DIDROLUTA

INSTRUCTIONS for medical use of the medicinal product DIDEROLUTA (DYDROLUTA)

Composition:

active substance: dydrogesterone;

1 tablet contains 10 mg of dydrogesterone;

excipients: lactose monohydrate, pregelatinized starch, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate;

film coating: lactose monohydrate, hypromellose (E 464), titanium dioxide (E 171), triacetin (E 1518).

Pharmaceutical form. Film-coated tablets.

Basic physico-chemical properties: round, biconvex, film-coated tablets of white to almost white color, with "711" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Sex gland hormones and drugs used in disorders of the reproductive system. Progestogens. Pregnanedione 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, parallel-group study was conducted to compare the efficacy, safety, and tolerability of orally administered dydrogesterone 30 mg once daily with intravaginal micronized progesterone capsules 600 mg once daily for luteal phase support in assisted reproductive technology (ART) (LOTUS I). A randomized, open-label, multicenter, parallel-group study was conducted to compare the efficacy, safety, and tolerability of orally administered dydrogesterone 30 mg once daily with intravaginal progesterone 8% gel (Crinone) 90 mg once daily for luteal phase support in ART (LOTUS II).

The clinical trials LOTUS I and LOTUS II 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 heartbeats at gestational week 12 (week 10 of pregnancy)—was achieved. In the study population, the rate of pregnancy confirmed at gestational week 12 (week 10 of pregnancy) was 37.6% and 33.1% (LOTUS I) and 36.7% and 34.7% (LOTUS II), respectively. The difference in pregnancy rates between the two groups was 4.7 (95% CI, -1.2; 10.6) (LOTUS I) and 2 (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 abortions is expected, particularly before week 12 of gestation (week 10 of pregnancy), as the anticipated pregnancy rate during this period is approximately 35%. The safety profile observed in both LOTUS studies was consistent with the expected profile based on the established safety profile of dydrogesterone, as well as the studied patient population and indication.

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. After 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 overall exposure (AUC) of dydrogesterone and DHD. The observed effect of concomitant food intake on the peak plasma concentration of dydrogesterone is considered clinically insignificant. Therefore, the medicinal product can be taken independently of food intake.

Distribution. After oral administration of dydrogesterone, the apparent volume of distribution is large, approximately 22,000 L. More than 90% of dydrogesterone and DHD is 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 substantially 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 elimination half-life of both dydrogesterone and DHD is approximately 15 hours. A common characteristic of all major 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. The 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 after 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;
• threatened miscarriage and recurrent miscarriage associated with progesterone deficiency.

The medicinal product may be used as cyclic add-back therapy to estrogen treatment in women with intact uterus:

• for prevention of endometrial hyperplasia during menopause;
• in dysfunctional uterine bleeding;
• in secondary amenorrhea.

Contraindications

• Undiagnosed vaginal bleeding;
• severe liver disease currently present or in medical history, if liver function tests have not returned to normal;
• contraindications for estrogens should be considered when they 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 (meningioma or history of meningioma).

Treatment for luteal phase support in assisted reproductive technologies 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 carried out by cytochrome P450 (CYP) isoenzymes, almost exclusively by the CYP3A4 isoenzyme, resulting in several minor metabolites. The major 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, known as strong inhibitors of cytochrome enzymes, have been shown to exhibit 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 treatment with dydrogesterone for pathological bleeding, organic causes 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 occurs for the first time or worsens during treatment, discontinuation of therapy should be considered:

• severe headache, migraine or symptoms indicating cerebral ischaemia;
• significant increase in blood pressure;
• occurrence of venous thromboembolism.

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

Conditions requiring monitoring

The following rare conditions are known to be influenced by sex hormones and may therefore occur or worsen during pregnancy or during treatment with 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 is present or has occurred previously and/or worsened during pregnancy or previous hormone treatment, the patient should be under close surveillance. It should be considered that these conditions may recur or worsen during dydrogesterone therapy, and therefore discontinuation of therapy should be considered in such cases. Patients with a history of depression should be under close surveillance. If severe depression recurs, treatment with dydrogesterone should be discontinued.

Meningioma

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

The following warnings apply to use of the medicinal product for the indication "prevention of endometrial hyperplasia in the menopausal period"

See also warnings in the instructions for medical use of oestrogen preparations. Hormone replacement therapy for treatment of postmenopausal symptoms should be used only when symptoms negatively affect quality of life. In all cases, the benefit-risk balance of hormone replacement therapy should be carefully evaluated at least once a year. Hormone replacement therapy should be continued only if the benefit outweighs the risk.

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

Medical examination / follow-up medical monitoring

Before starting hormone replacement therapy or resuming it after a break, a complete personal and family history should be taken. Based on the history, as well as contraindications and warnings for the medicinal product, a physical examination of the patient (including pelvic examination and breast examination) should be performed. Periodic examinations are recommended during treatment, the frequency and nature of which depend on individual patient characteristics. Women should be informed about changes in the breasts that 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 practices, taking into account the individual clinical needs of the patient.

Endometrial hyperplasia and carcinoma

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

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

Breast cancer

All available data indicate an increased risk of breast cancer in women taking combined oestrogen-progestogen therapy or oestrogen-only hormone replacement therapy. This risk depends on the duration of hormone replacement therapy use. Combined oestrogen-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 oestrogen-progestogen hormone replacement therapy, evident after approximately 3 (from 1 to 4) years. Results from a large meta-analysis showed that after discontinuation of treatment, this increased risk decreases over time, and the time required to return to baseline risk level depends on the duration of prior hormone replacement therapy use. If such therapy lasted more than 5 years, this risk may persist for 10 years or longer.

