Femoston conti

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FEMOSTON® CONTI (FEMOSTON® CONTI)

Composition:

Active substances: estradiol; dydrogesterone;

1 tablet contains micronized estradiol hemihydrate equivalent to 1 mg of estradiol; micronized dydrogesterone 5 mg;

Excipients: lactose monohydrate; hypromellose (HPMC 2910); corn starch; colloidal anhydrous silicon dioxide; magnesium stearate;

Film coating: Combined film coating Orange I (polyethylene glycol 400, hypromellose (HPMC 2910), iron oxide yellow (E 172), iron oxide red (E 172), titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablet of orange-pink color with the imprint "379" on one side. Diameter 7 mm, tablet weight approximately 144 mg.

Pharmacotherapeutic group. Medicinal products for treatment of disorders of the genitourinary system and sex hormones. Progestogens in combination with estrogens. Dydrogesterone and estrogen. ATC code G03F A14.

Pharmacological Properties.

Pharmacodynamics.

Estradiol

The active component, 17ß-estradiol, is chemically and biologically identical to the natural female sex hormone estradiol. It replaces the declining endogenous estrogen production in menopausal women and alleviates menopausal symptoms.

Estrogens prevent bone mass loss following menopause or oophorectomy.

Dydrogesterone

Dydrogesterone is an orally active progestagen with activity comparable to that of parenterally administered progesterone.

Since estrogens stimulate endometrial growth, if a progestagen is not co-administered, they increase the risk of endometrial hyperplasia and carcinoma. Adding a progestagen to estrogen therapy significantly reduces the estrogen-induced risk of endometrial hyperplasia in women with an intact uterus.

Clinical Trial Data

Reduction of Estrogen Deficiency Symptoms and Improvement of Bleeding Profile

Reduction of menopausal symptoms was observed within the first few weeks of treatment.

Amenorrhea (absence of bleeding and spotting) was observed in 88% of women during the 10th–12th month of treatment. Irregular bleeding and/or spotting occurred in 15% of women during the first 3 months of treatment and in 12% during the 10th–12th month 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 of estrogens persists only during their administration. After discontinuation of hormone replacement therapy (HRT), the rate of bone mass decline is similar to that in women who did not receive such therapy.

Data from the WHI (Women's Health Initiative) study and meta-analyses of other trials indicate that HRT use in predominantly healthy women, either as estrogen monotherapy or in combination with a progestagen, reduces the risk of fractures of the hip, vertebrae, and other fractures associated with osteoporosis. HRT may also prevent fractures in women with low bone density and/or diagnosed osteoporosis, although data in this regard are limited.

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

FEMOSTONE®CONTI also affected bone mineral density at the femoral sites. After one year of treatment with FEMOSTONE®CONTI, bone mineral density at the femoral neck was 1.5% ± 4.5% (mean ± SD), at the trochanter 3.7% ± 6.0% (mean ± SD), and at Ward's triangle 2.1% ± 7.2% (mean ± SD).

The percentage of women in whom bone mineral density was maintained or increased at these three femoral sites after treatment with FEMOSTONE®CONTI was 71%, 66%, and 81%, respectively.

Pharmacokinetics.

Estradiol

Absorption

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

The table presents 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).

Estradiol 1 mg

	E2	E1	Parameters	E1S
Cmax (pg/mL)	71 (36)	310 (99)	Cmax (ng/mL)	9.3 (3.9)
Cmin (pg/mL)	18.6 (9.4)	114 (50)	Cmin (ng/mL)	2.099 (1.340)
Cav (pg/mL)	30.1 (11.0)	194 (72)	Cav (ng/mL)	4.695 (2.350)
AUC0-24 (pg·h/mL)	725 (270)	4767 (1857)	AUC0-24 (ng·h/mL)	112.7 (55.1)

Distribution

Estrogens may be present in either free or bound form. Approximately 98–99% of an estradiol dose is bound to plasma proteins, of which 30–52% is bound to albumin and about 46–69% to sex hormone-binding globulin (SHBG).

