Climedix

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLIMEDIX® (KLIMEDIX®)

Composition:

Active substances: drospirenone, estradiol;

One tablet contains 2.0 mg drospirenone and 1.0 mg estradiol (as 1.03 mg estradiol hemihydrate);

Excipients: lactose monohydrate, maize starch, pregelatinized maize starch, povidone K-25, magnesium stearate;

Film coating: Oparay II 85G18490 white (polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, lecithin (E 322)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex film-coated tablets, white or almost white, approximately 6 mm in diameter; one side is marked with "GD3", the other side is unmarked.

Pharmacotherapeutic group. Sex hormones. Estrogen-progestogen combinations. ATC code G03FA17.

Pharmacological Properties.

Pharmacodynamics.

Estradiol.

Klimedix contains synthetic 17β-estradiol, which is chemically and biologically identical to the estradiol produced in the human body. It compensates for the reduced estrogen production in menopausal women and alleviates symptoms of the postmenopausal period. Estrogens prevent loss of bone mass after menopause or oophorectomy.

Drospirenone.

Drospirenone is a synthetic progestogen.

Since estrogens stimulate endometrial growth, estrogen monotherapy increases the risk of endometrial hyperplasia and endometrial cancer. The addition of a progestogen reduces, but does not completely eliminate, the estrogen-induced risk of endometrial hyperplasia in women with an intact uterus.

Drospirenone exhibits antimineralocorticoid activity antagonistic to aldosterone. Therefore, increased excretion of sodium and water and reduced excretion of potassium may occur.

In preclinical studies, drospirenone showed no estrogenic, glucocorticoid, or antiglucocorticoid activity.

Data from clinical studies.

Reduction of estrogen deficiency symptoms and improvement of bleeding profile.

During the first few weeks of treatment, a reduction in menopausal symptoms was achieved.

Amenorrhea was observed in 73% of women during 10–12 months of treatment. Menstrual-like bleeding and/or spotting occurred in 59% of women during the first three months of therapy and in 27% of women during months 10–12 of treatment.

Prevention of osteoporosis.

Estrogen deficiency during menopause is associated with increased bone turnover rate and decreased bone mass.

The effect of estrogens on bone mineral density is dose-dependent. Effective protection is maintained during the treatment period. After discontinuation of hormone replacement therapy (HRT), bone mass loss occurs at the same rate as in untreated women.

Results from the WHI study and meta-analyses of other studies show that HRT, used alone or in combination with a progestogen, primarily in healthy women, reduces the risk of hip fractures, vertebral fractures, and other fractures associated with osteoporosis. HRT may also prevent fractures in women with low bone mineral density and/or established osteoporosis, although data confirming this effect are limited.

After 2 years of treatment with Klimedix, femoral bone mineral density increased by 3.96 ± 3.15% (mean ± standard deviation) in patients with osteoporosis and by 2.78 ± 1.89% (mean ± standard deviation) in individuals without osteoporosis. The proportion of women who maintained or increased femoral bone mineral density during treatment was 94.4% in those with osteoporosis and 96.4% in those without.

An effect of Klimedix on lumbar spine bone mineral density was also demonstrated. After 2 years of treatment, the increase in density was 5.61 ± 3.34% (mean ± standard deviation) in women with osteoporosis and 4.92 ± 3.02% (mean ± standard deviation) in women without osteoporosis. During treatment, maintenance or increase in lumbar spine bone mineral density was observed in 100% of women with osteoporosis and in 96.4% of women without osteoporosis.

Antimineralocorticoid activity.

Drospirenone exerts competitive antagonistic effects on aldosterone, which may result in a reduction in blood pressure in women with arterial hypertension. In a double-blind, placebo-controlled study in postmenopausal women with arterial hypertension receiving Klimedix (n=123) for 8 weeks, a significant reduction in systolic/diastolic blood pressure was observed (office measurements obtained with a cuff compared to baseline: -12/-9 mm Hg, including placebo effect: -3/-4 mm Hg; 24-hour ambulatory blood pressure monitoring compared to baseline: -5/-3 mm Hg, including placebo effect: -3/-2 mm Hg).