Hormone replacement therapy, particularly combined oestrogen-progestogen therapy, increases mammographic breast density, which may negatively affect radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Epidemiological data from a large meta-analysis showed a slightly increased risk in women using oestrogen monotherapy or oestrogen-progestogen combination as hormone replacement therapy; this risk becomes evident within 5 years of use and decreases over time after discontinuation of therapy. Some other studies, including WHI, have shown that use of combined hormone replacement therapy may be associated with the same or slightly lower risk (see "Adverse reactions").

Venous thromboembolism

Hormone replacement therapy 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 hormone replacement therapy than later.

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

Well-established risk factors for venous thromboembolism include oestrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus 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 prevent venous thromboembolism after surgery. If planned surgery requires prolonged immobilization, hormone replacement therapy is recommended to be temporarily discontinued 4–6 weeks before surgery. Treatment should not be resumed until the woman regains 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 a combination of defects) is detected, hormone replacement therapy is contraindicated.

In women already receiving long-term anticoagulant therapy, the benefit and risk of hormone replacement therapy should be carefully weighed.

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

Ischaemic heart disease

Randomized controlled trials have not shown evidence of protection against myocardial infarction in women with or without ischaemic heart disease who are receiving combined oestrogen-progestogen therapy or oestrogen-only hormone replacement therapy. Combined oestrogen-progestogen therapy: the relative risk of ischaemic heart disease during hormone replacement therapy is slightly increased. Since the baseline absolute risk of ischaemic heart disease largely depends on age, the number of additional cases of ischaemic heart disease due to oestrogen-progestogen use is very small in healthy women at menopause onset but increases with age.

Ischaemic stroke

Combined oestrogen-progestogen therapy and oestrogen monotherapy are associated with a 1- to 1.5-fold increased risk of ischaemic 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 hormone replacement therapy increases with age.

Important information about excipients

This medicinal product contains lactose monohydrate. Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 the development of hypospadias 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 available to date. 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 affect the speed of reactions while driving or operating machinery

The medicinal product has negligible influence on the ability to drive and use machines.

Rarely, dydrogesterone may cause mild drowsiness and/or dizziness, especially in 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 the use of the medicinal product. The doses, regimen, 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 may be achieved by administering 1 tablet of the medicinal product daily from day 11 to day 25 of the cycle.

Endometriosis

From 1 to 3 tablets of the medicinal product daily from day 5 to day 25 of the cycle or throughout the entire cycle. Doses equivalent to 10 mg daily should be evenly distributed throughout the day. It is recommended to initiate treatment with the highest dose.

Dysmenorrhea

From 1 to 2 tablets of the medicinal product daily from day 5 to day 25 of the cycle. Doses equivalent to 10 mg daily 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 the medicinal product 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 abortion.

Support of the luteal phase in assisted reproductive technologies

1 tablet of the medicinal product 3 times daily (30 mg daily). 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 the medicinal product immediately, followed by 1 tablet every 8 hours. Doses equivalent to 10 mg daily 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 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 immediately resumed at the dose that proved effective.

Habitual abortion

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

If symptoms of threatened pregnancy loss occur during treatment, therapy should be continued as described for threatened miscarriage.

Dysfunctional uterine bleeding

To stop bleeding, administer 2 tablets daily for 5–7 days. Blood loss significantly decreases within a few days. Withdrawal bleeding usually occurs several days after completion of this treatment, and patients should be informed about this. To prevent further episodes of heavy uterine bleeding, administer 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 cycle normalization in the patient.

Secondary amenorrhea

From 1 to 2 tablets of the medicinal product 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, and for the subsequent 14 days, add 1 or 2 tablets containing 10 mg dydrogesterone to estrogen therapy. For a dosage of 10 mg dydrogesterone twice daily, tablet intake should be evenly distributed throughout the day. Withdrawal bleeding usually occurs during dydrogesterone administration.

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

Method of administration

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 medicinal product 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 effects (maximum daily dose taken by humans was 360 mg).

Treatment. No specific treatment is required. Symptomatic treatment may be considered in case of overdose.

Adverse Reactions

When dydrogesterone was used in clinical trials 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 indications without concomitant estrogen therapy, in two company-sponsored interventional clinical trials on luteal phase support in assisted reproductive technologies using dydrogesterone (n=1036), and from spontaneous reporting. The frequency categories are based on the most conservative approach: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000).

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

Blood and lymphatic system disorders: rare: haemolytic anaemia*.

Psychiatric disorders: uncommon: depressed mood.

Immune system disorders: rare: hypersensitivity reactions.

Nervous system disorders: common: headache and migraine; uncommon: dizziness; rare: somnolence.

Gastrointestinal disorders: common: nausea, vomiting, abdominal pain.

Hepatobiliary disorders: uncommon: liver function abnormalities associated with 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 of the breasts; rare: breast swelling.

General disorders and administration site conditions: rare: oedema.

Investigations: uncommon: weight gain.

*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 observed in clinical trials).

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

• breast cancer, endometrial hyperplasia and carcinoma, ovarian cancer**;
• venous thromboembolism;
• myocardial infarction, ischaemic heart disease, ischaemic stroke.

** The use of estrogen-only therapy 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 resulted in one additional case per 2000 users. Among approximately 2 in 2000 women aged 50–54 years who did not use HRT, ovarian cancer was diagnosed over a 5-year period.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. 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: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of the reach and sight of children.

Packaging. 10 tablets in a blister; 2 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. Hauffe Pharma Münster GmbH.

Manufacturer's address and place of business. Schlebrüggenkamp 15, Uppenberg, Münster, North Rhine-Westphalia, 48159, Germany.