INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DANIESTA® (Daniesta)

Composition:

Active substance: dydrogesterone;

1 film-coated tablet contains 10 mg of dydrogesterone;

Excipients: lactose monohydrate, hypromellose, maize starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: polyvinyl alcohol, macrogol, titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white to almost white, round, biconvex film-coated tablets.

Pharmacotherapeutic group. Sex hormones and drugs used in pathologies of the genital system. Progestogens. Pregnadiene derivatives. ATC code G03DB01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Dydrogesterone is a synthetic progestogen with oral bioavailability that induces secretory transformation of the endometrium in an estrogen-stimulated uterus. It prevents the increased risk of endometrial hyperplasia and/or endometrial cancer caused by estrogens. Dydrogesterone has no estrogenic, androgenic, anabolic, or corticoid properties.

Dydrogesterone does not suppress ovulation. This means that the possibility of fertilization of the oocyte in women of reproductive age remains during treatment with dydrogesterone.

In postmenopausal women with an intact uterus, estrogen replacement therapy leads to an increased risk of endometrial hyperplasia and endometrial cancer. The addition of a progestogen prevents this additional risk.

Clinical Efficacy and Safety

A double-blind, double-dummy, randomized, multicenter study with two parallel groups was conducted to compare the efficacy, safety, and tolerability of orally administered dydrogesterone 30 mg once daily and intravaginal micronized progesterone 600 mg once daily for luteal phase support in assisted reproductive technology (ART) (LOTUS I).

A randomized, open-label, multicenter study with two parallel groups was conducted to compare the efficacy, safety, and tolerability of orally administered dydrogesterone 30 mg once daily and intravaginal 8% progesterone gel 90 mg once daily for luteal phase support in ART (LOTUS II).

LOTUS I and LOTUS II clinical trials confirmed the following

The primary objective of the studies—to demonstrate non-inferiority of oral dydrogesterone compared to intravaginal micronized progesterone in terms of presence of fetal heartbeat at week 12 of gestation (week 10 of pregnancy)—was achieved.

In the study population, the rate of pregnancy confirmed at week 12 of gestation (week 10 of pregnancy) was 37.6% and 33.1% (LOTUS I) and 36.7% and 34.7% (LOTUS II). The difference in pregnancy rates between the two groups was 4.7 (95% CI, -1.2; 10.6) (LOTUS I) and 2.0 (95% CI, -4.0; 8.0) (LOTUS II).

In the safety-evaluable population (1029 subjects (LOTUS I) and 1030 subjects (LOTUS II) who received at least one dose of study medication), treatment-emergent adverse events (TEAEs) reported most frequently were identical in both treatment groups.

Given the nature of the investigated indication and patient population, a certain number of early abortions/spontaneous miscarriages is expected, particularly before week 12 of gestation (week 10 of pregnancy), as the predicted pregnancy rate during this period is approximately 35%.

The safety profile observed in both LOTUS studies was consistent with the expected profile, considering the established safety profile of dydrogesterone, as well as the patient population and indication studied.

Pharmacokinetics

Absorption

After oral administration of dydrogesterone in film-coated tablets, it is rapidly absorbed. Maximum plasma concentrations (Cmax) of approximately 3.2 ng/mL for the parent compound dydrogesterone and 57 ng/mL for its active metabolite 20-alpha-dihydrodydrogesterone (DHD) are reached within 0.5–1.5 hours after administration. Total exposure over time (AUC) is approximately 9.1 and 220 ng·h/mL for dydrogesterone and DHD, respectively.

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

The observed effect of concomitant food intake on the peak plasma concentration of dydrogesterone is considered clinically insignificant. Therefore, dydrogesterone film-coated tablets may be taken independently of meals.

Distribution

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

Metabolism

After oral administration, dydrogesterone is rapidly metabolized to DHD. The concentration of the main active metabolite DHD reaches its peak at the same time as dydrogesterone. Plasma concentrations of DHD are significantly higher than those of the parent compound. The ratios of AUC and Cmax of DHD to those of dydrogesterone are approximately 25 and 20, respectively. The mean terminal half-life of both dydrogesterone and DHD is approximately 15 hours. A common feature of all characteristic metabolites is the preservation of the 4,6-diene-3-one structure of the parent compound and the absence of 17-alpha-hydroxylation, which explains the lack of estrogenic and androgenic effects of dydrogesterone.

