Climonor

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLIМONORM (KLIMONORMÒ)

Composition:

Active substances: estradiol valerate, levonorgestrel;

1 film-coated tablet of yellow color contains 2 mg of estradiol valerate;

Excipients: lactose monohydrate; potato starch; gelatin; magnesium stearate; talc; purified water;

Film coating containing Opadry®II 57U220031 Yellow: hypromellose;
polydextrose; titanium dioxide (E 171); talc; maltodextrin; medium-chain triglycerides; yellow iron oxide (E 172); black iron oxide (E 172);

1 film-coated tablet of brown color contains 2 mg of estradiol valerate and 0.15 mg of levonorgestrel;

Excipients: lactose monohydrate; potato starch; gelatin; magnesium stearate; talc; purified water;

Film coating containing Opadry®II 57U265010 Brown: hypromellose; polydextrose; titanium dioxide (E 171); talc; maltodextrin; medium-chain triglycerides; yellow iron oxide (E 172); black iron oxide (E 172); red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round-shaped, film-coated tablets, yellow in color; round-shaped, film-coated tablets, brown in color.

Pharmacotherapeutic group. Sex gland hormones. Combined preparations containing estrogens and gestagens. ATC code G03FB09.

Pharmacological properties.

Pharmacodynamics.

The active ingredient, synthetic 17β-estradiol valerate, is metabolized in the body to 17β-estradiol. 17β-estradiol is identical in its chemical and biological properties to endogenous estradiol. It replaces hormones that are produced in insufficient amounts in women during menopause and minimizes symptoms characteristic of this period.

Due to the cyclic combination of estradiol valerate and levonorgestrel, the mitogenic effect of estrogens on the endometrium is inhibited. Thus, the risk of developing endometrial hyperplasia and endometrial cancer caused by estrogen monotherapy in women is reduced.

Clinical trial data

Reduction of estrogen deficiency symptoms and improvement of bleeding profile. Reduction in the severity of climacteric disorders was observed within the first weeks of treatment. Withdrawal bleeding occurred in 84.4% of cycles during the first year of treatment. The average duration of bleeding was 5 days.

Breakthrough bleeding and/or spotting occurred in 12.9% of women during the first three months of treatment and in 7.9% of women during months 10–12 of treatment.

Amenorrhea (absence of bleeding or spotting) was observed in 6.4% of cycles during the first year of treatment.

Pharmacokinetics.

Estradiol valerate

Absorption. After oral administration, estradiol valerate is completely absorbed from the gastrointestinal tract.

Distribution. After oral administration of 4 mg estradiol valerate, corresponding to 2 yellow tablets of the first phase of Climonor application, the maximum estradiol level is reached within 8–12 hours. After oral administration of 8 mg estradiol valerate, the maximum estradiol level is 40–52 pg/mL. The plasma half-life is approximately 1 hour on average. Estradiol is partially bound to plasma proteins.

Metabolism. Orally administered estradiol undergoes approximately 90% hepatic first-pass metabolism, primarily to estrone, estrone sulfate, and estriol, as well as to free or methylated catecholestrogens. The metabolic process mainly occurs in the liver but also takes place in other tissues.

Elimination. Elimination of estradiol and its metabolites (estrone and estriol) occurs via urine within 48 hours, primarily as conjugates with sulfuric and glucuronic acids, and to a small extent as unchanged estradiol. A portion is excreted in feces.

Levonorgestrel

Absorption. After oral administration, levonorgestrel is rapidly and completely absorbed from the gastrointestinal tract.

Distribution. After oral administration of 0.3 mg levonorgestrel, corresponding to 2 brown tablets of the second phase of Climonor application, the maximum plasma concentration of levonorgestrel is approximately 6 ng/mL, reached within 1–2 hours after administration. The half-life is 2 hours in the distribution phase and 10–24 hours in the elimination phase. In plasma, 93–95% of levonorgestrel is bound to albumin and, more specifically, to sex hormone-binding globulin (SHBG).

Metabolism. First-pass effect is not observed.

