Femoston^® mini (Tablets) Instructions for Use

Marketing Authorization Holder

Abbott Healthcare Products, B.V. (Netherlands)

Manufactured By

Abbott Biologicals, B.V. (Netherlands)

Contact Information

ABBOTT LABORATORIES LLC (Russia)

ATC Code

G03FA14 (Dydrogesterone and estrogens)

Active Substances

Dydrogesterone (Rec.INN registered by WHO)

Estradiol (Rec.INN registered by WHO)

Dosage Form

Femoston® mini

Film-coated tablets, 2.5 mg+0.5 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex, engraved with “379” on one side; the appearance of the tablet on the cross-section: white, rough surface.

Excipients: lactose monohydrate, hypromellose (HPMC 2910), corn starch, colloidal anhydrous silicon dioxide, magnesium stearate; film coating film coating YELLOW 1* (macrogol 3350, polyvinyl alcohol, talc, titanium dioxide (E171), yellow iron oxide (E172)).

* A ready-made film coating of identical composition may be used, for example, Opadry^® II yellow 85F32331.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; gestagens in combination with estrogens; gestagens and estrogens, fixed combinations

Pharmacological Action

The drug Femoston^® mini is a combined drug for HRT and contains 2 active substances: the estrogen estradiol and the progestagen Dydrogesterone.

Estradiol

One of the active substances of the drug is synthetic 17β-estradiol, identical in chemical composition and biological action to the endogenous female human sex hormone estradiol. Estradiol compensates for the deficiency of estrogens in the body of a postmenopausal woman and relieves menopausal symptoms within the first weeks of therapy.

Dydrogesterone

The progestagen Dydrogesterone is effective when taken orally and has activity similar to parenterally administered progesterone. When used in HRT, the use of dydrogesterone provides full secretory transformation of the endometrium, thereby reducing the risk of endometrial hyperplasia against the background of estrogen intake in women with an intact uterus.

Information obtained from clinical studies

Effect on the severity of menopausal symptoms

When prescribing the drug Femoston^® mini, relief of menopausal symptoms was achieved within the first weeks of treatment: a reduction in the frequency of moderate and severe “hot flashes” was statistically significant compared to placebo, starting from the 4th week of therapy. The number of moderate and severe “hot flashes” further decreased until the cessation of therapy at the 13th week.

Effect on the severity of symptoms associated with estrogen deficiency and the nature of bleeding

Clinical studies have shown that the drug Femoston^® mini provides relief of symptoms associated with estrogen deficiency and the nature of bleeding. In two studies, amenorrhea (absence of bleeding and spotting) was observed in 91% and 88% of women, respectively, within 10-12 months from the start of treatment. Irregular bleeding or spotting occurred in 10% and 21% of women, respectively, during the first 3 months of treatment and in 9% and 12% during 10-12 months from the start of treatment.

Pharmacokinetics

Estradiol

Absorption

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

The table below shows the steady-state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulfate (E1S) for an estradiol dose of 0.5 mg.

Distribution

Estrogen can be found in both bound and free states. About 98-99% of the estradiol dose binds to plasma proteins, of which 30-52% binds to albumin and about 46-69% binds to sex hormone-binding globulin (SHBG).

Metabolism

After oral administration, estradiol is actively metabolized. The main unconjugated and conjugated metabolites are estrone and estrone sulfate. These metabolites can exhibit estrogenic activity themselves or after conversion to estradiol. Estrone sulfate may undergo intrahepatic metabolism.

Excretion

Estrone and estradiol are excreted in the urine, mainly in the form of glucuronides. T_1/2 is 10-16 h.

Estrogens are excreted in the milk of nursing mothers.

Time to reach steady-state concentration

With daily oral administration of the drug tablets at a dose of 0.5 + 2.5 mg, C_ss of estradiol is achieved after 5 days of administration, most often by days 8-11.

Dydrogesterone

Absorption

After oral administration, Dydrogesterone is rapidly absorbed. The T_max value for dydrogesterone is from 0.5 to 1.5 h. The absolute bioavailability of dydrogesterone at a dose of 20 mg orally (compared to 7.8 mg IV) is 28%.

