6 months after the last menstruation.

Prevention of osteoporosis in postmenopausal women at high risk of fractures. Femoston should be used in patients only if they are intolerant to or have contraindications to other drugs for the prevention of osteoporosis (see section "Special instructions").

Experience in treating women over 65 years of age is limited.

Contraindication

Previously diagnosed, current or suspected breast cancer; Known or suspected estrogen-sensitive tumors (e.g. endometrial cancer); Unexplained vaginal bleeding; Untreated endometrial hyperplasia; History of active venous thromboembolism (deep vein thrombosis, pulmonary embolism);

acute or recent thromboembolic arterial disease (e.g. angina pectoris, myocardial infarction); acute liver disease or a history of liver disease in which liver function tests have not returned to normal; known hypersensitivity to the active substances or to any of the excipients of the drug; porphyria.

Interaction with other medicinal products and other types of interactions

Drug interaction studies have not been conducted.

The effectiveness of estrogens and progestogens may be impaired.

The metabolism of estrogens (and progestogens) may be enhanced by concomitant use of substances known to induce enzymes involved in drug metabolism. This applies in particular to P450 enzymes. Such substances include anticonvulsants (phenobarbital, carbamazepine, phenytoin) and antibacterial/antiviral agents (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Although ritonavir and nelfinavir are known to be potent inhibitors, they actually have an inducing effect when used concomitantly with steroid hormones.

Herbal preparations containing St. John's wort (Hypericum perforatum) may also enhance the metabolism of estrogens (and progestogens).

Clinically, increased metabolism of estrogens and progestogens may manifest as decreased efficacy and changes in bleeding profile.

Application features

For the treatment of estrogen deficiency symptoms in postmenopausal women, HRT should only be initiated if these symptoms significantly impair quality of life. The benefits and risks of HRT should be carefully assessed regularly, at least annually, and treatment should only be continued if the benefits outweigh the risks.

Data on the risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in younger women, the benefit-risk ratio is more favourable in these women than in older women.

Medical examination/follow-up

Before starting HRT or when restarting HRT after a break, a complete medical history (including family history) should be taken. A physical examination (including gynaecological and breast examination) should be performed, taking into account the medical history, contraindications and precautions for use. Regular check-ups are recommended during treatment, the frequency and extent of which are determined individually. Women should be informed about any changes in the breasts that should be reported to their doctor or nurse (see section below on “Breast cancer”). Regular breast examinations, including appropriate imaging techniques such as mammography, should be performed in accordance with current guidelines for healthy women, taking into account the medical needs of each individual woman.

Diseases in which it is necessary to monitor the condition of patients

Patients with any of the following conditions, present or past, and/or aggravated during pregnancy or previous hormonal therapy, should be closely monitored. It should be borne in mind that these conditions may recur or worsen during treatment with Femoston. These include:

leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic diseases (see below); risk factors for estrogen-sensitive tumors, such as a first-degree hereditary predisposition to breast cancer; arterial hypertension; liver disease (hepatic adenoma); diabetes mellitus with or without vascular symptoms; gallstone disease; migraine or (severe) headache; systemic lupus erythematosus; history of endometrial hyperplasia (see below); epilepsy; bronchial asthma; otosclerosis; meningioma.

Reasons for immediate discontinuation of therapy

Hormone replacement therapy should be discontinued immediately if a contraindication is identified, as well as in the following situations:

the appearance of jaundice or impaired liver function; a significant increase in blood pressure; the appearance of a migraine-like headache for the first time; pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer is increased with long-term use of estrogen-only HRT. The observed increased risk of endometrial cancer in women taking estrogen-only HRT ranges from 2- to 12-fold compared with those not taking estrogen, depending on the duration of treatment and the dose of estrogen (see section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years.

Cyclical combination of estrogen and progestogen for at least 12 days per month/per 28-day cycle or continuous combined estrogen-progestogen therapy in women with a preserved uterus avoids the excess risk associated with estrogen-only use.

Breakthrough uterine bleeding or spotting may occur during the first months of treatment. If they occur some time after the start of treatment or persist after discontinuation of therapy, their cause should be investigated, including by performing an endometrial biopsy to exclude malignancy.

All available evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen HRT, and probably also in women taking oestrogen-only HRT. This risk depends on the duration of use.

Combined estrogen-progestogen therapy

Both the randomised placebo-controlled Women's Health Initiative Study (WHI) and epidemiological studies have consistently shown an increased risk of breast cancer in women using combined oestrogen-progestagen HRT. The increased risk becomes apparent after approximately 3 years (see section 4.8).