Biotransformation

After oral administration, estradiol is extensively metabolized. The main 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 recirculation.

Elimination

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

Dose- and time-dependence

With daily oral administration of the drug, estradiol concentrations reach steady state levels after approximately 5 days. In most cases, steady-state concentrations are achieved between days 8 and 11 of treatment.

Dydrogesterone

Absorption

After oral administration, dydrogesterone is rapidly absorbed, with a Tmax between 0.5 and 1.5 hours.

The following table presents mean steady-state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD). Data are presented as mean (SD).

Dydrogesterone 5 mg

	D	DGD
Cmax (ng/ml)	0.90 (0.59)	24.68 (10.89)
AUC0-t (ng*hr/ml)	1.55 (1.08)	98.37 (43.21)
AUCinf (ng*hr/ml)	-	121.36 (63.63)

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

Distribution

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

Biotransformation

After oral administration, dydrogesterone is rapidly metabolized to form DHD. Plasma levels of the main active metabolite, 20α-dihydrodydrogesterone (DHD), reach peak concentrations at the same time as dydrogesterone. Plasma levels of DHD are significantly higher compared to the parent compound. The AUC and Cmax ratios of DHD to dydrogesterone are approximately 25 and 20, respectively. The mean terminal half-life of dydrogesterone and DHD is about 15 hours. A common feature of all metabolites is the preservation of the 4,6-diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the lack of estrogenic and androgenic effects of dydrogesterone.

Elimination

After oral administration of radiolabeled dydrogesterone, on average, 63% of the dose is excreted in urine. The apparent total plasma clearance of dydrogesterone is high, approximately 20 L/min. Complete elimination occurs within 72 hours. DHD is excreted in urine predominantly as glucuronide conjugates.

Dose and time dependence

The pharmacokinetics after single and multiple administrations are linear over the oral dose range of 2.5 to 20 mg. Comparison of single-dose and multiple-dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD are not altered by repeated administration. Steady-state conditions are generally achieved after 3 days of treatment.

Clinical characteristics.

Indications.

Hormone replacement therapy (HRT) for the relief of symptoms due to estrogen deficiency in postmenopausal women, not earlier than 12 months after the last menstrual period.

Prevention of osteoporosis in postmenopausal women at high risk of fractures. FEMOSTON® CONTI should be used in patients only if they are intolerant of or have contraindications to other medicinal products used for the prevention of osteoporosis (see section "Special precautions for use").

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

Contraindications.

• Diagnosed, current, or suspected breast cancer;
• established or suspected estrogen-sensitive tumors (e.g., endometrial cancer);
• established or suspected progestagen-sensitive tumors;
• meningioma or history of meningioma;
• vaginal bleeding of unknown origin;
• untreated endometrial hyperplasia;
• venous thromboembolism, current or in history (deep vein thrombosis, pulmonary embolism);
• presence of thrombophilic disorders (e.g., protein C, protein S or antithrombin deficiency; see section "Special precautions for use");
• acute or recently experienced arterial thromboembolic disease (e.g., angina pectoris, myocardial infarction);
• acute liver disease or liver disease in history, if liver function tests have not normalized;
• porphyria;
• known hypersensitivity to the active substances or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Studies on drug interactions have not been conducted.

Effectiveness of estrogens and progestagens may be impaired.

• Metabolism of estrogens (and progestagens) may be enhanced when co-administered with substances capable of inducing enzymes involved in drug metabolism, particularly CYP450 2B6, 3A4, 3A5, and 3A7. Such substances include anticonvulsants (phenobarbital, carbamazepine, phenytoin) and antibacterial/antiviral agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz).
• Although ritonavir and nelfinavir are known as potent inhibitors of CYP450 3A4, 3A5, and 3A7, they actually have an inducing effect when co-administered with steroid hormones.
• Herbal preparations containing Hypericum perforatum (St. John's wort) may also enhance the metabolism of estrogens (and progestagens) via CYP450 3A4.
• Clinically, increased metabolism of estrogens and progestagens may manifest as reduced efficacy and changes in bleeding patterns.