The table below shows the pharmacokinetic parameters of dydrogesterone (D) and 20α-dihydrodydrogesterone (DHD) for dydrogesterone at a dose of 2.5 mg.

After a single dose, food delays the C_max of dydrogesterone in plasma by about 1 h, which leads to a decrease in the C_max of dydrogesterone in plasma by about 20%, without affecting the extent of exposure of dydrogesterone and DHD.

Distribution

After oral administration of dydrogesterone, the apparent V_d is significant and is about 22000 L. Dydrogesterone and DHD bind to plasma proteins by more than 90%.

Metabolism

After oral administration, Dydrogesterone is rapidly metabolized to DHD. The concentration of the main metabolite 20α-dihydrodydrogesterone (DHD) peaks at the same time as Dydrogesterone. The concentration of DHD in plasma is significantly higher than that of dydrogesterone. The AUC and C_max ratios of DHD and dydrogesterone are approximately 25 and 20, respectively. The mean T_1/2 of dydrogesterone and DHD is about 15 h. A common characteristic of all metabolites of dydrogesterone is the preservation of the 4,6-diene-3-one configuration of the parent substance and the absence of 17α-hydroxylation. This explains the absence of estrogenic and androgenic effects of dydrogesterone.

Excretion

After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted in the urine. The apparent total clearance of dydrogesterone from plasma in the body is high and is approximately 20 L/min. Complete elimination of dydrogesterone occurs within 72 h. DHD is excreted in the urine mainly in the form of a glucuronic acid conjugate.

Time to reach steady-state concentration

The pharmacokinetics are linear, both after single and multiple dosing in the range from 2.5 to 20 mg. Comparison of single and multiple dose kinetics shows that the pharmacokinetics of D and DHD do not change as a result of repeated dose administration.

C_ss was usually achieved after 3 days of treatment.

Indications

• Menopausal hormone therapy (HRT) for disorders caused by estrogen deficiency in postmenopausal women (not earlier than 12 months after the last menstruation).

ICD codes

Dosage Regimen

The tablets should be taken orally with water, regardless of meals, preferably at the same time of day.

HRT with the drug Femoston^® mini for natural menopause should not be started earlier than 12 months after the last menstruation. In the case of menopause after surgery (bilateral oophorectomy, hysterectomy with appendages), treatment can be started immediately after the operation (as prescribed by a doctor if symptoms are present).

Each package is designed for a 28-day course of the drug.

The drug Femoston^® mini is taken daily for 28 days in a continuous regimen, 1 tablet/day. Immediately after the end of the 28-day cycle, you should start taking Femoston^® mini from a new package.

To initiate and continue HRT for disorders associated with estrogen deficiency, the combination of Dydrogesterone + estradiol should be used at the lowest effective dose and for the shortest period of time.

Combined HRT in a continuous regimen can be started with the drug Femoston^® mini depending on the time since menopause and the severity of estrogen deficiency symptoms. If necessary, the hormone dose can be adjusted accordingly in the future.

When switching from another HRT drug with a continuous sequential or cyclic regimen, the current cycle should be completed and the switch to Femoston^® mini should be made the next day after completion.

For patients who have not previously received HRT, or when switching from another continuous combined HRT regimen, Femoston^® mini can be started on any day.

If a patient misses a tablet, it should be taken within 12 hours of the usual time of administration. If more than 12 hours have passed, the missed tablet should not be taken, and the next tablet should be taken at the usual time the next day. Missing a dose may increase the likelihood of “breakthrough” uterine bleeding or “spotting”.

Special patient groups

Experience with the drug in elderly patients (≥65 years) is limited.

There are no indications for the use of the drug Femoston^® mini in children and adolescents under 18 years of age.

Adverse Reactions

In clinical studies of patients receiving therapy with the combination estradiol + Dydrogesterone, the most common were: headache, abdominal pain, breast tension/tenderness and back pain.

Adverse reactions possible during therapy with the combination Dydrogesterone + estradiol are distributed by system-organ class with an indication of the frequency of their occurrence according to WHO recommendations: very common (>1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from available data).