Elimination

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

Dose and Time Dependence

Pharmacokinetics of single and multiple doses are linear following oral administration in the dose range of 2.5–20 mg. Comparison of single-dose and multiple-dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD do not change upon repeated administration. Steady-state conditions are usually achieved within 3 days of treatment.

Clinical characteristics.

Indications.

Irregular menstrual cycles;
endometriosis;
dysmenorrhea;
infertility due to luteal phase deficiency;
luteal phase support in assisted reproductive technologies (ART);
threatened and habitual miscarriage associated with progesterone deficiency.

Danoesta® can be used as cyclic supplementation to estrogen therapy in women with intact uterus:

for prevention of endometrial hyperplasia in the menopausal period;
in dysfunctional uterine bleeding;
in secondary amenorrhea.

Contraindications.

Undiagnosed vaginal bleeding;
current or past history of severe liver disease, if liver function tests have not normalized;
contraindications to estrogens should be considered when estrogens are used in combination with progestogens such as dydrogesterone;
known hypersensitivity to the active substance or to any of the excipients;
established or suspected progestogen-dependent neoplasms (e.g., meningioma or history of meningioma).

Treatment for luteal phase support in assisted reproductive technologies (ART) should be discontinued if abortion/miscarriage is diagnosed.

Interaction with other medicinal products and other forms of interaction.

In vitro studies indicate that the main metabolic pathway leading to the formation of the primary pharmacologically active metabolite 20α-dihydrodydrogesterone (DHD) is catalyzed by human cytosolic aldo-keto reductase 1C (AKR 1C). In addition to cytosolic metabolism, metabolic transformations are mediated by cytochrome P450 (CYP) isoenzymes, predominantly CYP3A4, resulting in several minor metabolites. The main active metabolite DHD is a substrate for metabolic transformation by CYP3A4. Therefore, the metabolism of dydrogesterone and DHD may be accelerated when co-administered with substances that induce cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine), antimicrobial agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz), and herbal preparations containing St. John's wort (Hypericum perforatum), sage, or Ginkgo biloba.

Ritonavir and nelfinavir are known as potent inhibitors of cytochrome enzymes but demonstrate enzyme-inducing properties when co-administered with steroid hormones. Clinically, increased metabolism of dydrogesterone may lead to reduced efficacy.

In vitro studies have shown that dydrogesterone and DHD, at clinically relevant concentrations, do not inhibit or induce cytochrome P450 enzymes involved in drug metabolism.

Special precautions for use.

Before starting dydrogesterone for the treatment of pathological bleeding, an organic cause of bleeding should be excluded.

Breakthrough bleeding or spotting may occur during the first months of treatment. If breakthrough bleeding or spotting continues to occur after some time on treatment or persists after treatment has ended, the cause should be investigated, including, if necessary, ruling out endometrial malignancy by endometrial biopsy.

If any of the following conditions occur for the first time or worsen during treatment, discontinuation of therapy should be considered:

severe headache, migraine, or symptoms that may indicate cerebral ischemia;
significant increase in blood pressure;
occurrence of venous thromboembolism.

In cases of habitual or threatened miscarriage, the viability of the fetus should be determined and monitored during treatment to confirm that pregnancy continues and the embryo is alive.

Conditions requiring monitoring

The following rare conditions are known to be influenced by sex hormones, and therefore may develop or worsen during pregnancy or while taking sex hormones: cholestatic jaundice, herpes gestationis, severe pruritus, otosclerosis, porphyria, depression, and abnormal liver function tests due to acute or chronic liver disease. If any of these conditions are present or have occurred previously and/or worsened during pregnancy or previous hormone therapy, the patient should be closely monitored. It should be considered that these conditions may recur or worsen during dydrogesterone therapy; therefore, discontinuation of therapy should be considered in such cases.

Meningioma

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

Patients with a history of depression should be closely monitored. If severe depression recurs, dydrogesterone treatment should be discontinued.

The following warnings apply to the use of the medicinal product Dydrogesterone® for the indication "prevention of endometrial hyperplasia during menopause"

See also warnings in the instructions for medical use of estrogen-containing drugs.

Hormone replacement therapy (HRT) for the treatment of postmenopausal symptoms should be used only when symptoms negatively affect quality of life. In all cases, the benefit-risk balance of HRT should be carefully evaluated at least once a year. HRT should be continued only if benefits outweigh risks.