Elimination. Plasma clearance is 106 mL/h/kg. Levonorgestrel is excreted as reduced and/or hydroxylated metabolites, primarily conjugated with sulfuric and glucuronic acids. Elimination from the body occurs equally via urine and feces. A small amount of levonorgestrel passes into breast milk.

Clinical characteristics.

Indications.

Climonor is indicated for hormone replacement therapy (HRT) in women suffering from estrogen-deficiency symptoms due to menopause.

There is limited experience in treating women aged 65 years and older.

Contraindications.

• Diagnosed, suspected, or history of hormone-sensitive breast cancer.
• Estrogen-dependent malignant tumors (e.g., endometrial cancer) or suspicion thereof.
• Vaginal bleeding of unknown etiology.
• Untreated endometrial hyperplasia.
• Current or past history of venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism).
• Current or recent arterial thromboembolic events (e.g., angina, myocardial infarction).
• Thrombophilia (e.g., protein C, S, or antithrombin deficiency; see section "Special precautions").
• High risk of venous or arterial thrombosis.
• Current or past history of liver tumors (benign or malignant).
• Acute liver disease currently or in history – until normalization of liver function tests.
• Severe liver disease.
• Hypersensitivity to any component of the drug.
• Porphyria.
• Severe hypertriglyceridemia.
• Pregnancy or suspected pregnancy.

Interaction with other medicinal products and other forms of interaction.

The metabolism of estrogens and progestogens may be enhanced when co-administered with drugs that induce metabolizing enzymes, particularly cytochrome P450-dependent enzyme systems. These include anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, primidone) and drugs used to treat infectious diseases (e.g., rifampicin, rifabutin, nevirapine, efavirenz), griseofulvin, meprobamate, phenylbutazone and its salts.

Maximum enzyme induction may not manifest within the first 2–3 weeks but may then become persistent and last at least 4 weeks after discontinuation of the inducing drug.

Although ritonavir and nelfinavir are known as potent inhibitors, when used concomitantly with steroid hormones, they may exhibit enzyme-inducing properties.

Herbal medicinal products containing St. John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens.

Enhanced metabolism of estrogens and progestogens may lead to reduced clinical efficacy of these hormones and changes in the pattern of uterine bleeding.

Plasma levels of active substances in Climonor may increase when co-administered with drugs (e.g., ketoconazole) that inhibit metabolizing enzymes. Estrogens may enhance the effects and adverse reactions of imipramine.

Concomitant use of cyclosporine may lead to increased levels of cyclosporine, creatinine, and transaminases in blood due to reduced hepatic clearance of cyclosporine.

Estrogens may enhance the effects of medicinal products containing corticosteroids.

Concomitant thyroid hormone replacement therapy may increase the requirement for levothyroxine.

Due to changes in intestinal flora caused by concomitant use of activated charcoal and/or antibiotics (e.g., ampicillin or tetracyclines), reduced levels of active substances may occur; therefore, the effectiveness of Climonor may decrease, and an increase in intermenstrual bleeding may be observed.

Due to the effect of estrogen on glucose tolerance (reduced) and insulin response, dosage adjustments of oral antidiabetic agents or insulin, or changes in insulin requirements, may be necessary.

Estrogens may affect the results of certain laboratory tests, such as thyroid function tests (see section "Special precautions") or glucose tolerance.

The use of sex steroids may affect laboratory test results, including biochemical parameters of liver, adrenal, and kidney function, levels of binding proteins (e.g., sex hormone-binding globulin), lipids/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes generally remain within normal laboratory reference ranges.

Special precautions for use.

HRT should only be initiated for the treatment of symptoms typical of the postmenopausal period that significantly affect quality of life. In any case, a careful benefit-risk assessment should be performed at least annually. HRT should be continued only if the benefits outweigh the potential risks.

There are limited data on assessing the risks of HRT in cases of premature menopause. Since the absolute risk of possible adverse reactions is lower in younger women, the benefit-risk ratio in younger women may be more favorable than in older women.