* Adverse effects obtained from spontaneous reports were included in the “rare” frequency.

Other adverse reactions caused by the use of the combination of estrogen and progestagen (including estradiol + Dydrogesterone)

Benign, malignant and unspecified neoplasms estrogen-dependent benign and malignant neoplasms, incl. endometrial cancer and ovarian cancer; increase in the size of progestagen-dependent neoplasms, incl. meningioma.

Immune system disorders systemic lupus erythematosus.

Metabolism and nutrition disorders hypertriglyceridemia, worsening of concomitant porphyria.

Nervous system disorders risk of developing dementia, chorea, provocation of epileptic seizures.

Vascular disorders arterial thromboembolism.

Gastrointestinal disorders pancreatitis (in patients with hypertriglyceridemia).

Skin and subcutaneous tissue disorders erythema multiforme.

Renal and urinary disorders urinary incontinence, cystitis.

Reproductive system and breast disorders: fibrocystic mastopathy, cervical erosion.

Laboratory and instrumental data increased concentration of thyroid hormones in plasma.

Risk of developing breast cancer

A 2-fold increase in the risk of diagnosing breast cancer has been reported in women taking combined estrogen-progestagen therapy for more than 5 years. The increased risk in those receiving estrogen-only therapy is lower than in those receiving combined estrogen-progestagen therapy. The level of risk depends on the duration of drug use (see section “Special Instructions”).

The following are estimated absolute risk values determined from the results of the largest randomized placebo-controlled trial (WHI study) and the largest meta-analysis of prospective epidemiological studies.

Largest meta-analysis of prospective epidemiological studies

Estimated additional risk of breast cancer after 5 years of treatment in women with BMI 27 (kg/m²)

Note since the incidence of breast cancer varies in EU countries, the number of additional cases of breast cancer also changes proportionally.

Estimated additional risk of breast cancer after 10 years of use in women with BMI 27 (kg/m²)

* Based on the background incidence in women with BMI 27 (kg/m2) in England in 2015.

Note since the baseline incidence of breast cancer varies in each European Union country, the number of additional breast cancer cases will also differ proportionally.

WHI studies (USA) – additional risk of breast cancer after 5 years of use

¹When the analysis was limited to women who had never used HRT prior to study enrollment, no increased risk was found during the first 5 years of treatment; after 5 years, the risk was higher than in never-users of HRT.

² Group of women in the WHI study with a hysterectomy, where no increased risk of breast cancer was found.

Endometrial cancer (EC)

Postmenopausal women with an intact uterus. The risk of EC is approximately 5 cases per 1000 women with a uterus not using HRT. Women with a uterus are not recommended estrogen-only HRT preparations, as this increases the risk of EC. Depending on the duration of estrogen-only therapy and the dose, the increased risk of EC according to epidemiological studies ranges from 5 to 55 additional diagnosed cases per 1000 women aged 50-65 years. Adding a progestogen to estrogen-only therapy for at least 12 days per cycle significantly reduces this increased risk. In the MWS (Million Women Study), the use of combined (cyclic or continuous) HRT regimens for 5 years did not increase the risk of endometrial cancer (relative risk – 1 (0.8-1.2)).

Ovarian cancer

Use of estrogen-only HRT or combined estrogen and progestogen HRT was associated with a slight increase in the risk of diagnosed ovarian cancer. Data from a meta-analysis of 52 epidemiological studies indicate an increased risk of developing ovarian cancer in women currently using HRT compared to women who never used HRT (hazard ratio 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking HRT for 5 years, this resulted in approximately one additional case per 2000 patients. In women aged 50 to 54 years who do not take HRT, approximately two women per 2000 are diagnosed with ovarian cancer over 5 years.

Risk of venous thromboembolism (VTE)

With HRT, the relative risk of VTE, i.e., deep vein thrombosis of the lower extremities or pulmonary embolism, increases by 1.3-3.0 times. This complication is more likely in the first year of HRT than in subsequent years. The results of the WHI study are presented below.

WHI studies (USA). Additional risk of VTE over 5 years of use

¹Studies involving women with a history of hysterectomy.