Effect of estrogen-containing HRT on other medicinal products

Hormonal contraceptives containing estrogens have been shown to significantly reduce plasma concentrations of lamotrigine when co-administered, due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, a similar interaction is expected, potentially leading to reduced seizure control in women taking both products.

Pharmacodynamic interactions

During clinical trials of hepatitis C virus (HCV) treatment with the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT (alanine aminotransferase) levels exceeding five times the upper limit of normal were observed significantly more frequently in women using ethinylestradiol-containing medicinal products, such as combined hormonal contraceptives (CHCs). Additionally, ALT elevations were also observed in women using ethinylestradiol-containing medicinal products, such as CHCs, during treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. In women receiving other estrogens besides ethinylestradiol, such as estradiol, when treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, the degree of ALT elevation was similar to that in women not receiving estrogens; however, due to the limited number of women receiving other estrogens, caution is advised when co-administering this product with the following combination therapies: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir (see section "Special precautions for use").

Estrogens may interfere with the metabolism of other medicinal products

Estrogens may inhibit CYP450 enzymes involved in drug metabolism through competitive inhibition. This should be particularly considered with medicinal products having a narrow therapeutic index, such as:

• tacrolimus and cyclosporine A (CYP450 3A4, 3A3);
• fentanyl (CYP450 3A4);
• theophylline (CYP450 1A2).

Clinically, this may lead to increased plasma levels of these substances to toxic concentrations. Therefore, careful monitoring of drug levels over a prolonged period may be required, along with dose reductions of tacrolimus, fentanyl, cyclosporine A, and theophylline.

Special precautions for use.

For the treatment of estrogen deficiency symptoms in postmenopausal women, hormone replacement therapy (HRT) should be initiated only if these symptoms significantly impair quality of life. A careful assessment of benefits and risks of HRT should be performed regularly, at least annually, and treatment should be continued only if benefits outweigh risks.

Data on 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 in these women is more favorable compared to older women.

Medical examination/follow-up monitoring

Prior to initiating HRT or resuming HRT after a break, a complete medical history (including family history) should be obtained. A physical examination (including gynecological examination and breast examination) should be performed, taking into account the patient's history, contraindications, and warnings. Regular check-ups should be recommended during treatment, with frequency and extent determined individually. Women should be informed about which changes in the breasts should be reported to a physician or nurse (see section below "Breast cancer"). Examinations, including appropriate imaging methods such as mammography, should be performed according to established screening practices, modified according to individual clinical needs.

Conditions requiring monitoring

Patients with any of the following conditions currently present, in the past, or with worsening during pregnancy or previous hormonal therapy should be closely monitored. It should be considered that these conditions may recur or worsen during treatment with FEMOSTON® CONTI. These include:

• leiomyoma (uterine fibroids) or endometriosis;
• risk factors for thromboembolic disorders (see below);
• risk factors for estrogen-sensitive tumors, e.g., first-degree familial predisposition to breast cancer;
• arterial hypertension;
• liver disease (e.g., hepatic adenoma);
• diabetes mellitus with or without vascular complications;
• cholelithiasis;
• migraine or (severe) headache;
• systemic lupus erythematosus;
• history of endometrial hyperplasia (see below);
• epilepsy;
• bronchial asthma;
• otosclerosis.

Meningioma

Cases of meningioma (single and multiple) have been reported during treatment with FEMOSTON® CONTI. Patients should be monitored for signs and symptoms of meningioma according to clinical practice. If a patient is diagnosed with meningioma, any treatment with FEMOSTON® CONTI must be discontinued (see section "Contraindications"). Tumor regression has been observed after discontinuation of treatment.

Reasons for immediate discontinuation of therapy

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

• onset of jaundice or liver function impairment;
• significant increase in blood pressure;
• new onset of migraine-like headache;
• pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased with prolonged estrogen-only HRT. The observed increase in endometrial cancer risk among women taking only estrogen preparations ranges from 2 to 12 times compared to non-users, depending on duration of treatment and estrogen dose (see section "Adverse reactions"). After discontinuation of treatment, the risk may remain elevated for at least 10 years.