Medical examinations/monitoring

A thorough personal and family medical history should be obtained before initiating or resuming HRT. A physical examination (including gynecological and breast examination) should be performed based on the above information, as well as contraindications and warnings regarding the use of this medicinal product. Regular follow-up examinations should be performed during treatment, the frequency and nature of which should depend on individual characteristics of each woman.

Women should be informed about which changes in the breast area they should report to their physician (see "Breast cancer" below). Diagnostic procedures, including imaging methods such as mammography, should be performed according to current medical practice guidelines for preventive measures and individual clinical needs.

In some patients, undesirable manifestations of estrogenic stimulation, such as abnormal uterine bleeding, may occur during HRT. Frequent or persistent uterine bleeding during treatment is an indication for a comprehensive evaluation of the endometrial status.

Conditions requiring monitoring

The patient requires regular monitoring if she has or has had any of the following conditions or diseases in her history, or if she experienced or had worsening of any of the following conditions or diseases during pregnancy or previous hormonal therapy/HRT with the use of Klimonor.

• Leiomyoma (uterine fibroids) or endometriosis;
• Risk factors for thromboembolic disorders (see below);
• Risk factors for estrogen-dependent tumors, e.g., breast cancer, in first-degree relatives;
• Arterial hypertension;
• Diabetes mellitus with or without vascular complications;
• Cholelithiasis;
• Migraine or (severe) headache;
• Systemic lupus erythematosus;
• History of endometrial hyperplasia (see below);
• Epilepsy;
• Asthma;
• Otosclerosis;
• Fibrocystic mastopathy;
• Dubin-Johnson or Rotor syndrome;
• Recurrence of cholestatic jaundice or cholestatic pruritus first occurring during pregnancy or previous use of steroid sex hormones;
• Severe obesity;
• Chorea minor;
• Hereditary angioedema;
• Sickle cell anemia.

Situations requiring immediate discontinuation of treatment

Treatment must be immediately discontinued if any contraindication or the following conditions occur:

• Jaundice or liver function abnormalities;
• Marked increase in blood pressure;
• Development of migraine-like headache;
• Pregnancy;
• Recurrence of cholestatic jaundice or cholestatic pruritus first occurring during pregnancy or previous use of steroid sex hormones;
• Migraine or new-onset frequent and unusually severe headaches, or other symptoms that may be prodromal signs of cerebrovascular disorders;
• Symptoms of thrombosis or suspicion thereof;
• Visual disturbances and other similar disorders.

Endometrial hyperplasia and cancer

In women with an intact uterus, the risk of endometrial hyperplasia and cancer is increased with prolonged estrogen-only therapy. Depending on the duration of treatment and estrogen dose (see section "Adverse reactions"), a 2- to 12-fold increased risk of endometrial cancer has been observed in women receiving estrogen-only therapy compared to women not using HRT. After cessation of treatment, this risk may remain elevated for at least 10 years. The addition of a progestogen administered cyclically for at least 12 days per month or continuously combined estrogen-progestogen therapy in women with an intact uterus counteracts the additional risk associated with estrogen-only therapy.

Breakthrough bleeding or spotting may occur during the first months of treatment. If breakthrough bleeding or spotting occurs after a period of treatment or continues after discontinuation of therapy, the cause should be investigated, including endometrial biopsy to exclude malignant endometrial tumors.

Fibroid tumors (uterine fibroids) may increase in size under the influence of estrogens. If this is observed, treatment should be discontinued.

If endometriosis develops during treatment, therapy should be discontinued.

Breast cancer

Available data indicate an increased risk of breast cancer associated with the duration of use in women receiving combinations of estrogens and progestogens. This may also apply to HRT with estrogen-only preparations. Levonorgestrel/ethinylestradiol is contraindicated in women with current or past history of breast cancer, as breast cancer may be hormone-sensitive (see section "Contraindications").