Risk of coronary heart disease is slightly increased in the group of combined HRT users over 60 years of age.

Risk of ischemic stroke

Use of estrogen-only and combined HRT preparations is associated with an increase in the relative risk of developing ischemic stroke by up to 1.5 times. The risk of hemorrhagic stroke does not increase during HRT.

The relative risk does not depend on age or duration of HRT, but since the baseline risk is highly dependent on age, the overall risk of stroke in women on HRT increases with age.

WHI studies, combined. Additional risk of ischemic stroke¹ over 5 years of use

¹Ischemic and hemorrhagic stroke are not separated.

Contraindications

• Hypersensitivity to dydrogesterone, estradiol and/or to any excipient in the preparation;
• Pregnancy and breastfeeding period ("Pregnancy and lactation");
• Diagnosed or suspected breast cancer, or history of;
• Diagnosed or suspected estrogen-dependent malignant neoplasms (e.g., endometrial cancer);
• Diagnosed or suspected progestogen-dependent neoplasms (e.g., meningioma);
• Vaginal bleeding of unknown etiology;
• Untreated endometrial hyperplasia;
• Current or history of thrombosis (arterial and venous) and thromboembolism (including thrombosis, deep vein thrombosis, pulmonary embolism; myocardial infarction, angina);
• Identified hereditary or acquired predisposition to arterial or venous thrombosis/thromboembolism, e.g., antithrombin III deficiency, protein C deficiency, protein S deficiency (see section "Special Precautions");
• Current or history of acute or chronic liver diseases (until liver function tests normalize), including malignant liver tumors (see sections "Special Precautions" and "Pharmacokinetics");
• Porphyria;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Use of Femoston^® mini should be stopped immediately if contraindications are identified and/or if the following conditions occur

• Jaundice and/or liver function disorders;
• Uncontrolled arterial hypertension;
• Migraine-like headache occurring for the first time during use of HRT preparations;
• Pregnancy.

With caution

Use of HRT preparations, including Femoston^® mini, requires medical supervision in the presence of any of the following diseases/conditions and risk factors

• Uterine leiomyoma, endometriosis;
• Risk factors for developing venous thromboembolism (VTE);
• Presence of risk factors for estrogen-dependent tumors (e.g., first-degree relatives with breast cancer);
• Arterial hypertension;
• Benign liver tumors;
• Diabetes mellitus, both with and without vascular complications;
• Cholelithiasis;
• Migraine or severe headache;
• Systemic lupus erythematosus;
• History of endometrial hyperplasia;
• Epilepsy;
• Bronchial asthma;
• Otosclerosis.

It should be taken into account that these diseases/conditions and risk factors may recur or worsen during therapy with Femoston^® mini.

Use in Pregnancy and Lactation

Pregnancy

Use of Femoston^® mini during pregnancy is contraindicated.

If pregnancy occurs during use of the preparation, its use should be discontinued immediately.

Results of most epidemiological studies analyzing data on unintentional use of estrogen and progestogen combinations by pregnant women in early pregnancy indicate no teratogenic or fetotoxic effects of the preparations. Available data on the use of the Dydrogesterone + estradiol combination by pregnant women are limited.

Breastfeeding period

Use of Femoston^® mini during breastfeeding is contraindicated.

Fertility

Femoston^® mini is not used in women of reproductive age.

Use in Hepatic Impairment

Current or history of acute or chronic liver diseases (until liver function tests normalize) is a contraindication to the use of the preparation.

Use in Renal Impairment

Estrogens may cause fluid retention in the body, so patients with impaired renal function should be under medical supervision.

Pediatric Use

There are no indications for the use of Femoston^® mini in children.

Geriatric Use

Experience with the use of the preparation in elderly patients (≥65 years) is limited.

Special Precautions

The preparation is prescribed only in the presence of symptoms that adversely affect the woman’s quality of life. Therapy should be continued as long as the benefit from taking the preparation outweighs the risk of adverse reactions.

Experience with the use of the preparation in women over 65 years of age is limited.