Klimedix must not be used for the treatment of arterial hypertension. Women with arterial hypertension should receive treatment according to established hypertension management guidelines.

Pharmacokinetics.

Drospirenone.

Absorption.

After oral administration, drospirenone is rapidly and almost completely absorbed. Maximum serum concentration is reached approximately 1 hour after single oral administration of Klimedix and amounts to 21.9 ng/mL. With repeated administration, maximum steady-state concentration of 35.9 ng/mL is reached after approximately 10 days. Bioavailability is 76–85% and is independent of food intake.

Distribution.

After oral administration, serum concentration of drospirenone declines in two phases, with a mean terminal half-life of approximately 35–39 hours. Drospirenone binds to serum albumin but does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3–5% of total drospirenone concentration circulates as free steroid. The mean apparent volume of distribution of drospirenone is 3.7–4.2 L/kg.

Metabolism.

After oral intake, drospirenone undergoes extensive metabolism. The main metabolites in plasma are the acid form of drospirenone, resulting from lactone ring opening, and 4,5-dihydro-drospirenone-3-sulfate, formed via reduction followed by sulfation. These two primary metabolites are pharmacologically inactive. Drospirenone is also subject to oxidative metabolism catalyzed by cytochrome P450 3A4.

Elimination.

Total serum clearance of drospirenone is 1.2–1.5 mL/min/kg, with individual variations of approximately 25%. Only very small amounts of unchanged drospirenone are excreted. Metabolites are excreted in feces and urine in a ratio of approximately 1.2:1.4. The elimination half-life of metabolites in urine and feces is approximately 40 hours.

Steady-state concentration and linearity.

Steady-state concentration is reached after approximately 10 days of daily oral administration of Klimedix. Due to the relationship between terminal half-life and dosing interval, serum concentration of drospirenone accumulates approximately 2–3 times. At steady state, mean serum concentration of drospirenone ranges from 14 to 36 ng/mL after administration of Klimedix. Pharmacokinetic properties of drospirenone are dose-proportional in the dose range of 1–4 mg.

Estradiol.

Absorption.

After oral administration, estradiol is rapidly and completely absorbed. During absorption and first-pass metabolism in the liver, estradiol undergoes extensive metabolism, reducing its absolute bioavailability after oral administration to approximately 5% of the administered dose. Maximum concentration of approximately 22 pg/mL is reached about 6–8 hours after single oral administration of Klimedix. Food intake does not affect estradiol bioavailability compared to administration on an empty stomach.

Distribution.

After oral administration of Klimedix, only gradual changes in serum estradiol concentration are observed over the 24-hour dosing interval. Due to the large volume of circulating estrogen sulfates and glucuronides on one hand, and enterohepatic recirculation on the other, the terminal half-life of estradiol is a composite parameter dependent on all these processes and lasts approximately 13–20 hours after oral administration.

Estradiol binds non-specifically to serum albumin and specifically to sex hormone-binding globulin (SHBG). Only 1–2% of estradiol circulates as free steroid, while 40–45% is bound to SHBG. The apparent volume of distribution of estradiol after single intravenous administration is approximately 1 L/kg.

Metabolism.

Estradiol is rapidly metabolized, forming a large number of metabolites and conjugates, including estrone and estrone sulfate. Pharmacologically active metabolites of estradiol include estrone and estriol. Only estrone is present in significant concentrations in plasma. Serum estrone concentration is approximately 6 times higher than estradiol concentration. Serum concentrations of estrone conjugates are approximately 26 times higher than those of free estrone.

Elimination.

Metabolic clearance is approximately 30 mL/min/kg. Estradiol metabolites are excreted in urine and bile, with an elimination half-life of approximately 1 day.

Steady-state concentration.

After daily oral administration of Klimedix, steady-state concentration of estradiol is reached after approximately 5 days. Serum estradiol concentration accumulates by approximately 2 times. Oral administration of estradiol induces SHBG production, affecting distribution among serum proteins, resulting in increased SHBG-bound fraction and decreased albumin-bound and unbound fractions, indicating nonlinear pharmacokinetics of estradiol after Klimedix administration. With a 24-hour dosing interval, mean steady-state serum concentration of estradiol ranges from 20 to 43 pg/mL after Klimedix administration. Pharmacokinetic properties of estradiol are directly proportional to dose in the 1–2 mg dose range.