Epidemiological studies have not shown a consistent association between the use of combined oral contraceptives (COCs) and the risk of breast cancer. Studies do not show a link between current or past use of COCs and the risk of breast cancer. However, some studies have reported a slight increase in the risk of breast cancer among women currently taking or who have recently taken (within less than 6 months since last use) COCs (see section "Adverse reactions").

Combined estrogen-progestogen therapy

Results from a randomized placebo-controlled trial (WHI) and meta-analyses of prospective epidemiological studies show an increased risk of breast cancer in women using combined estrogen-progestogen HRT, with this risk becoming 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 with hysterectomy who received only estrogen therapy for HRT. Observational studies mostly report a slight increase in the risk of breast cancer in women who received only estrogen therapy for HRT, but this risk is lower than with combined estrogen-progestogen therapy (see section "Adverse reactions").

According to results from a large meta-analysis, after discontinuation of treatment, the risk gradually decreases, and the time to return to baseline levels depends on the duration of prior HRT use. If HRT lasted more than 5 years, the risk may persist for 10 or more years.

HRT, particularly with combined estrogen-progestogen preparations, increases breast tissue density on mammographic images, which may complicate radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer occurs much less frequently than breast cancer. A slightly increased risk of ovarian cancer has been observed with long-term (at least 5–10 years) estrogen-only therapy in women undergoing HRT (see section "Adverse reactions"). Results from some studies, including the WHI study, suggest that the corresponding risk with long-term use of combined HRT is similar or slightly lower (see section "Adverse reactions").

Venous thromboembolism (VTE)

HRT is associated with a small increase in the risk of venous thromboembolism (VTE) [deep vein thrombosis or pulmonary embolism (PE)]. The risk of VTE is higher during the first year of HRT than later (see section "Adverse reactions").

Patients with known thrombophilia have an increased risk of VTE. HRT increases this risk and is therefore contraindicated in such patients (see section "Contraindications").

Controlled randomized clinical trials and epidemiological studies have shown a 2- to 3-fold increased risk of VTE in women undergoing HRT compared to women not undergoing HRT. It is estimated that among 1000 women not receiving hormonal therapy, approximately 3 cases of VTE occur over 5 years in the age group 50–59 years and 8 cases in the age group 60–69 years. Correspondingly, among 1000 healthy women using an HRT medicinal product for 5 years, there will be 2 to 6 additional cases (optimal estimate = 4) of VTE in the age group 50–59 years and 5 to 15 cases (optimal estimate = 9) in the age group 60–69 years.

Well-established risk factors for VTE include: estrogen use, advanced age, major surgery, prolonged immobilization, significant overweight (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus, and cancer. The possible role of varicose veins in VTE development remains uncertain.

A synergistic increase in thrombosis risk should be considered if a woman has multiple risk factors simultaneously or if one risk factor is particularly pronounced. In such cases, this increased risk may be greater than with multiple risk factors alone. HRT should not be prescribed if the benefit-risk assessment is unfavorable.

The risk of VTE may temporarily increase due to prolonged immobilization, severe trauma, or major surgery. Prophylactic measures to prevent VTE should be implemented for patients undergoing HRT, as for all patients after surgery. Temporary discontinuation of HRT should be considered depending on the cause and duration of immobilization.

HRT may be resumed only after full restoration of mobility.

In women without a history of VTE, but with first-degree relatives who had VTE at a young age, screening for thrombophilia should be considered. Prior to this, the woman should be informed that such screening has limited value (only a portion of disorders leading to increased thrombophilia predisposition are identified). If a predisposition to thrombus formation is confirmed, there is a family history of thrombosis, or the identified disorder is severe (e.g., antithrombin, protein S and/or C deficiency, or a combination of these), HRT is contraindicated.

Women receiving anticoagulant therapy require careful benefit-risk assessment before initiating HRT.

If VTE develops after starting HRT, the drug should be discontinued. Patients should be advised to seek immediate medical attention if they notice possible symptoms of thromboembolism (especially painful leg swelling, sudden chest pain, or dyspnea).

Ischemic heart disease (IHD)

Randomized controlled trials have not demonstrated that combined HRT with estrogens/progestogens or estrogen-only therapy protects women from myocardial infarction, regardless of the presence or absence of IHD.