Evidence regarding risks associated with HRT for the treatment of premature menopause is limited. Due to the low absolute risk in younger women, the benefit-risk balance in this group may be more favorable than in older women.

Medical examination/follow-up monitoring

Before initiating HRT or reinitiating it after a break, a complete personal and family medical history should be obtained. Based on the history, as well as contraindications and warnings, a physical examination of the patient (including pelvic examination and breast examination) should be performed. Periodic examinations are recommended during treatment, with frequency and type depending on individual patient characteristics. Women should be informed about which breast changes they should report to their physician or nurse (see below Breast cancer). Breast examinations, including appropriate imaging methods such as mammography, should be performed according to current screening guidelines, taking into account individual clinical needs.

Endometrial hyperplasia and endometrial carcinoma

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial carcinoma is increased with long-term estrogen-only therapy. Depending on duration of treatment and estrogen dose, the risk may be 2 to 12 times higher than in women not taking estrogens. This risk persists for at least 10 years after discontinuation of estrogen therapy. Adding progestogens such as dydrogesterone, cyclically for at least 12 days per month/28-day cycle or as continuous combined estrogen-progestogen therapy, in women with an intact uterus, can prevent the excess risk associated with estrogen-only HRT.

Breakthrough bleeding or spotting may occur during the first months of treatment. If breakthrough bleeding or spotting occurs after some time on therapy or continues after treatment ends, further investigation is indicated. This may include endometrial biopsy to exclude malignancy.

Breast cancer

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

Combined estrogen-progestogen therapy: randomized placebo-controlled studies such as the Women’s Health Initiative (WHI) and meta-analyses of prospective epidemiological studies have shown an increased risk of breast cancer in women taking estrogen-progestogen HRT, evident after approximately 3 (1 to 4) years. Results from large meta-analyses indicate that after discontinuation of treatment, this increased risk decreases over time, and the time required to return to baseline risk depends on the prior duration of HRT. If treatment lasted more than 5 years, this risk may persist for 10 years or longer.

HRT, particularly combined estrogen-progestogen therapy, increases mammographic breast density, which may impair radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer occurs much less frequently than breast cancer. Epidemiological data from large meta-analyses have shown a slightly increased risk in women using estrogen-only or estrogen-progestogen HRT; this risk becomes evident within 5 years of use and decreases over time after stopping therapy. Some other studies, including WHI, have shown that combined HRT may be associated with a similar or slightly lower risk (see "Adverse reactions").

Venous thromboembolism

HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism, i.e., deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely during the first year of HRT than later.

Patients with known thrombophilic conditions have an increased risk of venous thromboembolism, and HRT may further increase this risk. Therefore, HRT is contraindicated in this patient group.

Well-established risk factors for venous thromboembolism 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 possible role of varicose veins in the development of venous thromboembolism.

As in all postoperative patients, preventive measures should be considered to avoid venous thromboembolism after surgery. If planned surgery requires prolonged immobilization, HRT should be temporarily discontinued 4–6 weeks before surgery. Treatment should not be resumed until the woman has regained full mobility.

Women without a personal history of venous thromboembolism but with a family history of thrombosis in first-degree relatives at a young age may be offered screening after careful discussion of its limitations (only a portion of thrombophilic defects can be detected by screening). If a thrombophilic defect associated with thrombosis in family members or a defect associated with a severe anomaly (e.g., antithrombin, protein S or protein C deficiency, or combination of defects) is detected, HRT is contraindicated.

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

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

Ischemic heart disease

Randomized controlled trials have not shown evidence of protection against myocardial infarction in women with or without ischemic heart disease receiving combined estrogen-progestogen therapy or estrogen-only HRT.

Combined estrogen-progestogen therapy: the relative risk of ischemic heart disease during HRT is slightly increased. Since the baseline absolute risk of ischemic heart disease largely depends on age, the number of additional cases of ischemic heart disease due to estrogen-progestogen use is very low in healthy women at menopause but increases with age.

Ischemic stroke

Combined estrogen-progestogen therapy and estrogen-only therapy are associated with a 1- to 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 largely depends on age, the overall risk of stroke in women taking HRT increases with age.