Special patient populations.

Hepatic impairment.

Pharmacokinetic properties of a single oral dose of 3 mg drospirenone combined with 1 mg estradiol were evaluated in 10 patients with moderate hepatic impairment (Child-Pugh class B) and 10 healthy women of comparable age, weight, and smoking history. Mean serum concentration-time profiles for drospirenone were similar in both groups during the absorption/distribution phase, with identical Cmax and tmax values, suggesting that liver impairment does not affect absorption rate. In patients with moderate hepatic impairment, compared to healthy women without liver disease, the mean terminal half-life was nearly 1.8 times longer, and apparent total clearance (CL/f) after oral administration was reduced by approximately 50%.

Renal impairment.

The effect of renal impairment on the pharmacokinetics of drospirenone (3 mg daily for 14 days) was studied in patients with normal renal function and those with mild to moderate renal impairment. At steady state, serum concentrations of drospirenone in women with mild renal impairment (creatinine clearance 50–80 mL/min) were similar to those in women with normal renal function (creatinine clearance >80 mL/min). In women with moderate renal impairment (creatinine clearance 30–50 mL/min), serum concentrations of drospirenone were on average 37% higher than in women with normal renal function. Linear regression analysis of drospirenone AUC (0–24 hours) versus creatinine clearance showed a 3.5% increase per 10 mL/min decrease in creatinine clearance. This minor increase is not considered clinically significant.

Preclinical safety data.

Animal studies with estradiol and drospirenone showed expected estrogenic and progestogenic effects. No additional preclinical safety data beyond those already mentioned in other sections of this Klimedix prescribing information are available.

Clinical characteristics.

Indications.

• Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women more than 1 year after menopause.
• Prevention of osteoporosis in postmenopausal women at high risk of bone fractures and who have contraindications to or intolerance of other medicinal products used for osteoporosis prevention (see section "Special precautions for use").

Experience with the use of the drug in women aged 65 years and older is limited.

Contraindications.

• Genital bleeding of unknown etiology.
• Breast cancer, suspicion thereof, or history of such condition.
• Estrogen-dependent malignant tumors or suspicion thereof (e.g., endometrial cancer).
• Untreated endometrial hyperplasia.
• Venous thromboembolism or history thereof (deep vein thrombosis, pulmonary embolism).
• Acute arterial thromboembolism or recent occurrence (e.g., angina, myocardial infarction, stroke).
• High risk of venous or arterial thrombosis.
• Acute liver disease or history of liver disease until liver function tests return to normal.
• Severe liver disease.
• Current or past history of liver tumors (benign or malignant).
• Predisposition to thrombosis (e.g., protein C deficiency, protein S deficiency, or antithrombin deficiency; see section "Special precautions for use").
• Renal dysfunction or acute renal failure.
• Adrenal insufficiency.
• Known anaphylactic reactions, Quincke's edema, hypersensitivity to the active substances or to any of the excipients of the drug.
• Porphyria.
• Severe hypertriglyceridemia.
• Hypersensitivity to peanuts or soy.

Interaction with other medicinal products and other types of interactions.

Note: Information regarding concomitantly administered medicinal products should be reviewed to identify potential interactions.

Pharmacodynamic interactions

During clinical trials of combination therapy for hepatitis C virus (HCV) using ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevations in ALT levels exceeding five times the upper limit of normal (ULN) were observed more frequently in women receiving medicinal products containing ethinylestradiol, such as combined oral contraceptives (COCs). In women receiving estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was similar to that in women not receiving estrogens. However, due to the limited number of women receiving non-ethinylestradiol estrogens, caution should be exercised when co-administering combination HCV therapy containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as glecaprevir/pibrentasvir (see section "Special precautions for use").

Pharmacokinetic interactions

Effect of other medicinal products on Klimedix.