Estrogen monotherapy

The WHI trial did not find an increased risk of breast cancer in hysterectomised women taking oestrogen-only HRT. Pilot studies have mostly reported a small increased risk of breast cancer, which is significantly lower than in patients taking combinations of oestrogens and progestogens (see section 4.8).

The increased risk becomes apparent after several years of use and increases with increasing duration of use, but returns to baseline within several (maximum 5) years after cessation of treatment.

Hormone replacement therapy, especially combined estrogen-progestagen therapy, increases the density of mammographic images, which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Epidemiological data from a large meta-analysis have shown a slightly increased risk in women using oestrogen-only or combined oestrogen-progestagen hormone replacement therapy; this risk becomes apparent within 5 years of use and decreases over time after discontinuation of therapy. Some other studies, including the WHI study, suggest that the use of combined HRT may be associated with the same or slightly lower risk (see section 4.8).

Venous thromboembolism

HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This is most likely to occur during the first year of HRT use (see section 4.8).

Patients with known thrombophilic conditions are at increased risk of VTE, and HRT may further increase this risk. Therefore, hormone replacement therapy is contraindicated in this group of patients (see section 4.3).

Generally recognized risk factors for VTE include estrogen use, older age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and carcinoma. There is no consensus on the role of varicose veins in the development of VTE.

As with all postoperative patients, precautions should be taken to prevent VTE after surgery. If prolonged immobilization is expected after elective surgery, it is recommended that HRT be temporarily discontinued 4-6 weeks before surgery. Treatment should not be resumed until the woman has regained full mobility.

Women without a history of VTE but with a first-degree relative who has had thrombosis at a young age may be offered screening after careful discussion of its limitations (screening only detects a subset of thrombophilic disorders).

If a congenital thrombophilic disorder is identified, accompanied by a family history of thrombosis, or if the disorder is severe (e.g., antithrombin, protein S, or protein C deficiency, or a combination of disorders), HRT is contraindicated.

In women already taking regular anticoagulant therapy, the benefits and risks of HRT should be carefully weighed.

If VTE develops after initiation of therapy, the drug should be discontinued immediately. Patients should be advised to seek immediate medical attention if they develop potential symptoms of thromboembolism (e.g. painful swelling of a leg, sudden chest pain, shortness of breath).

Coronary heart disease (CHD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without coronary heart disease who take combined oestrogen-progestagen HRT or oestrogen-only HRT.

Combined estrogen-progestogen therapy

The relative risk of CHD with combined estrogen-progestogen HRT is slightly increased. Since the baseline absolute risk of CHD is largely age-dependent, the number of additional cases of CHD due to estrogen and progestogen use is very small in healthy women close to menopause, but will increase with age.

Estrogen monotherapy

Data from randomized controlled trials have not shown an increased risk of CHD in hysterectomized women taking estrogen monotherapy.

Combined estrogen-progestogen therapy and estrogen monotherapy are associated with an increased risk of ischemic stroke of up to 1.5 times. The relative risk does not change with age or time since menopause. However, as the baseline absolute risk of stroke is largely age-dependent, the overall risk of stroke in women taking HRT will increase with age (see section 4.8).

Other states

Estrogens may cause fluid retention, and therefore patients with impaired cardiac or renal function should be carefully monitored.

Women with pre-existing hypertriglyceridemia should be closely monitored during estrogen replacement therapy or hormone replacement therapy, as in rare cases, women with this condition have had their plasma triglyceride levels rise significantly during estrogen treatment, resulting in pancreatitis.

Estrogens increase thyroxine-binding globulin (TBG), leading to increased circulating thyroid hormones as measured by protein-bound iodine (PBI), T4 levels (by column assay or radioimmunoassay), or T3 levels (by radioimmunoassay). Triiodothyronine (T3) uptake is reduced as a result of increased TGB levels. Free triiodothyronine (T3) and thyroxine (T4) concentrations are not altered. Other serum binding proteins, corticoid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may be increased, leading to increased serum concentrations of corticosteroids and sex hormones. Free and/or biologically active hormone concentrations are not altered. Concentrations of other plasma proteins (angiotensin-renin substrate, alpha-I-antitrypsin, ceruloplasmin) may increase.

HRT does not improve cognitive function. There is no evidence of an increased risk of probable dementia in women who start treatment with combined or estrogen-only products after the age of 65.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Femoston is not a contraceptive.

Ability to influence reaction speed when driving vehicles or other mechanisms

Femoston has no or negligible influence on the ability to drive or use machines.

Use during pregnancy or breastfeeding

Femoston is not indicated for use during pregnancy. If pregnancy occurs during treatment with Femoston, the drug should be discontinued immediately.