Results from two large clinical trials [WHI and HERS (Heart and Estrogen/Progestin Replacement Study)] indicate an increased risk of cardiovascular disease during the first year of use, with no overall health benefits observed. Data from controlled randomized trials on other HRT medicinal products regarding their effects on cardiovascular disease or mortality are insufficient.

Combined estrogen-progestogen therapy

The relative risk of IHD with combined estrogen-progestogen therapy is slightly increased. Since the baseline risk of IHD largely depends on age, the number of additional cases associated with estrogen-progestogen HRT in healthy premenopausal women is very low. However, this number increases with advancing age.

Estrogen-only therapy

Results from randomized controlled trials do not indicate an increased risk of IHD in women with hysterectomy receiving estrogen-only therapy.

Stroke

Combined estrogen-progestogen therapy and estrogen-only therapy are associated with a 1.5-fold increased risk of stroke. The relative risk does not depend on age or time since menopause onset. Since the baseline risk of stroke largely depends on age, the overall risk of stroke in women increases with age during HRT (see section "Adverse reactions").

A large-scale randomized clinical trial (WHI study) showed an increased risk of acute cerebrovascular events (as a secondary endpoint) in healthy women receiving HRT with continuous combined conjugated equine estrogens and medroxyprogesterone acetate (MPA).

It is estimated that among 1000 women not receiving HRT, approximately 3 cases of acute cerebrovascular events occur over 5 years in the age group 50–59 years and 11 cases in the age group 60–69 years. Among 1000 women taking combined conjugated equine estrogens and MPA for 5 years, the number of additional cerebrovascular events will be: 0 to 3 cases (optimal estimate = 1) in the age group 50–59 years and 1 to 9 cases (optimal estimate = 4) in the age group 60–69 years.

Other conditions

Treatment with this medicinal product has no contraceptive effect and does not protect against HIV.

Estrogen use may cause fluid retention. Therefore, patients with impaired cardiac or renal function should be closely monitored. Close monitoring is required in patients with end-stage renal failure, as circulating levels of the active ingredients of Klimonor are expected to be elevated.

Chloasma may rarely occur, particularly in women with a history of chloasma gravidarum. Women with a predisposition to chloasma or with a history of chloasma should minimize sun exposure or ultraviolet radiation.

Estrogens are known to promote gallstone formation. Some women may be predisposed to gallbladder disease during estrogen use.

Rarely, benign and, even more rarely, malignant liver tumors have been reported after use of hormonal substances such as those contained in HRT products. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhage.

No association has been established between HRT and the development of arterial hypertension. Minor increases in blood pressure have been reported in women undergoing HRT, but clinically significant elevations are rare. However, if persistently high blood pressure readings are recorded during HRT, discontinuation of HRT should be considered.

Careful monitoring is required in patients with mild liver dysfunction, including hyperbilirubinemia such as Dubin-Johnson or Rotor syndrome, and periodic monitoring of liver function tests is necessary. HRT should be discontinued if liver function deteriorates. Although HRT may affect peripheral insulin resistance and glucose tolerance, overall, changes in therapy are generally not required in diabetic patients undergoing HRT. However, careful monitoring of health status is necessary in women with diabetes mellitus during HRT.

Patients with prolactinoma require careful medical supervision (including periodic measurement of prolactin levels).

Women with a history of hypertriglyceridemia require special monitoring during estrogen-only therapy or combined estrogen-progestogen HRT, as isolated cases of marked increases in plasma triglyceride levels leading to pancreatitis have been reported with estrogen-only therapy in such patients.