Excipients

This medicinal product contains lactose monohydrate. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

It is estimated that more than 9 million pregnant women have taken dydrogesterone. To date, no evidence of harmful effects of dydrogesterone when used during pregnancy has been found.

Literature includes a study suggesting that use of certain progestogens may be associated with an increased risk of hypospadias. However, since this has not been confirmed in other studies, the role of progestogens in hypospadias development cannot be definitively established. Clinical studies involving a limited number of women treated with dydrogesterone in early pregnancy have not shown an increased risk. No other epidemiological data are currently available.

In preclinical studies of embryofetal and postnatal development, effects were consistent with the pharmacological profile. Adverse effects occurred only when drug exposure greatly exceeded the maximum human exposure.

Dydrogesterone may be used during pregnancy when clearly indicated.

Breastfeeding period

There are no data on the passage of dydrogesterone into breast milk. Studies on the passage of dydrogesterone into breast milk have not been conducted.

Experience with other progestogens indicates that progestogens and their metabolites pass into breast milk in small amounts. The risk to the infant is unknown; therefore, dydrogesterone should not be used during breastfeeding.

Fertility

There is no evidence that dydrogesterone at therapeutic doses reduces fertility.

Ability to influence reaction speed when driving or operating machinery.

Dydrogesterone® has negligible influence on the ability to drive vehicles and operate machinery.

Rarely, dydrogesterone may cause mild drowsiness and/or dizziness, especially within the first few hours after administration. Therefore, driving or operating machinery should be done with caution.

Dosage and Administration

The following dosage regimens are recommended for treatment with the medicinal product Daniste®. Dosages, regimens, and duration of treatment may be adjusted depending on the severity of the disorder and the individual clinical response of the patient.

Irregular menstrual cycles

A 28-day cycle can be achieved by administering 1 tablet of Daniste® daily from day 11 to day 25 of the cycle.

Endometriosis

From 1 to 3 tablets of Daniste® daily from day 5 to day 25 of the cycle, or throughout the entire cycle. Doses that are multiples of 10 mg per day should be evenly distributed throughout the day. It is recommended to initiate treatment with the highest dose.

Dysmenorrhea

From 1 to 2 tablets of Daniste® daily from day 5 to day 25 of the cycle. Doses that are multiples of 10 mg per day should be evenly distributed throughout the day. It is recommended to initiate treatment with the highest dose.

Infertility due to luteal phase deficiency

1 tablet of Daniste® daily from day 14 to day 25 of the cycle.

This treatment should be continued for a minimum of 6 consecutive cycles. It is recommended to continue treatment during the first months of pregnancy at the same doses as used for habitual miscarriage.

Support of the luteal phase in assisted reproductive technologies (ART)

1 tablet of Daniste® 3 times daily (30 mg per day). Treatment should begin on the day of oocyte retrieval and continue for 10 weeks if pregnancy is confirmed.

Threatened miscarriage

Initial dose: 4 tablets of Daniste® immediately, followed by 1 tablet of Daniste® every 8 hours. Doses that are multiples of 10 mg per day should be evenly distributed throughout the day. It is recommended to initiate treatment with the highest dose.

If symptoms do not resolve or recur during treatment, the dose should be increased by 1 tablet of Daniste® every 8 hours.

After symptoms resolve, the effective dose should be maintained for one week, after which it may be gradually reduced. If symptoms recur, treatment should be promptly resumed at the dosage previously found effective.

Habitual miscarriage

Treatment should begin prior to conception. 1 tablet of Daniste® daily up to week 20 of pregnancy, after which the dose may be gradually tapered.

If symptoms of threatened pregnancy loss occur during treatment, continue treatment as described for threatened miscarriage.

Dysfunctional uterine bleeding

To stop bleeding, administer 2 tablets of Daniste® daily for 5–7 days. Blood loss significantly decreases within a few days. Withdrawal bleeding typically occurs several days after completion of treatment, and patients should be informed about this possibility.

To prevent further episodes of heavy uterine bleeding, Daniste® should be administered at a dose of 1 tablet daily from day 11 to day 25 of the cycle, if necessary in combination with estrogen, for 2–3 cycles. After this, treatment may be discontinued to assess whether menstrual cycle normalization has occurred.

Secondary amenorrhea

From 1 to 2 tablets of Daniste® daily from day 11 to day 25 of the cycle to ensure optimal secretory transformation of the endometrium adequately stimulated by endogenous or exogenous estrogens.