Data on risks associated with HRT in the case of premature menopause are limited. Due to the low level of absolute risk in younger women, the benefit-risk ratio may be more favorable in them than in older women.

Medical examination

Before prescribing or resuming therapy with Femoston^® mini, a complete medical and family history must be taken and a general and gynecological examination (including breast examination) of the patient must be performed to identify possible contraindications and conditions requiring precautions. During treatment with Femoston^® mini, periodic examinations are recommended, the frequency and nature of which are determined individually, but not less than once every 6 months. Instrumental examination methods (e.g., mammography) are advisable for additional breast examination. Women should be informed about possible changes in the breasts that need to be reported to the attending physician (see subsection ‘Breast cancer’).

Use of estrogens may affect the results of the following laboratory tests: glucose tolerance test, thyroid and liver function tests.

Conditions that require medical supervision

Use of HRT preparations, including Femoston^® mini, requires medical supervision in the presence of any of the following diseases/conditions and risk factors

• Uterine leiomyoma, endometriosis;
• Risk factors for developing venous thromboembolism (VTE);
• Presence of risk factors for estrogen-dependent tumors (e.g., first-degree relatives with breast cancer);
• Arterial hypertension;
• Benign liver tumors;
• Diabetes mellitus, both with and without vascular complications;
• Cholelithiasis;
• Migraine or severe headache;
• Systemic lupus erythematosus;
• History of endometrial hyperplasia;
• Epilepsy;
• Bronchial asthma;
• Otosclerosis.

It should be taken into account that these diseases/conditions and risk factors may recur or worsen during therapy with Femoston^® mini.

Endometrial hyperplasia and cancer

In women with an intact uterus, the risk of developing endometrial hyperplasia and cancer increases with long-term estrogen-only therapy. The risk of developing endometrial cancer in patients using estrogen-only therapy depends on the dose and duration of treatment and increases from 2 to 12 times compared to patients not receiving therapy (see section "Adverse Reactions"); the risk may remain elevated for up to 10 years after discontinuation of therapy.

In women with an intact uterus, the use of estrogen-only HRT preparations is not recommended due to the increased risk of endometrial cancer.

Cyclic use of a progestogen (for at least 12 days of a 28-day cycle), or use of combined HRT preparations in a continuous regimen in women with an intact uterus can prevent the estrogen-induced increased risk of hyperplasia and endometrial cancer.

For timely diagnosis, ultrasound screening is advisable, and if necessary, histological (cytological) examination should be performed.

During the first months of treatment with the preparation, "breakthrough" bleeding and/or scanty bloody vaginal discharge may occur. If such bleeding appears some time after the start of therapy or continues after discontinuation of treatment, their cause should be determined. Endometrial biopsy may be performed to rule out malignancy.

Breast cancer (BC)

Results of clinical studies indicate an increased risk of developing BC in women receiving HRT with estrogen monotherapy or combined preparations (estrogen + progestogen). This risk depends on the duration of HRT. In women taking combined HRT preparations for more than 5 years, the risk of developing BC may increase up to 2 times.

HRT with combined (estrogen+progestogen) preparations. A randomized placebo-controlled study (the Women’s Health Initiative (WHI) study) and a meta-analysis of prospective epidemiological studies showed an increased risk of developing BC in women taking HRT with combined (estrogen + progestogen) preparations. The increased risk of BC is observed after approximately 3 (1-4) years of HRT (see section "Adverse Reactions").

Estrogen-only therapy . According to the WHI study, no increased risk of developing BC was observed in women with prior hysterectomy receiving estrogen-only HRT.

Data from the results of a large meta-analysis indicate a decrease in the increased risk of BC after discontinuation of HRT. The time required for the risk to return to baseline depends on the duration of therapy. If HRT was used for more than 5 years, the increased risk of developing BC may persist for 10 years or more.

Most observational studies have shown a small increase in the risk of BC, and this risk was significantly lower in women taking combined estrogen-progestogen therapy (see section "Adverse Reactions").

During HRT, especially HRT with combined (estrogen + progestogen) preparations, an increase in breast tissue density is observed during mammography, which may complicate the diagnosis of BC.