Estrogens increase the level of thyroxine-binding globulin, leading to increased circulating total thyroid hormone, measured as protein-bound iodine, T4 (by chromatographic separation or radioimmunoassay), or T3 (by radioimmunoassay). T3 resin uptake is reduced, reflecting increased thyroxine-binding globulin (TBG). Free T4 and T3 concentrations remain unchanged. Levels of other serum proteins may increase, e.g., corticosteroid-binding globulin (CBG), sex hormone-binding globulin (SHBG), resulting in increased circulating concentrations of corticosteroids and sex steroids, respectively. Concentrations of free or biologically active hormones remain unchanged. Levels of other plasma proteins may increase (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

There are no data on improvement of cognitive function. However, some data suggest an increased risk of possible dementia development in women who initiate continuous combined HRT or estrogen-only therapy at age 65 or older.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate angioedema symptoms.

Other excipients

Klimonor is contraindicated in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Klimonor should not be prescribed during pregnancy or breastfeeding. If pregnancy occurs during treatment with Klimonor, treatment must be discontinued immediately.

Clinical data based on a limited number of pregnancy cases do not indicate a negative effect of levonorgestrel on the fetus.

Results from most epidemiological studies currently do not indicate teratogenic or fetotoxic effects of estrogen-progestogen combinations when accidentally taken during pregnancy.

Ability to affect reaction speed when driving or operating machinery.

No effect on the ability to drive or operate machinery has been observed.

Method of Administration and Dosage

Klimonor is an HRT preparation intended for cyclic administration.

For the first 9 days, take 1 yellow tablet daily. Then, for the next 12 days, take 1 brown tablet daily.

After all tablets have been taken over the 3-week period, a 7-day tablet-free interval follows. During this time, withdrawal bleeding resembling menstruation is expected to occur.

After the 7-day break, begin taking tablets from the next pack regardless of whether withdrawal bleeding has stopped or is still ongoing.

Starting Treatment with Klimonor

If HRT preparations have not been used previously

Treatment may be started on any day.

Switching from another HRT preparation

Women switching from a continuous combined HRT preparation may start Klimonor immediately after completing the previous cycle. Women switching from a cyclic HRT regimen should start taking Klimonor after the tablet-free interval of the previous treatment.

For both initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest possible duration should be used (see section "Special Warnings and Precautions for Use").

Missed Dose

If a tablet is missed, it should be taken within the next 12 hours.

Otherwise, continue taking tablets at the usual time the next day, without taking the missed tablet. Missing tablets increases the risk of breakthrough bleeding or spotting.

Method and Duration of Administration

Klimonor should be taken at the same time each day, without chewing and with sufficient liquid. To minimize gastrointestinal disturbances, it is recommended to take the tablets in the evening.

The duration of treatment is determined by the physician.

Children

Do not use in this patient group.

Overdose

Symptoms of overdose: Nausea, vomiting, breast tenderness, and vaginal bleeding may indicate overdose.

Treatment of overdose: If necessary, treatment should be symptomatic.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated based on available data).

During clinical studies involving 588 women and post-marketing surveillance data including 10,115 women, the following adverse effects possibly related to the use of the drug were reported.

Systems and organs	Common	Uncommon	Rare
Investigations		Elevated blood glucose levels, anaemia, weight change, hyperbilirubinaemia
Nervous system disorders	Headache/migraine	Memory impairment*, confusion/dizziness	Sleep disorders
Eye disorders		Visual disturbances
Gastrointestinal disorders		Nausea/vomiting, abdominal distension, abdominal pain, constipation*, dyspeptic symptoms
Skin and subcutaneous tissue disorders		Acne/seborrhea, pruritus	Hair loss
Infections and infestations		Respiratory tract infections/bronchitis
Vascular disorders	Arterial hypertension	Tachycardia/palpitations, varicose veins, haemorrhoids, cardiovascular disorders	Thrombosis**, superficial thrombophlebitis, arterial hypotension
General disorders		Hot flushes, fatigue, swelling/feeling of heaviness in legs, pelvic pain
Immune system disorders		Hypersensitivity reactions/allergy
Hepatobiliary disorders		Cholangitis, cholecystitis, liver function abnormalities
Reproductive system and breast disorders	Benign breast neoplasms (benign breast diseases), breast tension/discomfort	Intermenstrual bleeding/menstrual cycle disturbances, mastitis*, vaginitis*, cervical hyperplasia*/dysplasia*, endometrial hyperplasia, endometrial hypertrophy*, vulvovaginitis, breast cancer
Psychiatric disorders		Mood lability including anxiety and depression	Changes in libido

* The only reported adverse reaction for which a causal relationship with the drug may fall into the "uncommon" category, at least based on the small sample size of clinical trials (n = 588).