Prevention of endometrial hyperplasia during menopause

During each 28-day cycle of estrogen therapy, administer estrogen alone for the first 14 days, followed by 1 or 2 tablets containing 10 mg of dydrogesterone daily in addition to estrogen therapy for the next 14 days. For a dosage of 10 mg dydrogesterone twice daily, tablet intake should be evenly distributed throughout the day. Withdrawal bleeding typically occurs during dydrogesterone administration.

Combined estrogen and progestogen therapy in postmenopausal women should be limited to the lowest effective dose and shortest duration consistent with therapeutic goals and individual risks, and the continued need for such treatment should be periodically reassessed (see "Special precautions for use").

Administration method

For oral use.

When higher doses are used, tablets should be evenly distributed throughout the day.

Children

Dydrogesterone should not be used before the onset of menstruation. The safety and efficacy of dydrogesterone in adolescents aged 12 to 18 years have not been established.

Overdose

Symptoms

Dydrogesterone is a drug with very low toxicity. Theoretically possible symptoms in case of overdose include nausea, vomiting, drowsiness, and dizziness. There are no known cases in which dydrogesterone overdose has led to harmful consequences (maximum daily dose taken by a human was 360 mg).

Treatment

Specific treatment is not required. Symptomatic treatment may be considered in case of overdose.

Adverse Reactions

In clinical trials of dydrogesterone used for indications without concomitant estrogen therapy, the most frequently reported adverse reactions were: vaginal bleeding, migraine/headache, nausea, vomiting, abdominal pain, menstrual disorders, and breast pain/tenderness.

The adverse reactions listed below were observed at the frequencies indicated in clinical trials of dydrogesterone (n=3483) for non-estrogen-treated indications, in two company-sponsored interventional clinical trials on luteal phase support in assisted reproductive technology (ART) using dydrogesterone (n=1036), and from spontaneous reports. The frequency categories are defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000).

Benign, malignant and unspecified neoplasms (including cysts and polyps):
Rare: increase in size of progesterone-dependent neoplasms (e.g., meningioma)*.

Blood and lymphatic system disorders
Rare: haemolytic anaemia*.

Psychiatric disorders
Uncommon: depressed mood.

Immune system disorders
Rare: hypersensitivity reactions.

Nervous system disorders
Common: headache, migraine.
Uncommon: dizziness.
Rare: somnolence.

Gastrointestinal disorders
Common: nausea, vomiting, abdominal pain.

Hepatobiliary disorders
Uncommon: liver function abnormalities, accompanied by weakness or malaise, jaundice, and abdominal pain.

Skin and subcutaneous tissue disorders
Uncommon: allergic dermatitis (e.g., rash, pruritus, urticaria).
Rare: angioneurotic oedema*.

Reproductive system and breast disorders
Very common: vaginal bleeding.
Common: menstrual disorders (including metrorrhagia, menorrhagia, oligo-/amenorrhoea, dysmenorrhoea, and irregular menstruation), breast pain/tenderness.
Rare: breast swelling.

General disorders and administration site conditions
Rare: oedema.

Investigations
Uncommon: weight increase.

*Adverse reactions from spontaneous reports not observed in clinical trials were categorized as "rare" based on the assumption that the upper limit of the 95% confidence interval of the expected frequency does not exceed 3/x, where x=3483 (total number of subjects in clinical trials).

Adverse reactions associated with estrogen-progestogen therapy (see also section "Special Warnings and Precautions for Use" and prescribing information for estrogen-containing products):

Breast cancer, endometrial hyperplasia and carcinoma, ovarian cancer**;
Venous thromboembolism;
Myocardial infarction, ischaemic heart disease, ischaemic stroke.

** Use of estrogen-only or combined estrogen-progestogen hormone replacement therapy (HRT) has been associated with a slightly increased risk of ovarian cancer diagnosis (see "Special Warnings and Precautions for Use"). A meta-analysis of 52 epidemiological studies showed an increased risk of ovarian cancer in women who used HRT compared to women who never used HRT (RR 1.43; 95% CI 1.31–1.56). In women aged 50–54 years who used HRT for 5 years, this corresponds to one additional case per 2000 users. Among approximately 2 out of 2000 women aged 50–54 years who did not use HRT, ovarian cancer was diagnosed over a 5-year period.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of operation.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.