Femoston conti mini film-coated tablets 2.5 mg/0.5 mg blister No. 28

Instructions for use Femoston conti mini film-coated tablets 2.5 mg/0.5 mg blister No. 28

Composition

active ingredients: dydrogesterone; estradiol;

1 tablet contains 2.5 mg of micronized dydrogesterone and micronized estradiol hemihydrate, which is equivalent to 0.5 mg of estradiol;

excipients: lactose monohydrate; hypromellose (HPMC 2910); corn starch; colloidal anhydrous silica; magnesium stearate; film coating Yellow 1 (macrogol 3350, polyvinyl alcohol, talc, titanium dioxide (E 171), iron oxide yellow (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, biconvex, yellow tablets, film-coated, with the inscription "379" on one side.

Pharmacotherapeutic group

Preparations for the treatment of diseases of the genitourinary system and sex hormones. Progestogens in combination with estrogens. Dydrogesterone and estrogen. ATX code G03F A14.

Pharmacological properties

Pharmacodynamics

Estradiol

The active ingredient, 17ß-estradiol, is chemically and biologically similar to endogenous human estradiol. Estradiol replaces the loss of estrogen production in menopausal women and alleviates menopausal symptoms.

Dydrogesterone

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

Because estrogens stimulate endometrial growth, estrogen monotherapy increases the risk of endometrial hyperplasia and cancer. The addition of a progestogen to therapy significantly reduces the estrogen-induced risk of endometrial hyperplasia 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.

When taking FEMOSTON® CONTI MINI starting from the 4th week of treatment, the reduction in moderate and severe hot flashes was statistically significant compared to placebo. The number of moderate and severe hot flashes continued to decrease until the end of the treatment period at 13 weeks. In two studies, amenorrhea (absence of bleeding or spotting) was observed in 91% and 88% of women, respectively, during the 10th and 12th months of treatment. Irregular bleeding and/or spotting occurred in 10% and 21% of women during the first 3 months of treatment, and in 9% and 12% during the 10th and 12th months of treatment.

Pharmacokinetics

Estradiol

Absorption

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

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 means (SD).

Table 1

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% is bound to albumin and about 46–69% to sex hormone binding globulin (SHBG).

Metabolism

After oral administration, estradiol is extensively metabolized. The major 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 participate in enterohepatic circulation.

Breeding

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

Dose and time dependence

With daily use of FEMOSTON® CONTI MINI, 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 0.5–1.5 hours.

Table 2 presents the mean steady-state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DH). Data are presented as mean (SD).

Table 2

After a single dose, food delays the peak plasma concentration of dydrogesterone by approximately 1 hour, resulting in a decrease in peak plasma concentrations of dydrogesterone by approximately 20%, without affecting the extent of exposure to dydrogesterone and DHD.

After oral administration of dydrogesterone, the apparent volume of distribution is significant and is approximately 22,000 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.

Metabolism.

After oral administration, dydrogesterone is rapidly metabolized to DHD. The levels of the main active metabolite 20α-dihydrodydrogesterone (DHD) peak at the same time as dydrogesterone. DHD plasma levels are significantly higher than those of the parent compound. The AUC and Cmax ratios of DHD to dydrogesterone are approximately 25 and 20, respectively. The mean terminal half-lives of dydrogesterone and DHD are approximately 15 hours. A common feature of all metabolites is the retention 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. The apparent total plasma clearance of dydrogesterone in the body is high and is approximately 20 l/min. Complete excretion occurs within 72 hours. DHD is present in the urine mainly as a glucuronic acid conjugate.

Dependence on dose and time.

The pharmacokinetics of single and multiple doses are linear in the oral dose range of 2.5 to 20 mg. Comparison of single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD do not change as a result of repeated administration. Steady-state conditions are usually reached after 3 days of treatment.

Indication

Hormone replacement therapy (HRT) to eliminate symptoms caused by estrogen deficiency in postmenopausal women, no earlier than 12 months after the last menstruation.