** Venous thromboembolism (e.g., deep vein thrombosis of the lower limbs and pelvis, and pulmonary embolism) occurs more frequently in women receiving HRT than in those who do not. Further information is provided in the sections "Contraindications" and "Special precautions for use".

Breast cancer risk

Women receiving combined estrogen-progestogen therapy for more than 5 years have a twofold increased risk of breast cancer. In any case, the risk in patients taking estrogen-only preparations is considerably lower than in those taking a combination of estrogen and progestogen. The risk also depends on the duration of therapy (see section "Special precautions for use").

Below is an estimate of absolute risk based on results from a large randomized placebo-controlled trial (WHI) and a meta-analysis of a large prospective epidemiological study (MWS).

MWS study: predicted additional risk of breast cancer after 5 years of HRT use in women with BMI 27 (kg/m²)

Age at start of HRT (years)	Incidence per 1000 women not using HRT over a 5-year period (50–54 years)*	Risk ratio	Additional cases per 1000 women using HRT over 5 years
Estrogen-only therapy
50	13.3	1.2	2.7
Combined estrogen-progestogen therapy
50	13.3	1.6	8.0
* Based on baseline breast cancer incidence rates in England in 2015 in women with BMI 27 (kg/m²). Note: Since background breast cancer incidence varies across EU countries, the number of additional breast cancer cases will also change proportionally.

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

Age at start of HRT (years)	Incidence per 1000 women not using HRT over a 10-year period (50–59 years)*	Risk ratio	Additional cases per 1000 women using HRT over 10 years
Estrogen-only HRT
50	26.6	1.3	7.1
Combined estrogen-progestogen HRT
50	26.6	1.8	20.8

• Based on baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²).

Note: Since background breast cancer incidence varies across EU countries, the number of additional breast cancer cases will also change proportionally.

WHI study in the USA: additional risk of developing breast cancer after 5 years of HRT use

Age group (years)	Incidence per 1000 women in the placebo group over 5 years	Relative risk (95% CI [confidence interval])	Additional cases per 1000 women receiving HRT over 5 years (95% CI)
Estrogen-only therapy (CEE [conjugated equine estrogens])
50	21	0.8 (0.7–1.0)	−4 (−6 to 0)* ±
Estrogen and progestogen (CEE + MPA [medroxyprogesterone acetate])
50	17	1.2 (1.0–1.5)	+4 (0 to 9)
* WHI — study in women without a uterus, in which no increased risk of breast cancer was found. ± When analysis was limited to women who had not used HRT prior to the study, no increased risk was observed during the first 5 years of treatment; after 5 years, the risk was higher than in women not using HRT.

Endometrial cancer

Postmenopausal women with intact uterus

The risk of endometrial cancer is approximately 5 cases per 1000 women with intact uterus who do not receive HRT. Estrogen monotherapy is not recommended in women with intact uterus, as it increases the risk of developing endometrial cancer (see section "Special instructions"). Depending on the duration of estrogen monotherapy and the prescribed doses, 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 progestogen to estrogen therapy for at least 12 days per cycle can prevent this increased risk. In the MWS study, combined (sequential or continuous) HRT used for 5 years did not increase the risk of endometrial cancer [relative risk 1.0 (95% CI 0.8–1.2)].

Ovarian cancer

Long-term use of estrogen-only and combined estrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer. According to results from the MWS study, 5 years of HRT led to 1 additional case per 2500 women receiving treatment.

Liver cancer

After administration of steroid hormones, benign liver tumors have been observed in isolated cases, and malignant tumors less frequently, which sometimes caused life-threatening intra-abdominal bleeding. Liver tumors should be considered as a possible diagnosis when performing differential diagnosis in patients presenting with severe epigastric pain, hepatomegaly, or signs of intra-abdominal hemorrhage.