Ovarian cancer

Ovarian cancer is much less common than BC. Epidemiological data from a large-scale meta-analysis indicate a slight increase in the risk of developing ovarian cancer in women receiving HRT with both combined preparations and estrogen-only preparations. According to the studies conducted, the risk of developing ovarian cancer increases with therapy duration of more than 5 years, and gradually decreases after its discontinuation.

Results of a number of other studies, including WHI, indicate that combined HRT is associated with a similar or slightly lower risk of developing ovarian cancer (see section "Adverse Reactions").

Venous thromboembolism

HRT is associated with a 1.3-3-fold risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. This phenomenon is most likely during the first year of HRT.

If there is a family history of thrombosis/thromboembolism in first-degree relatives under 50 years of age, as well as a history of recurrent pregnancy loss, a hemostasis study should be performed (only part of the coagulation system disorders are detected during screening).

A thorough assessment of the expected benefit versus possible risk is necessary in patients taking anticoagulant drugs on a continuous basis.

If a thrombophilic condition is identified in a family member and/or in case of the seriousness or severity of the defect (e.g., antithrombin III deficiency, protein S or C deficiency, or a combination of defects), Femoston^® mini is contraindicated (see section "Contraindications").

Since patients with diagnosed thrombophilic conditions have an increased risk of developing venous thromboembolism, prescribing Femoston^® mini, which increases this risk, is contraindicated.

In most cases, risk factors for VTE include: use of estrogens, advanced age, major surgical interventions, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy or postpartum period, systemic lupus erythematosus and cancer. There is no consensus on the possible role of varicose veins in the development of VTE.

In the postoperative period, VTE prophylaxis is mandatory. To prevent VTE in case of prolonged immobilization after surgery, major surgery, surgery on the lower limbs, pelvic area or neurosurgery, extensive trauma, use of the preparation is stopped and resumed only after the woman has fully regained mobility. In case of planned surgery, use of the preparation is stopped 4-6 weeks before surgery.

If VTE develops after the start of therapy, then the preparation should be discontinued, and patients should be informed that they must immediately consult their doctor if any possible symptoms of thrombosis/thromboembolism occur (e.g., pain or swelling in the lower limbs, sudden chest pain, shortness of breath).

Coronary heart disease (CHD)

Randomized controlled clinical trials found no evidence of a protective effect of HRT against myocardial infarction in women with/without CHD who received HRT with combined (estrogen + progestogen) preparations or estrogen-only.

HRT with combined (estrogen+progestogen) preparations. The relative risk of CHD during use of HRT with combined (estrogen + progestogen) preparations is slightly increased. Since the absolute risk of CHD is highly dependent on age, the number of additional cases of CHD due to the use of HRT with combined (estrogen + progestogen) preparations in healthy premenopausal women is very small, but it increases with age.

The risk is slightly higher in women over 60 years of age.

Risk of ischemic stroke

Combined estrogen and progestogen therapy or estrogen-only therapy is associated with an increase in the relative risk of ischemic stroke by 1.5 times. The risk of hemorrhagic stroke does not increase with the use of HRT preparations. The relative risk does not depend on age or time of menopause onset, however, the baseline risk is highly dependent on age, thus the overall risk of stroke in women receiving HRT will increase with age (see section "Adverse Reactions").

Hepatitis C/Elevated ALT

During clinical trials with female patients receiving treatment for hepatitis C virus (HCV) infections with the ombitasvir/paritaprevir/ritonavir combination regimen with or without dasabuvir, an increase in ALT exceeding the upper limit of normal by more than 5 times was significantly more frequent in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives.

Furthermore, among patients receiving glecaprevir/pibrentasvir, elevated ALT activity was also observed in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives. In women using medicinal products containing estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was the same as in women not receiving any estrogens; however, due to the limited number of women taking estradiol-type estrogens, caution should be exercised during the concomitant use of ombitasvir/paritaprevir/ritonavir with the combination regimen consisting of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with the regimen consisting of glecaprevir/pibrentasvir (see the “Drug Interactions” section).

Other Conditions

Estrogens may cause fluid retention, which may adversely affect patients with impaired renal and cardiac function. This group of patients should be under medical supervision.