Contraindication

Known hypersensitivity to the active substances or to any of the excipients.

Previously diagnosed or suspected breast cancer.

Known or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer).

Established or suspected progestogen-dependent neoplasms (e.g. meningioma).

Genital bleeding of unknown etiology.

Untreated endometrial hyperplasia.

Venous thromboembolism (deep vein thrombosis, pulmonary embolism) in the past or present.

Presence of thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, see section "Special warnings and precautions for use").

Acute or recent thromboembolic arterial disease (e.g. angina pectoris, myocardial infarction).

Acute liver disease or history of liver disease if liver function tests have not returned to normal.

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, especially cytochrome P450 enzymes 2B6, 3A4, 3A5, 3A7. Such substances include anticonvulsants (e.g. phenobarbital, carbamazepine, phenytoin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

- Despite the fact that ritonavir and nelfinavir are known as potent inhibitors of CYP450 3A4, A5, A7, when used simultaneously with steroid hormones, they, on the contrary, induce these enzymes.

- Herbal preparations containing St. John's wort (Hypericum perforatum) may increase the metabolism of estrogens and progestogens due to their effect on CYP450 3A4.

- It has been clinically proven that increased metabolism of estrogens and progestogens can lead to a weakening of their effect and a change in the uterine bleeding profile.

The effect of HRT with estrogens on other medications

Hormonal contraceptives containing estrogens have been shown to significantly reduce plasma concentrations of lamotrigine when administered concomitantly with lamotrigine due to stimulation of lamotrigine glucuronidation. This may result in reduced seizure control. Although the potential for interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists that could result in reduced seizure control in women taking both drugs concomitantly.

In clinical trials of hepatitis C virus (HCV) treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, alanine aminotransferase (ALT) elevations greater than 5 times the upper limit of normal were significantly more common in women using ethinyl estradiol-containing medicinal products, such as combined hormonal contraceptives (CHCs). In women using medicinal products containing estrogens other than ethinyl estradiol, such as estradiol, the extent of ALT elevations was similar to that in women not taking any estrogens; however, due to the limited number of women taking other estrogens, caution should be exercised when using this drug concomitantly with ombitasvir/paritaprevir/ritonavir combination therapy with or without dasabuvir, as well as with glecaprevir/pibrentasvir therapy (see section 4.4).

Estrogens may interfere with the metabolism of other drugs

Estrogens may inhibit CYP450 enzymes involved in drug metabolism by competitive inhibition. This should be considered especially for drugs with a narrow therapeutic index, such as:

- tacrolimus and cyclosporine A (CYP450 3A4, 3A3);

- fentanyl (CYP450 3A4);

- theophylline (CYP450 1A2).

Clinically, this may result in increased plasma levels of such substances to toxic concentrations. Thus, careful monitoring of drug levels over a long period of time may be required, as well as dose reduction of tacrolimus, fentanyl, cyclosporine A, and theophylline.

Application features

For the treatment of symptoms associated with postmenopausal women, hormone replacement therapy (HRT) should be initiated only if symptoms are present and adversely affect quality of life. In all cases, a careful risk-benefit analysis should be performed at least annually, and HRT should be continued only if the benefits outweigh the risks.

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

Medical examination/follow-up

Before initiating or reinstituting hormone replacement therapy, a complete personal and family medical history should be taken. A physical examination (including a gynaecological and breast examination) should be performed, taking into account the patient's medical history, contraindications and warnings for the use of this product. Periodic examinations are recommended during treatment, the frequency and extent of which should be determined individually. Women should be advised of any changes in their breasts that they should report to their doctor or nurse (see "Breast cancer" below). Examinations, including appropriate imaging techniques such as mammography, should be performed in accordance with current screening practices, modified according to individual clinical needs.