Cyclic combination of an estrogen with a progestagen for at least 12 days per month/28-day cycle or continuous combined estrogen-progestagen therapy in women with an intact uterus prevents the excess risk associated with estrogen-only therapy.

During the first months of treatment, breakthrough uterine bleeding or spotting may occur. If these occur after a period of treatment or persist after discontinuation of therapy, their cause should be investigated. This may include endometrial biopsy to exclude malignant neoplasms.

Breast cancer

All available data indicate an increased risk of breast cancer in women taking combined estrogen-progestagen HRT or estrogen-only HRT. This risk depends on the duration of use.

Combined estrogen-progestagen therapy

Both the randomized placebo-controlled Women’s Health Initiative (WHI) study and meta-analyses of prospective epidemiological studies consistently show an increased risk of breast cancer in women using combined estrogen-progestagen HRT. The increased risk becomes apparent after approximately 3 (1–4) years (see section "Adverse reactions").

Estrogen-only therapy

The WHI study did not show an increased risk of breast cancer in women after hysterectomy who received estrogen-only HRT. Experimental studies have generally reported a slight increase in the risk of breast cancer diagnosis, which is substantially lower than in patients receiving combinations of estrogens and progestagens (see section "Adverse reactions").

Results from a large meta-analysis showed that after discontinuation of treatment, the increased risk diminishes over time, and the time required to return to baseline levels depends on the prior duration of HRT use. In cases where HRT was used for more than 5 years, the risk may persist for 10 years or longer. HRT, particularly combined estrogen-progestagen therapy, increases mammographic breast density, which may negatively affect radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer occurs significantly less frequently than breast cancer. Epidemiological data from a large meta-analysis indicated a slightly increased risk in women receiving estrogen-only therapy or combined estrogen-progestagen therapy as HRT; this risk appears 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 a similar or slightly lower risk (see section "Adverse reactions").

Venous thromboembolism (VTE)

HRT is associated with a 1.3–3-fold increased risk of venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. The occurrence of such events is most likely during the first year of HRT compared to later (see section "Adverse reactions").

Patients with known thrombophilic disorders have an increased risk of VTE, and HRT may further increase this risk. Therefore, hormone replacement therapy is contraindicated in this group of patients (see section "Contraindications").

Well-established risk factors for VTE include: estrogen use, advanced 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 VTE development. As for all postoperative patients, preventive measures should be taken to avoid VTE after surgical procedures. If prolonged immobilization is expected after planned surgery, temporary discontinuation of HRT is recommended 4–6 weeks before surgery. Treatment may be resumed only when the woman has fully regained mobility.

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

If a congenital thrombophilic disorder associated with a family history of thrombosis is identified, 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 receiving long-term anticoagulant therapy, the benefits and risks of HRT use should be carefully weighed.

If VTE develops after starting therapy, the drug should be discontinued immediately. Patients should be warned to seek immediate medical attention if potential symptoms of thromboembolism occur (e.g., painful leg swelling, sudden chest pain, dyspnea).

Ischemic heart disease (IHD)

There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without IHD who received combined estrogen-progestagen HRT or estrogen-only HRT.

Combined estrogen-progestagen therapy

The relative risk of IHD with combined estrogen-progestagen HRT is slightly increased. Since the baseline absolute risk of IHD largely depends on age, the number of additional IHD cases due to estrogen and progestagen use is very small in healthy women close to menopause but increases with older age.

Estrogen-only therapy

Data from randomized controlled trials did not show an increased risk of IHD in women after hysterectomy receiving estrogen-only therapy.

Ischemic stroke

Combined estrogen-progestagen therapy and estrogen-only therapy are associated with up to a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, since the baseline absolute risk of stroke largely depends on age, the overall risk of stroke in women taking HRT increases with age (see section "Adverse reactions").

Other conditions

• Estrogens may cause fluid retention; therefore, patients with cardiac or renal dysfunction should be carefully monitored.