Substances increasing sex hormone clearance (reducing efficacy via enzyme induction)

The metabolism of estrogens (and progestogens) may be enhanced by concomitant administration of enzyme-inducing substances, particularly cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infective agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz); possibly also felbamate, griseofulvin, oxcarbazepine, topiramate. Ritonavir and nelfinavir, although known as potent inhibitors, may exhibit enzyme-inducing properties when co-administered with steroid hormones. Herbal preparations containing St. John's wort (Hypericum perforatum) may stimulate the metabolism of estrogens and progestogens.

Clinically, increased metabolism of estrogens and progestogens may lead to reduced efficacy and changes in uterine bleeding patterns.

Enzyme induction may become evident within a few days of treatment. Maximum enzyme induction generally occurs within several weeks. After discontinuation of the inducing agent, enzyme induction may persist for approximately 4 weeks.

Substances with variable effects on sex hormone clearance

When co-administered with HRT, most HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors, may increase or decrease plasma concentrations of estrogens or progestins, or both. These changes may be clinically significant in some cases.

Therefore, information regarding the medical use of concomitantly administered HIV/HCV medicinal products should be reviewed to identify potential interactions and other recommendations.

Substances reducing sex hormone clearance (enzyme inhibitors)

Strong or moderate CYP3A4 inhibitors, such as azole antifungal agents (e.g., fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase plasma concentrations of estrogens, progestins, or both.

In a multiple-dose study of drospirenone (3 mg/day)/estradiol (1.5 mg/day), concomitant administration of the potent CYP3A4 inhibitor ketoconazole for 10 days resulted in a 2.30-fold increase in drospirenone AUC (0–24 hours) (90% CI: 2.08, 2.54). No changes were observed for estradiol; however, AUC (0–24 hours) of its less active metabolite, estrone, increased by 1.39-fold (90% CI: 1.27, 1.52).

Effect of Klimedix on other medicinal products

In vitro, drospirenone has been shown to weakly or moderately inhibit cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Based on results from an in vivo interaction study conducted in healthy female volunteers receiving drospirenone at the recommended dose of 3 mg/day, using omeprazole, simvastatin, or midazolam as probe substrates, clinically significant interactions between drospirenone and other medicinal products metabolized by cytochrome P450 are unlikely.

It is unlikely that combined use of Klimedix with NSAIDs (nonsteroidal anti-inflammatory drugs) or ACE inhibitors/angiotensin II receptor antagonists increases serum potassium concentration. However, simultaneous use of these three types of drugs may cause a slight increase in serum potassium levels, more pronounced in women with diabetes.

In women with arterial hypertension, additional blood pressure reduction may occur during treatment with Klimedix (see section "Special precautions for use").

It is known that hormonal contraceptives containing estrogens substantially reduce lamotrigine plasma concentrations 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, which may lead to reduced seizure control in women taking both medicinal products concurrently.

Alcohol abuse during HRT may lead to increased circulating estrogen levels in blood.

Other types of interactions

Laboratory tests.

The use of sex hormones may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, levels of binding proteins (e.g., sex hormone-binding globulin), lipids/lipoprotein fractions, and coagulation and fibrinolysis parameters. Generally, changes remain within normal limits. Drospirenone causes an increase in plasma renin activity and plasma aldosterone levels due to its moderate antimineralocorticoid activity.

Special precautions for use.

When treating disorders associated with the postmenopausal period, hormone replacement therapy (HRT) should only be initiated in the presence of symptoms that impair quality of life. In all cases, a thorough benefit-risk assessment must be performed at least once a year, and HRT should be continued only if benefits outweigh the risks.

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

Medical examination/follow-up monitoring.

Prior to initiating or resuming HRT, a detailed personal and family medical history should be obtained, and a physical examination (including pelvic and breast examination) should be performed, taking into account contraindications (see section "Contraindications") and warnings (see section "Special precautions for use"). Such examinations should be repeated periodically. The frequency and type of examinations should be based on established medical practice guidelines, adapted to individual patient characteristics. Women should be informed about which breast changes require reporting to their physician or nurse (see section "Breast cancer" below). Examinations, including appropriate imaging methods such as mammography, should be performed according to established screening practices, adapted to individual clinical needs.

Conditions requiring monitoring.