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® CONTI MINI. These include:

leiomyoma (uterine fibroids) or endometriosis;

risk factors for thromboembolic disorders (see below);

risk factors for estrogen-dependent tumors, such as a first-degree hereditary predisposition to breast cancer;

arterial hypertension;

liver disease (e.g. liver adenoma);

diabetes mellitus with or without vascular complications;

gallstone disease;

migraine or (severe) headache;

systemic lupus erythematosus;

history of endometrial hyperplasia (see below);

epilepsy;

bronchial asthma;

otosclerosis.

Reasons for immediate discontinuation of therapy

Therapy should be discontinued if a contraindication is identified, as well as in the following situations:

the appearance of jaundice or deterioration of liver function;

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 carcinoma is increased when estrogens are used alone for long periods of time. A 2- to 12-fold increased risk of endometrial cancer has been observed in women taking estrogen alone compared with those not taking it, 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.

Breakthrough uterine bleeding or spotting may occur during the first months of treatment. If this occurs some time after the start of treatment or persists after its discontinuation, the cause should be investigated, which may include endometrial biopsy to exclude malignancy.

Breast cancer

Overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestogen or estrogen-only HRT, which depends on the duration of HRT.

Combined estrogen-progestogen therapy

Both the randomised placebo-controlled Women's Health Initiative Study (WHI) and a meta-analysis of prospective epidemiological studies have consistently shown an increased risk of breast cancer in women using combined oestrogen-progestagen HRT, which becomes apparent after approximately 3 (1-4) years (see section 4.8).

Estrogen-only therapy

The Women's Health Initiative study (WHI) did not find an increased risk of breast cancer in hysterectomised women taking oestrogen-only HRT. Observational studies have mostly reported a small increased risk of breast cancer, which is substantially lower than in patients taking combined oestrogen-progestagen (see section 4.8).

The results of a large meta-analysis showed that after stopping treatment, the increased risk will decrease over time, and the time taken to return to baseline depends on the duration of previous HRT use. In cases where HRT has been used for more than 5 years, the risk may persist for 10 years or longer. HRT, 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 a 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 more likely to occur in the first year of HRT than later (see section 4.8).

Patients with known thrombophilic states 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 cancer. There is no consensus on the role of varicose veins in the development of VTE.

As with all postoperative patients, prophylactic measures should be taken to prevent VTE after surgery. If prolonged immobilization is necessary 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 personal history of VTE but with a first-degree relative history of thrombosis at a young age may be offered screening after careful discussion of its limitations (screening only detects a subset of thrombophilic disorders).

HRT is contraindicated if a thrombophilic disorder is identified that is different from the type of thrombosis in family members, or if the disorder is severe (e.g., antithrombin, protein S, or protein C deficiency, or a combination of disorders).

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

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

Coronary heart disease (CHD)

Randomized controlled trials have not provided evidence of protection against myocardial infarction in women with or without coronary heart disease who took combined estrogen-progestogen HRT or estrogen-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.

Data from randomized controlled trials have not shown an increased risk of CHD in women after hysterectomy who receive estrogen-only therapy.

Ischemic stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increased risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline 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 rare cases of significant increases in plasma triglyceride levels, leading to pancreatitis, have been reported in such women with estrogen therapy.

Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Estrogens increase thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone concentrations as measured by protein-bound iodine, thyroxine (by column assay or radioimmunoassay) or triiodothyronine (by radioimmunoassay). Triiodothyronine uptake is reduced, indicating elevated TSH levels. Free thyroxine and triiodothyronine concentrations are unchanged. Serum levels of other binding proteins, corticosteroid-binding globulin and sex hormone-binding globulin, may be increased, leading to increased circulating corticosteroid and sex hormone concentrations, respectively. Free or biologically active hormone concentrations are unchanged. Concentrations of other plasma proteins (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin) may increase.

HRT does not improve cognitive function. There has been some evidence of an increased risk of developing possible dementia in women who start long-term combined or oestrogen-only HRT after the age of 65.

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

Combined estrogen/progestin therapy is not a method of contraception.