• Women with a previous history of hypertriglyceridemia should be closely monitored during estrogen replacement or hormone replacement therapy, as in rare cases, plasma triglyceride levels have significantly increased during estrogen treatment, leading to pancreatitis.

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

• Estrogens increase levels of 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). T3 uptake is reduced due to elevated TBG levels. Concentrations of free triiodothyronine (T3) and thyroxine (T4) remain unchanged. Levels of other serum binding proteins, corticosteroid-binding globulin (CBG), and sex hormone-binding globulin (SHBG), may increase, leading to elevated levels of corticosteroids and sex hormones in the blood. Concentrations of free or biologically active hormones remain unchanged. Levels of other plasma proteins (angiotensinogen, alpha-1-antitrypsin, ceruloplasmin) may also increase.

• HRT does not improve cognitive function. Some data suggest an increased risk of possible dementia in women who initiate long-term combined or estrogen-only HRT after age 65.

• Patients with rare hereditary disorders such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not use this medication.

• FEMOSTON® CONTI is not a contraceptive.

Elevated ALT levels

In clinical trials involving patients treated for hepatitis C virus (HCV) infection with the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT levels exceeding the upper limit of normal by more than 5 times were observed significantly more frequently in women taking medications containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). Additionally, elevated ALT levels were also observed in women taking ethinylestradiol-containing medications, such as CHCs, among patients receiving glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. In women taking medications containing estrogens other than ethinylestradiol, such as estradiol, in combination with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, the degree of ALT elevation was similar to that in women not receiving any estrogens; however, due to the limited number of women taking other estrogens, caution is advised when co-administering this medication with the following combination therapies: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy

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

There are insufficient data on the use of estradiol/dydrogesterone in pregnant women.

Literature reports suggest that the use of certain progestagens has been associated with an increased risk of hypospadias. However, due to mixed factors during pregnancy, a definitive conclusion on the contribution of progestagens to hypospadias development cannot be made.

Currently, results from most epidemiological studies on accidental fetal exposure to combinations of estrogens and progestagens indicate no teratogenic or fetal toxic risk.

Breastfeeding

FEMOSTON® CONTI is not indicated for use during breastfeeding.

Effect on fertility

FEMOSTON® CONTI is not indicated for use in women of reproductive age.

Effect on ability to drive and use machines

FEMOSTON® CONTI has no effect or a negligible effect on the ability to drive a vehicle or operate machinery.

Method of administration and dosage.

FEMOSTON®CONTI should be taken orally every day according to the continuous combined regimen as described below.

Take 1 tablet daily throughout each 28-day cycle. Each blister pack is designed for 28 days of treatment. After this, a new cycle should be started immediately. These treatment cycles should be continuous and consecutive.

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

Continuous combined therapy may be initiated with FEMOSTON®CONTI depending on the time elapsed since the onset of menopause and the severity of symptoms. Women with natural menopause may start treatment 12 months after their last menstrual period. Women whose menopause resulted from surgical intervention may start treatment immediately.

The dosage should be individually adjusted according to clinical response.

In women who have not previously used hormone replacement therapy, or in women switching from continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women switching from cyclic or continuous sequential hormone replacement therapy, treatment should be started the day immediately following the end of the previous cycle.

If a dose 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, a missed tablet may increase the likelihood of breakthrough bleeding or spotting.

FEMOSTON®CONTI may be taken regardless of food intake.

Children.

This medicinal product is not intended for use in children.

Overdose.

Both estradiol and dydrogesterone are substances with low toxicity. In case of overdose, symptoms such as nausea, vomiting, breast tenderness, dizziness, abdominal pain, somnolence/fatigue, and withdrawal bleeding may occur. It is unlikely that specific or symptomatic treatment will be required in cases of overdose. The information provided above also applies to cases of overdose in children.