If any of the conditions listed below are currently present, have occurred in the past, or have worsened during pregnancy or previous hormonal therapy, the patient should be under close supervision. It should be considered that these conditions may recur or worsen during treatment with Klimedix. These include:

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

Reasons for immediate discontinuation of therapy

HRT should be immediately discontinued if any contraindication is detected or if any of the following conditions or diseases occur:

• jaundice or worsening liver function;
• significant increase in blood pressure;
• first occurrence of migraine-like headache;
• pregnancy;
• cholestatic pruritus occurring for the first time or during pregnancy, or after use of sex steroids;
• symptoms or suspicion of thrombosis.

Gallbladder disease.

Estrogens increase the lithogenicity of bile. Some women may be prone to gallbladder disease during estrogen therapy.

Endometrial hyperplasia and carcinoma.

In women with an intact uterus, prolonged estrogen monotherapy increases the risk of endometrial hyperplasia or carcinoma. This increased risk of endometrial cancer among patients receiving estrogen-only therapy, depending on duration of treatment and estrogen dose, is 2 to 12 times higher than in women not receiving estrogens (see section "Adverse reactions"). The elevated risk may persist for at least 10 years after discontinuation of treatment.

Adding a progestogen to the treatment regimen cyclically for at least 12 days per month (28-day cycle) or using continuous combined estrogen-progestogen therapy prevents the increased risks associated with estrogen-only HRT in women with an intact uterus.

Menstrual-like bleeding and spotting may occur during the first months of treatment. If such events occur after a period of treatment or continue after discontinuation of therapy, their causes should be investigated, and endometrial biopsy may be performed to exclude malignant endometrial neoplasms.

Breast cancer.

Overall data indicate an increased risk of breast cancer in women receiving combined estrogen-progestogen HRT and, likely, estrogen-only HRT, which depends on the duration of HRT.

Results from the randomized placebo-controlled Women's Health Initiative (WHI) study and meta-analyses of prospective epidemiological studies consistently confirm an increased risk of breast cancer in women receiving combined estrogen-progestogen HRT. This becomes evident after approximately 3 (1–4) years of therapy (see section "Adverse reactions"). Results from a large-scale meta-analysis showed that after discontinuation of treatment, the excess risk decreases over time, and the time required to return to baseline risk depends on the prior duration of HRT. If HRT was used for more than 5 years, the risk may persist for 10 years or longer.

HRT, particularly combined estrogen-progestogen therapy, increases mammographic breast density, which may negatively affect radiological diagnosis of breast cancer.

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 likelihood of these events is higher during the first year of HRT than in subsequent years (see section "Adverse reactions").

Well-established risk factors for VTE include estrogen use, advanced age, major surgery, obesity or family history of obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is currently no consensus on the role of varicose veins in VTE development.

Patients with known thrombophilia have an increased risk of VTE, and HRT may further increase this risk. Therefore, HRT is contraindicated in this patient group (see section "Contraindications").

As in all postoperative patients, preventive measures should be taken to avoid VTE after surgical procedures. If prolonged immobilization is required after elective surgery, HRT should be temporarily discontinued 4–6 weeks before surgery. Treatment may be resumed only after full restoration of mobility.

Women without a personal history of VTE but with a family history of thrombosis in first-degree relatives at a young age may be offered screening, provided the limitations of such screening are carefully discussed (screening may detect only a portion of thrombophilic disorders). If a specific thrombophilia variant, also present in other family members, is identified, or if the disorder is severe (e.g., antithrombin, protein S, or protein C deficiency, or multiple disorders), HRT is contraindicated.

In women already receiving long-term anticoagulant therapy, the benefit-risk ratio of HRT should be carefully evaluated.

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

Ischemic heart disease (IHD).

Data from randomized controlled trials indicate no protective effect against myocardial infarction in women with or without pre-existing IHD who receive combined estrogen-progestogen HRT or estrogen-only therapy. The relative risk of IHD with combined estrogen-progestogen HRT is slightly increased. Since the baseline absolute risk of IHD strongly depends on age, the number of additional IHD cases caused by estrogen and progestogen use is very small in healthy women approaching menopause but increases with advancing age.

Ischemic stroke.