There are no adequate data on the use of estradiol/dydrogesterone in women during pregnancy.

The scientific literature has reported that the use of some progestogens has been associated with an increased risk of hypospadias. However, due to confounding factors during pregnancy, it is not possible to definitively determine whether progestogens contribute to the development of hypospadias.

To date, the results of most epidemiological studies on accidental fetal exposure to combinations of estrogens and progestogens indicate no teratogenic or toxic risk to the fetus.

Breast-feeding

Femoston is not indicated for use during breastfeeding.

Impact on the ability to get pregnant.

Femoston is not indicated for use in women of childbearing age.

Method of administration and doses

Femoston is administered orally daily according to a continuous sequential regimen as described below.

Treatment begins with taking one tablet containing 1 mg of estradiol, once a day, every day for the first 14 days of a 28-day cycle.

After that, for the next 14 days, take 1 tablet containing 1 mg of estradiol and 10 mg of dydrogesterone, once a day, as indicated on the 28-day calendar pack.

After the end of the 28-day cycle, on day 29, a new 28-day cycle should be started immediately.

The treatment cycles follow each other and are continuous.

For the treatment of estrogen deficiency in postmenopausal women, the lowest effective dose should be used as initial and maintenance doses, and the duration of treatment should be as short as possible (see also section "Special warnings and precautions for use").

In general, sequential combination treatment should begin with Femoston, estradiol 1 mg + estradiol/dydrogesterone 1 mg/10 mg.

The dose should be individualized based on clinical response.

In women not using HRT or in women switching from continuous combined HRT, treatment can be started on any convenient day. In women switching from cyclic or continuous sequential HRT, treatment should be started immediately on the day after the end of the previous cycle.

If a tablet is missed, it is recommended to continue with the next tablet without taking the missed tablet. If a tablet is missed, the likelihood of breakthrough bleeding or spotting may increase.

Femoston can be taken regardless of meals.

Children

There is no appropriateness of using Femoston for this category of patients.

Overdose

Both estradiol and dydrogesterone are substances of low toxicity. Symptoms of overdose may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding. It is unlikely that any specific or symptomatic treatment will be required in the event of overdose.

The information described above also applies to overdose in children.

Adverse reactions

The most common adverse reactions in patients treated with estradiol/dydrogesterone during clinical trials were headache, abdominal pain, breast pain/tenderness, and back pain.

During clinical trials (n=4929), the adverse reactions listed in Table 3 were observed with the frequencies listed below.

*Adverse reactions reported from spontaneous reports that were not observed during clinical trials are included in the frequency category "rare".

Breast cancer risk

An increased risk of breast cancer diagnosis of up to 2 times has been reported in women taking combined estrogen-progestogen therapy for more than 5 years.

The increased risk in women taking estrogen monotherapy is significantly lower than in women taking combined estrogen-progestogen therapy.

The level of risk depends on the duration of use (see section "Special precautions for use").

Below are the results of the largest randomized placebo-controlled trial, the Women's Health Initiative (WHI), and the largest epidemiological study, the Million Women Study (MWS).

Million Women Study (MWS): estimated additional risk of breast cancer after 5 years of use

WHI study in the US: additional risk of breast cancer after 5 years of use

Endometrial cancer risk

Postmenopausal women with a retained uterus

The risk of endometrial cancer is about 5 cases for every 1000 women with an intact uterus who are not taking HRT.

Oestrogen-only HRT is not recommended for women with an intact uterus, as it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and the dose of oestrogen, the increased risk of endometrial cancer in epidemiological studies has ranged from 5 to 55 additional cases diagnosed in every 1000 women aged 50 to 65 years.

Adding a progestogen to estrogen monotherapy for at least 12 days per cycle may prevent this increased risk. In the Million Women Study, five years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer (hazard ratio 1.0 (0.8–1.2)).

Ovarian cancer

The use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer (see section 4.4).

A meta-analysis of 52 epidemiological studies reported an increased risk of ovarian cancer in women who used HRT compared with women who had never used HRT (hazard ratio 1.43, 95% CI 1.31–1.56). In women aged 50 to 54 years who used HRT for 5 years, this resulted in 1 additional case per 2000 women. In women aged 50 to 54 years who did not use HRT, ovarian cancer is diagnosed in approximately 2 per 2000 women over 5 years.

Risk of venous thromboembolism

HRT is associated with a 1.3- to 3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This is more likely to occur in the first year of HRT use (see section 4.4). The results of the WHI studies are presented below.

WHI study: additional risk of VTE over 5 years of use

(3) Research