In patients with hypertriglyceridemia, while taking MHT drugs, plasma triglyceride concentrations may increase significantly in very rare cases, contributing to the development of pancreatitis.

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

Estrogens increase the concentration of thyroxine-binding globulin, leading to a general increase in the concentration of circulating thyroid hormones, as measured by protein-bound iodine assay, thyroxine (T4) concentration – chromatographic or radioimmunoassay, or triiodothyronine (T3) – radioimmunoassay. The labeled triiodothyronine uptake test shows an increased level of thyroxine-binding globulin. Free T3 and T4 hormone concentrations remain unchanged. The concentrations of other binding proteins in the blood plasma (e.g., transcortin, sex hormone-binding globulin) may also increase, leading to an increase in the concentration of circulating glucocorticosteroids and sex hormones.

The concentrations of free or biologically active hormones do not change. An increase in the concentration of other plasma proteins (renin-angiotensin system, α-1-antitrypsin, ceruloplasmin) is possible.

The use of MHT does not improve cognitive function. There are reports of an increased risk of dementia in women who started MHT (combined or estrogen-only) after the age of 65.

Patients with lactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

Femoston^® mini is not a contraceptive.

Effect on the Ability to Drive and Operate Machinery

The drug does not have a significant effect on the ability to drive vehicles and operate machinery.

Overdose

Estradiol and Dydrogesterone are substances with low toxicity.

Symptoms Nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/weakness, withdrawal bleeding may occur.

Treatment Symptomatic therapy should be administered.

The information above also applies in case of unintentional overdose in children due to accidental ingestion of the drug.

Drug Interactions

Effect of Other Medicinal Products on the Estrogen + Progestogen Combination

The metabolism of estrogen and progestogen may be enhanced when taken concomitantly with drugs that induce hepatic microsomal cytochrome P450 enzymes (isoenzymes CYP2B6, 3A4, 3A5, 3A7): anticonvulsants (phenobarbital, carbamazepine, phenytoin) and antimicrobial drugs (rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors of CYP3A4, A5, A7, may enhance the metabolism of sex hormones when used concomitantly.

Herbal preparations containing St. John’s wort (Hypericum perforatum) may enhance the metabolism of estrogen and progestogen.

Enhanced metabolism of estrogens and progestogens may clinically manifest as a reduction in the drug’s effect and changes in the intensity of vaginal bleeding.

Effect of MHT with Estrogens on Other Medicinal Products

Hormonal contraceptives containing estrogens have been reported to significantly reduce lamotrigine plasma concentrations when used concomitantly due to enhanced lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between MHT drugs and lamotrigine has not been studied, a similar interaction is expected to exist and may lead to reduced seizure control in women during concomitant use.

Pharmacodynamic Drug Interaction

During clinical trials in female patients with hepatitis C virus receiving the combined treatment regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, an increase in ALT exceeding the upper limit of normal by more than 5 times was significantly more frequent in women using medicinal products containing ethinylestradiol, such as combined hormonal contraceptives. In women using medicinal products that contain estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was the same as in women not receiving any estrogens; however, due to the limited number of women taking estradiol-type estrogens, caution should be exercised during the concomitant use of ombitasvir/paritaprevir/ritonavir with the combination regimen consisting of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with the regimen consisting of glecaprevir/pibrentasvir (see the “Special Instructions” section).

Effect of Estrogen on Other Medicinal Products

Estrogens may affect the metabolism of other medicinal products by competitively binding to cytochrome P450 (CYP) isoenzymes involved in their biotransformation. This must be considered for drugs with a narrow therapeutic index, such as tacrolimus and cyclosporine A (CYP3A4, 3A3), fentanyl (CYP3A4), and theophylline (CYP1A2), as this type of interaction can lead to an increase in the plasma concentration of the aforementioned drugs to toxic levels. Consequently, careful monitoring of drug intake over a long period may be required, and possibly a reduction in the dose of tacrolimus, fentanyl, cyclosporine A, and theophylline.

No studies on interactions with other medicinal products have been conducted.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 4 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.