Combined estrogen-progestogen 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 risk of stroke significantly depends on age, the overall risk of stroke in women using HRT increases with age (see section "Adverse reactions").

Ovarian cancer.

Ovarian cancer occurs much less frequently than breast cancer.

Epidemiological data from a large-scale meta-analysis suggest a slightly/inconspicuously increased risk of ovarian cancer in women using estrogen-only or combined estrogen-progestogen HRT, which becomes more pronounced after 5 years of use and decreases over time after discontinuation.

Results from some studies, including the WHI study, indicate that combined HRT may be associated with a similar or slightly lower risk (see section "Adverse reactions").

Liver tumors.

In isolated cases, benign (rarely malignant) liver tumors have been observed after use of hormonal medications (e.g., for HRT). These tumors have sometimes led to life-threatening intra-abdominal hemorrhage.

Other conditions.

Estrogens may cause fluid retention; therefore, patients with impaired cardiac or renal function require careful monitoring.

Women with moderately elevated triglyceride levels require special monitoring. In such cases, HRT may lead to further triglyceride elevation, increasing the risk of pancreatitis.

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

Estrogens increase levels of thyroxine-binding globulin (TBG), leading to elevated total circulating thyroid hormone levels. This is reflected in increased protein-bound iodine, T4 levels (measured by column or radioimmunoassay), or T3 levels (measured by radioimmunoassay). T3 uptake is reduced, indicating elevated TBG. Free T3 and T4 concentrations remain unchanged. Levels of other serum binding proteins—corticosteroid-binding globulin and sex hormone-binding globulin—may increase, leading to elevated circulating corticosteroid and sex hormone levels, respectively. Concentrations of free or biologically active hormones remain unchanged. Levels of other plasma proteins (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin) may also increase.

HRT does not improve cognitive function. Limited data suggest that long-term use of combined HRT or estrogen-only therapy may increase the risk of dementia when initiated in women aged 65 years or older.

The progestogenic component of Klimedix, drospirenone, is an aldosterone antagonist with a mild potassium-sparing effect. In most cases, an increase in serum potassium levels is unlikely. However, in a clinical study, slight increases in serum potassium were observed in some patients with mild to moderate renal impairment receiving drospirenone concurrently with potassium-sparing agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, or NSAIDs). Therefore, during the first month of treatment, especially when co-administered with potassium-sparing drugs, serum potassium levels should be monitored in patients with renal impairment whose baseline potassium levels were at the upper limit of normal (see section "Interaction with other medicinal products and other forms of interaction").

In women with elevated blood pressure, treatment with Klimedix may lead to a reduction in blood pressure due to the aldosterone-antagonistic activity of drospirenone (see section "Pharmacodynamics"). Klimedix is not indicated for the treatment of arterial hypertension. Women with arterial hypertension should receive treatment according to appropriate therapeutic protocols.

Chloasma may occur in some cases, particularly in women with a history of chloasma gravidarum. Women prone to chloasma should avoid sun exposure or ultraviolet radiation during HRT.

Elevated ALT levels

During clinical trials involving patients receiving HCV treatments containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ALT levels increased more than 5-fold. This occurred more frequently in women receiving ethinylestradiol-containing medications, such as COCs. Additionally, in patients receiving antiviral agents containing glecaprevir/pibrentasvir, ALT elevation was observed when these patients were also taking ethinylestradiol-containing products, such as COCs. In women receiving estrogens other than ethinylestradiol, such as estradiol, the frequency of ALT elevation was similar to that in women not receiving estrogens. However, due to the limited number of women receiving non-ethinylestradiol estrogens, caution should be exercised when co-administering combined regimens containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or glecaprevir/pibrentasvir (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

Each Klimedix tablet contains 48.52 mg of lactose. Patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, who are on a lactose-free diet, should take this lactose content into account.

Mild liver dysfunction, including hyperbilirubinemia (e.g., Dubin-Johnson syndrome, Rotor syndrome), requires careful monitoring; periodic liver function tests are also necessary. If liver function tests show pathological changes, HRT should be discontinued.

Patients with prolactinoma require careful medical monitoring (including periodic prolactin level measurements).