Adverse reactions

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

The following adverse reactions were observed during clinical trials (n = 5108) at the frequencies stated below:

Table 1

MedDRA organ system classes	Very common, ≥ 1/10	Common, ≥ 1/100, < 1/10	Uncommon, ≥ 1/1,000, < 1/100	Rare, ≥ 1/10,000 to < 1/1,000
Infections and infestations		Vaginal candidiasis	Cystitis-like syndrome
Benign, malignant and unspecified neoplasms (including cysts and polyps)			Uterine fibroid enlargement
Blood and lymphatic system disorders				Hemolytic anemia*
Immune system disorders			Hypersensitivity
Psychiatric disorders		Depression, nervousness	Decreased libido
Central nervous system disorders	Headache	Migraine, dizziness		Meningioma*
Eye disorders				Corneal curvature increased*, intolerance to contact lenses*
Cardiac disorders				Myocardial infarction
Vascular disorders			Venous thromboembolism**, arterial hypertension, peripheral vascular disease, varicose veins	Stroke*
Gastrointestinal disorders	Abdominal pain	Nausea, vomiting, flatulence	Dyspepsia
Hepatobiliary disorders			Liver function abnormalities (in some cases associated with jaundice, asthenia or malaise and abdominal pain), gallbladder disorders
Skin and subcutaneous tissue disorders		Allergic skin reactions (e.g., rash, urticaria, pruritus)		Angioneurotic edema, nodular erythema*, vasculitis; chloasma or melasma, which may persist after discontinuation of treatment*
Musculoskeletal and connective tissue disorders	Back pain			Leg cramps*
Reproductive system and breast disorders	Breast pain/tenderness	Menstrual disorders (including postmenopausal bleeding, metrorrhagia, menorrhagia, oligo-/amenorrhea, irregular menstruation, dysmenorrhea), pelvic pain, cervical discharge	Breast enlargement, premenstrual syndrome (PMS)
General disorders and administration site conditions		Asthenic conditions (asthenia, fatigue, malaise), peripheral edema
Investigations		Weight increased	Weight decreased

*Adverse reactions reported from spontaneous reports, which were not observed during clinical trials, have been added to the "rare" frequency.

** See details below.

Breast cancer risk

Up to a two-fold increased risk of breast cancer diagnosis has been reported in women receiving combined estrogen-progestogen HRT for more than 5 years.

The increased risk in women receiving estrogen-only therapy is lower than in women receiving combined estrogen-progestogen therapy.

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

Below is an assessment of absolute risk based on results from the largest randomized placebo-controlled Women’s Health Initiative (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 use in women with a body mass index of 27 (kg/m²)

Age at initiation of HRT (years)	Number of cases per 1000 women who have never used HRT, over a 5-year period (50–54 years)1	Relative risk	Additional number of cases per 1000 women using HRT over 5 years
HRT with use of estrogen-only
50	13.3	1.2	2.7
HRT with use of combined estrogen and progestogen
50	13.3	1.6	8.0
Note: since breast cancer incidence varies across each EU country, the number of additional breast cancer cases will also change proportionally. 1 Based on baseline incidence rates in England in 2015 for women with a body mass index of 27 (kg/m2).

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

Age at start of HRT (years)	Number of cases per 1000 women who have never used HRT over a 10-year period (50–59 years)1	Relative risk	Number of additional cases per 1000 women using HRT over 10 years
HRT using estrogen-only therapy
50	26.6	1.3	7.1
HRT using combined estrogen and progestogen therapy
50	26.6	1.8	20.8
1 Based on baseline incidence rates in England in 2015 for women with a body mass index of 27 (kg/m²). Note: since breast cancer incidence varies in each EU country, the number of additional breast cancer cases will also change proportionally.

WHI study in the USA – additional risk of breast cancer after 5 years of use

Age range (years)	Number of cases per 1000 women in the placebo group over 5 years	Risk ratio and 95% confidence interval (CI)	Additional number of cases per 1000 women receiving HRT over 5 years (95% CI)
Conjugated equine estrogen (CEE) monotherapy HRT
50–79	21	0.8 (0.7–1.0)	4 (–6–0)2
CEE + MPA combined estrogen-progestin HRT ‡
50–79	17	1.2 (1.0–1.5)	+4 (0–9)
‡ When analysis was limited to women who had not used HRT prior to the study, no significant risk was observed during the first 5 years of treatment; after 5 years, the risk was higher than in those who had never used HRT. 2 WHI study in women without a uterus showed no increased risk of breast cancer. CEE – conjugated equine estrogen, MPA – medroxyprogesterone acetate

Endometrial cancer risk

Postmenopausal women with an intact uterus

The risk of endometrial cancer is approximately 5 cases per 1000 women with an intact uterus who do not use HRT.