Venous thromboembolism

The risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, is increased 1.3–3 fold with HRT. VTE is most likely to occur during the first year of HRT compared to subsequent years (see section "Special instructions"). The following presents relevant results from the WHI study.

WHI study: additional risk of VTE after 5 years of HRT

Age group (years)	Incidence per 1000 women in the placebo group over 5 years	Relative risk (95 % CI)	Additional cases per 1000 women receiving HRT over 5 years (95 % CI)
Oral estrogen-only therapy*
50−59	7	1.2 (0.6–2.4)	1 (−3–10)
Combined oral therapy with estrogen and progestogen
50−59	4	2.3 (1.2–4.3)	5 (1–13)
* Study in women with hysterectomy

Ischaemic heart disease

The risk of developing ischaemic heart disease is slightly increased in women receiving combined oestrogen-progestogen HRT over the age of 60 years (see section "Special precautions for use").

Stroke

Oestrogen-only therapy and combined oestrogen-progestogen therapy are associated with a 1.5-fold increased risk of ischaemic stroke. The risk of haemorrhagic stroke does not increase with HRT use. The relative risk does not depend on age or duration of treatment, but since the baseline risk is largely age-dependent, the overall risk of stroke in women receiving HRT increases with age (see section "Special precautions for use").

Combined data from WHI studies: additional risk of ischaemic stroke* after 5 years of HRT

Age group (years)	Incidence per 1000 women in the placebo group over 5 years	Relative risk (95% CI)	Additional cases per 1000 women receiving HRT over 5 years (95% CI)
50–59	8	1.3 (1.1–1.6)	3 (1–5)
* No differences were observed between ischemic and hemorrhagic stroke.

The following adverse reactions have also been reported in association with estrogen/progestogen combination therapy:

• gallbladder disease;
• skin and subcutaneous tissue disorders: chloasma, nodular erythema, erythema multiforme, vasculitic purpura;
• possible increased risk of dementia in women aged 65 years and older (see section "Special precautions");
• in women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Other observed adverse reactions include: intolerance to contact lenses, rash, urticaria, dysmenorrhea, breast enlargement, muscle cramps, hirsutism, galactorrhea, eczema, changes in vaginal discharge, leg pain, changes in glucose tolerance, increase in size of uterine leiomyomas, estrogen-dependent benign/malignant neoplasia, myocardial infarction and acute cerebrovascular accident, chorea, gallstone disease, increase in size of uterine fibroids, porphyria, fluid and salt retention, vaginal discharge, diarrhea, increased appetite, vaginal candidiasis, cervical erosions, ectropion, epistaxis, cystitis-like symptoms, back pain, upper genital tract infections.

Post-marketing experience

In five studies comparing the risk of breast cancer in ever-users of oral contraceptives (current or past users) versus never-users, no association was found between oral contraceptive use and risk of breast cancer (with effect estimates ranging from 0.90 to 1.12).

In three studies comparing the risk of breast cancer in current or recent users of oral contraceptives (within < 6 months since last use) versus never-users, one study reported no association between breast cancer risk and oral contraceptive use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies also observed an increased risk of breast cancer with long-term use, with relative risk ranging from 1.03 for less than 1 year of use to approximately 1.4 for more than 8–10 years of use.

Shelf life. 5 years.

Do not use the medicinal product after the expiry date.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

21 (21**×**1) film-coated tablets in a blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

DELPHARM LILLE SAS.

Manufacturer’s address and place of business.

Parc d'Activités Raubex-Est, 22 Rue de Tauwflers CS 50070,
LUS LEZ LANNOY, 59452, France.

In case of adverse events, side effects, or lack of therapeutic effect, please report to Zentiva Ukraine LLC, 5 "Y", Boryspilske Shose, Kyiv, 02660, Ukraine; tel./fax +38 044 517-75-00; e-mail: [email protected].