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia develops, the drug should be discontinued and appropriate measures taken to reduce blood calcium levels.

Estrogen therapy should be used with caution in women with hypoparathyroidism, as estrogen-induced hypocalcemia may occur.

Cases of retinal vessel thrombosis have been reported in women receiving estrogens. If sudden partial or complete vision loss, sudden onset of proptosis, diplopia, or migraine occurs, drug administration should be discontinued. If optic disc edema or retinal vessel damage is observed, estrogen use should be stopped.

As an aldosterone antagonist, drospirenone may increase the likelihood of hyponatremia in high-risk patients.

Serum levels of follicle-stimulating hormone and estradiol were not informative in managing patients with moderate to severe vasomotor symptoms.

Use during pregnancy or breastfeeding.

Pregnancy

Klimedix is contraindicated during pregnancy. If pregnancy occurs during treatment with Klimedix, the drug should be discontinued immediately. Clinical data on the effects of drospirenone during pregnancy are lacking. Animal studies indicate adverse effects during pregnancy and lactation (reproductive toxicity) (see section "Pharmacological properties"). The potential risk to humans is unknown. Current epidemiological data do not indicate teratogenic or embryotoxic effects of estrogen-progestogen combinations when accidentally used during pregnancy.

Breastfeeding

Klimedix is contraindicated in women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Klimedix does not affect reaction speed when driving or operating machinery.

Method of Administration and Dosage

If HRT has been prescribed for the first time or there is a switch to Climidex from a combined continuous HRT preparation, Climidex tablets may be started at any time. If switching to Climidex from a cyclic combined HRT preparation, the current cycle of therapy should be completed before starting Climidex.

Dosage.

One tablet daily. Each pack provides a 28-day course of treatment.

Method of Administration.

The tablet should be swallowed whole with a small amount of liquid, independent of food intake. Treatment should be continuous, meaning that the next pack should be started immediately after finishing the previous one, without any intervals. It is advisable to take the tablet at the same time each day.

If a dose is missed, it should be taken as soon as possible. If the missed dose is not taken within more than 24 hours, an extra tablet should not be taken. If several tablets have been missed consecutively, breakthrough bleeding may occur.

For treatment of postmenopausal symptoms, the lowest effective dose should be used.

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

Additional Information for Special Patient Populations

Elderly Patients.

There are no data indicating a need for dose adjustment in elderly patients. For use in women aged 65 years or older, see section "Special Warnings and Precautions for Use".

Patients with Hepatic Impairment.

Drospirenone is well tolerated in women with mild to moderate hepatic impairment (see section "Pharmacokinetics"). Climidex is contraindicated in women with severe hepatic impairment (see section "Contraindications").

Patients with Renal Impairment.

In women with mild to moderate renal impairment, slightly increased exposure to drospirenone has been observed; however, this effect is considered not clinically relevant (see section "Pharmacokinetics"). Climidex is contraindicated in women with severe renal impairment (see section "Contraindications").

Children.

Climidex is not indicated for use in children and adolescents.

Overdose.

In clinical studies conducted in male volunteers, doses of up to 100 mg drospirenone were well tolerated. Based on the overall experience with combined oral contraceptives, overdose may cause nausea, vomiting, and vaginal bleeding in girls and some women. There is no specific antidote; treatment should be symptomatic.

Adverse reactions

The frequency of adverse reactions reported during clinical trials with Climidex is summarized in the table below according to the MedDRA System Organ Class (SOC) classification. Information on adverse reactions was collected from 7 phase III clinical trials (N=2424 women) and is considered to have at least a potential causal relationship with the use of Climidex (estradiol 1 mg/drospirenone 0.5, 1, 2 or 3 mg).

The most frequently reported adverse reactions during treatment with Climidex were breast pain (>10%) and, during the first months of therapy, bleeding and spotting (>10%), which usually resolved with continued treatment (see section "Pharmacological properties"). The frequency of bleeding decreased with increasing duration of therapy.

The most appropriate MedDRA term is used to describe an individual adverse reaction, its synonyms, or associated conditions.

Additional information regarding specific patient groups.