HRT with estrogen-only therapy is not recommended for women with an intact uterus, as it increases the risk of endometrial cancer (see section "Special precautions"). Depending on the duration and dose of estrogen monotherapy, the increased risk of endometrial cancer observed in epidemiological studies ranged from 5 to 55 additional cases diagnosed per 1000 women aged 50 to 65 years.

Adding a progestagen to estrogen monotherapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study, use of combined (sequential or continuous) HRT for 5 years did not increase the risk of endometrial cancer [relative risk 1.0 (0.8–1.2)].

Ovarian cancer

Use|administration| of HRT |with| estrogen-only or combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer (see section "Special precautions").

Data from a meta-analysis of 52 epidemiological studies reported an increased risk of ovarian cancer in women using HRT compared to women who never used HRT (relative risk 1.43, 95%; confidence interval (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 out of 2000 women over a 5-year period.

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. The occurrence of such events is most likely during the first year of HRT use (see section "Special precautions"). The results from the WHI study are presented below.

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

Age range (years)	Number of cases per 1000 women in the placebo group over 5 years	Risk ratio and 95% CI	Additional number of cases per 1000 women receiving HRT over 5 years (95% CI)
Oral estrogen-only hormone replacement therapy3
50–59	7	1.2 (0.6–2.4)	1 (–3–10)
Oral estrogen/progestogen combination HRT
50–59	4	2.3 (1.2–4.3)	5 (1–13)

3 Studies involving women without a uterus.

Risk of ischaemic heart disease

The risk of ischaemic heart disease is slightly increased in women taking combined oestrogen-progestogen HRT at the age of 60 years and above (see section "Special precautions").

Risk of ischaemic stroke

The use of oestrogen-only therapy and combined oestrogen-progestogen HRT is associated with an approximately 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during HRT use.

The relative risk does not depend on age or duration of use; however, since the baseline risk is largely age-dependent, the overall risk of stroke in women taking HRT increases with advancing age (see section "Special precautions").

Pooled data from WHI studies: additional risk of ischaemic stroke⁴ during 5 years of treatment

Age range (years)	Number of cases per 1000 women in the placebo group over 5 years	Risk ratio and 95 % CI	Additional number of cases per 1000 women taking HRT over 5 years (95 % CI)
50–59	8	1.3 (1.1–1.6)	3 (1–5)

4 Differences between ischemic and hemorrhagic stroke were not observed.

Other adverse reactions reported with estrogen/progestogen therapy (including estradiol/dydrogesterone):

• Benign, malignant, and unspecified neoplasms: estrogen-dependent neoplasms, both benign and malignant, such as endometrial cancer and ovarian cancer. Increase in size of progestogen-dependent neoplasms (e.g., meningiomas);
• Immune system disorders: systemic lupus erythematosus (SLE);
• Metabolism and nutrition disorders: hypertriglyceridemia;
• Nervous system disorders: possible dementia, chorea, exacerbation of epilepsy;
• Vascular disorders: arterial thromboembolism;
• Gastrointestinal disorders: pancreatitis (in women with pre-existing hypertriglyceridemia);
• Skin and subcutaneous tissue disorders: erythema multiforme;
• Renal and urinary disorders: urinary incontinence;
• Reproductive system and breast disorders: fibrocystic changes in the breasts, cervical erosion;
• Congenital and genetic disorders: worsening of porphyria;
• Investigations: increased total thyroid hormone levels.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

28 tablets in a blister, 1, 2, or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Abbott Biologicals B.V.

Manufacturer's address.

Veerweg 12, 8121 AA Olst, The Netherlands.