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

Elevated ALT levels

In clinical trials in patients treated for hepatitis C virus (HCV) infection with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal were significantly more common in women using ethinyl estradiol-containing medicinal products, such as combined hormonal contraceptives (CHCs). In addition, ALT elevations were also observed in women using ethinyl estradiol-containing medicinal products, such as CHCs, also in patients treated with glecaprevir/pibrentasvir. In women using medicinal products containing estrogens other than ethinyl estradiol, such as estradiol, the extent of ALT elevations was similar to that in women not taking any estrogens; however, due to the limited number of women taking other estrogens, caution should be exercised when using this drug concomitantly with ombitasvir/paritaprevir/ritonavir combination therapy with or without dasabuvir, as well as with glecaprevir/pibrentasvir therapy (see section 4.5).

Use during pregnancy or breastfeeding

FEMOSTON® CONTI MINI is not indicated for use during pregnancy. If pregnancy occurs during treatment with FEMOSTON® CONTI MINI, the drug should be discontinued immediately.

To date, the results of most epidemiological studies on the accidental exposure of the fetus to a combination of estrogens and progestogens indicate the absence of a teratogenic or fetotoxic effect.

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

Breast-feeding

FEMOSTON® CONTI MINI is not indicated for use during breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

FEMOSTON® CONTI MINI has no or negligible influence on the ability to drive and use machines.

Method of administration and doses

For oral administration.

Long-term use of the combination: estrogen and progestin are taken daily without a break. You should take one tablet per day for a 28-day cycle.

FEMOSTON® CONTI MINI should be taken continuously, without interruption in taking tablets from different packs.

Long-term combination therapy can be started with FEMOSTON® CONTI MINI or FEMOSTON® CONTI depending on the time elapsed since the onset of menopause and the severity of symptoms.

Depending on the clinical response, the dosage may subsequently be adjusted according to individual needs.

Patients switching from long-term sequential or cyclical use of other drugs should complete a 28-day treatment cycle, after which they can switch to FEMOSTON® CONTI MINI. Patients switching from long-term use of combination drugs can start treatment with FEMOSTON® CONTI MINI at any time.

If a tablet is missed, it should be taken as soon as possible. If more than 12 hours have passed, treatment should be continued with the next tablet without taking the missed dose. In such cases, the likelihood of breakthrough bleeding or spotting may be increased.

FEMOSTON® CONTI MINI can be taken regardless of meals.

Children

The drug is not intended for use in children.

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 symptomatic treatment will be required in case of overdose. This also applies to cases of 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=5108), adverse reactions were observed and are grouped in Table 3 by corresponding frequency.

Table 3

* See below for more information.

Breast cancer risk

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

The increased risk in patients receiving estrogen monotherapy is lower than in those receiving combined estrogen-progestogen therapy.

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

Below is an estimate of the absolute risk based on the results of the largest randomized placebo-controlled trial, the Women's Health Initiative (WHI), and the largest meta-analysis of prospective epidemiological studies.

Largest meta-analysis of prospective epidemiological studies

Table 4

Estimated additional risk of breast cancer after 5 years of use in women with a body mass index of 27 kg/m2

Table 5

Estimated additional risk of breast cancer after 10 years of use in women with a body mass index of 27 kg/m2

Table 6

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.

Estrogen-only HRT is not recommended in women with a uterus due to an increased risk of endometrial cancer (see section 4.4). Depending on the duration of estrogen-only use and the dose of estrogen, 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-only therapy for at least 12 days per cycle may prevent this increased risk. In the Million Women Study (MWS), 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 having ovarian cancer diagnosed (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 had used HRT for 5 years, this resulted in 1 additional case per 2000 women. In women aged 50 to 54 years who had not used HRT, approximately 2 per 2000 women would be diagnosed with ovarian cancer over 5 years.

Risk of venous thromboembolism

HRT is associated with a 1.3–3-fold increase in the relative risk of developing venous thromboembolism.