The adverse reactions listed below are considered to be at least possibly related to the use of Klimedix and were observed during 2 clinical studies in women suffering from arterial hypertension.

Nutritional and metabolic disorders.

Hyperkalemia.

Cardiac disorders.

Heart failure, atrial flutter, QT interval prolongation, cardiomegaly.

Investigations.

Increased blood aldosterone level.

The following adverse reactions have also been reported during HRT: nodular erythema; multiform erythema; chloasma; hemorrhagic dermatitis.

Risk of breast cancer.

In women receiving combined estrogen-progestagen therapy for more than 5 years, a two-fold increased risk of developing breast cancer has been reported.

The increased risk in women receiving estrogen-only therapy is lower than in those receiving estrogen-progestagen combinations. The degree of risk depends on the duration of treatment (see section "Special precautions"). The absolute risk is based on the results presented below from the largest randomized placebo-controlled trial (the WHI study) and the largest epidemiological study (MWS).

Largest meta-analysis of prospective epidemiological studies: expected additional risk of breast cancer after 5 years of treatment in women with a BMI of 27 (kg/m²)

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

WHI study in the USA: additional risk of breast cancer after 5 years of treatment

Endometrial cancer risk

Postmenopausal women with intact uterus

The risk of endometrial cancer is approximately 5 cases per 1,000 women with intact uterus who do not receive HRT. Estrogen-only HRT is not recommended for women with intact uterus, as it increases the risk of endometrial cancer (see section "Special precautions"). Depending on the duration of estrogen-only therapy and estrogen dose, epidemiological studies have shown an increased risk of endometrial cancer ranging from 5 to 55 additional diagnosed cases per 1,000 women aged 50–65 years.

Adding progestogens to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study, combined (sequential or continuous) HRT use for five years did not increase the risk of endometrial cancer (RR 1.0 [0.8–1.2]).

Ovarian cancer

Use of estrogen-only therapy or combined estrogen-progestogen therapy is associated with a small increase in the risk of ovarian cancer (see section "Special precautions").

A meta-analysis of 52 epidemiological studies indicates an increased risk of ovarian cancer in women using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31–1.56). For women aged 50 to 54 years using HRT for five years, this corresponds to approximately one additional case per 2,000 users. Among women aged 50 to 54 years not using HRT, ovarian cancer was diagnosed in approximately 2 out of 2,000 women over five years.

Risk of venous thromboembolism (VTE)

With HRT, the relative risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism, is increased by 1.3 to 3 times. The likelihood of this complication is higher during the first year of HRT use (see section "Special precautions"). WHI study results are provided below.

WHI study – additional VTE risk after 5 years of treatment

Risk of ischaemic heart disease

The risk of ischaemic heart disease is slightly increased in women who received combined HRT after the age of 60 (see section "Special precautions").

Risk of ischaemic stroke

The relative risk of ischaemic stroke is increased 1.5-fold with estrogen-only and estrogen-progestogen therapy. The risk of haemorrhagic stroke is not increased with HRT.

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

Combined WHI studies – additional risk of ischaemic stroke* after 5 years of treatment

* Ischemic and hemorrhagic strokes were not differentiated.

Other adverse reactions reported with estrogen/progestogen therapy:

• gallbladder disease;
• skin and subcutaneous tissue disorders (chloasma, erythema multiforme, erythema nodosum, vasculitic purpura);
• possible dementia at age 65 and older (see section "Special warnings and precautions for use").

Other possible adverse reactions include: breast tenderness, liver tumors, hepatic function abnormalities, hypertriglyceridemia, changes in glucose tolerance, recurrence of endometriosis, prolactinoma, jaundice and/or cholestasis-related pruritus, epilepsy, asthma, porphyria, systemic lupus erythematosus, otosclerosis, chorea, Quincke's edema, peripheral edema, hypersensitivity reactions including rash and urticaria.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

This medicinal product requires no special storage conditions.

Keep out of reach and sight of children.

Packaging.

28 film-coated tablets in a blister; 1 or 3 blisters with a cardboard blister holder in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Gedeon Richter", Hungary.

Manufacturer's address and place of business.

H-1103 Budapest, 19-21 Demréi Street, Hungary.