Duphaston® [Dydrogesterone]

Pharmacological properties

Pharmacodynamics

Mechanism of action. Dydrogesterone is a selective progestogen that replaces some of the functions of progesterone. Like gestagen, dydrogesterone exclusively affects only the endometrium, the mucous membrane of the vagina and cervical canal.

Dydrogesterone does not inhibit ovulation. This means that the possibility of fertilization of the egg in non-pregnant women when taking dydrogesterone persists.

Dydrogesterone and its metabolites do not have thermogenic properties. In postmenopausal women with preserved uterus, estrogen replacement therapy leads to an increased risk of developing endometrial hyperplasia and endometrial cancer. Adding progestogens can prevent excessive risk.

Cyclic addition of dydrogesterone to women in whom the endometrium was stimulated by estrogen transfers it to the secretion phase.

Dydrogesterone has no masculinizing or virilizing properties. Dydrogesterone does not have anabolic or corticoid properties.

Clinical Efficiency and Safety

Support for the luteal phase with assisted reproductive technologies (ART). A double-blind, double-masked, randomized, multicenter study was conducted with two parallel groups to compare the efficacy, safety, and tolerability of dydrogesterone for oral use at a dose of 30 mg / day and intravaginal micronized progesterone in capsules at a dose of 600 mg / day to maintain the luteal phase with application of in vitro fertilization technologies (LOTUS I).

The main objective of the study - to demonstrate no less effective oral dydrogesterone compared with intravaginal micronized progesterone in terms of the presence of fetal heart contractions at the 12th week of gestation (10th week of pregnancy) - was achieved.

In the studied patient population, the pregnancy rate confirmed at the 12th week of gestation (10th week of pregnancy) was 37.6 and 33.1% in the groups of didrogesterone and micronized progesterone, respectively. The difference in the frequency of pregnancy between the two groups was 4.7 (95% confidence interval (CI) −1.2; 10.6).

In the sample of study subjects for safety assessment (1029 study subjects who received at least one dose of the study drug), the cases of adverse events that occurred during therapy, which were most often reported, were identical in both study groups.

Due to the nature of the testimony under study and the patient population under study, a certain number of early abortions / miscarriages is expected, especially before the 12th week of gestation (10th week of pregnancy), since the predicted rate of pregnancy during this period is about 35%.

The safety profile noted in this study was in line with what was expected, given the established safety profile of dydrogesterone, as well as the patient population being studied and the test indication.

Pharmacokinetics Unlike progesterone, didrogesterone is not excreted in the urine in the form of pregnanediol. Thus, it remains possible to determine the secretion of endogenous progesterone by the excretion of pregnandiol.

When administered orally, an average of 63% of the dose is excreted in the urine. Complete excretion occurs after 72 hours. Its main metabolite is 20-alpha-dihydrohydrogesterone (DHD), excreted in the urine in the state bound to glucuronic acid. A common property of all metabolites is the preservation of the structure of 4,6-dien-3-one of the starting material and the absence of 17-alpha-hydroxylation, which explains the lack of estrogen and androgen effects in dydrogesterone.

After oral administration of didrogesterone, the concentration in the blood plasma of DGD is significantly higher than the starting substance. The AUC ratio is about 30.

Dydrogesterone is rapidly absorbed.C_max dydrogesterone and DGD is achieved after 0.5–2.5 hours

Indications

• Irregular menstrual cycles; endometriosis; dysmenorrhea; infertility caused by luteal insufficiency; support for the luteal phase with the use of ART; threatening and common abortion associated with progesterone deficiency.

Duphaston can be used as a cyclical addition to estrogen therapy in women with an intact uterus:

• to prevent endometrial hyperplasia during menopause;
• with dysfunctional uterine bleeding;
• with secondary amenorrhea.

Application

Doses, regimen and duration of treatment can be adjusted depending on the severity of the disorder and the individual clinical response of the patient.

Irregular menstrual cycles. A cycle of 28 days can be achieved by administering 1 tablet of Duphaston per day from the 11th to the 25th day of the cycle.

Endometriosis From 1 to 3 tablets of Duphaston per day from the 5th to the 25th day of the cycle or throughout the cycle. Doses in multiples of 10 mg / day should be distributed evenly throughout the day. It is recommended to prescribe the maximum dose at the initial stage of treatment.

Dysmenorrhea. From 1 to 2 tablets of Duphaston per day from the 5th to the 25th day of the cycle. Doses in multiples of 10 mg / day should be distributed evenly throughout the day. It is recommended to prescribe the maximum dose at the initial stage of treatment.

Infertility caused by luteal insufficiency. 1 tablet Duphaston per day from the 14th to the 25th day 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 in the same doses as for a usual abortion.

Luteal phase support with ART 1 tablet Duphaston 3 times a day (30 mg / day). Treatment begins on the day of oocyte collection and continues for 10 weeks if pregnancy is confirmed.

Risk of miscarriage. Initial dose: 4 tablets of Duphaston immediately, then 1 tablet of Duphaston every 8 hours. Doses in multiples of 10 mg / day should be evenly distributed throughout the day. It is recommended to prescribe the maximum dose at the initial stage of treatment.

If symptoms do not disappear or reappear during treatment, the dose should be increased by 1 tablet of Duphaston every 8 hours.

After the disappearance of symptoms, the effective dose must be maintained for 1 week, then it can be gradually reduced. If symptoms reappear, treatment should be restored immediately with an effective dosage.

Habitual miscarriage. Treatment must be started before conception. 1 tablet Duphaston per day until the 20th week of pregnancy, after which you can gradually reduce the dose.

If symptoms of the threat of abortion appear during treatment, then therapy should be continued, as described in the event of an abortion threat.

Dysfunctional uterine bleeding. 2 tablets of Duphaston for 5–7 days in combination with estrogen.

A few days after the end of such treatment, withdrawal bleeding will appear.

In order to prevent further bleeding, Duphaston is prescribed 1 tablet per day from the 11th to the 25th day of the cycle.

In case of cystic hemorrhagic metropathy, 1 tablet of Duphaston per day is prescribed from the 11th to the 25th day of the cycle.

In some cases, it may be necessary to prescribe estrogen during the first half of the cycle. A few days after the cessation of such treatment, withdrawal bleeding will appear.

Such treatment should be continued for several cycles.

Secondary amenorrhea. For treatment, estrogen must be given at the same time. Estrogen is prescribed from the 1st to the 25th day of the cycle, from the 11th to the 25th day in combination with 1 tablet of Duphaston per day.

To create the prerequisites for subsequent cycles, therapy is started on the 5th day after the onset of bleeding by administering estrogens (from the 5th to the 25th day). Duphaston 10 mg is prescribed from the 11th to the 25th day.

To prevent endometrial hyperplasia during menopause. During each 28-day cycle of estrogen therapy, only estrogen is taken during the first 14 days and during the next 14 days, 1 or 2 tablets containing 10 mg of dydrogesterone are taken, in addition to estrogen therapy. In the case of dosing 10 mg of dydrogesterone 2 times a day, the tablets should be distributed throughout the day. Withdrawal bleeding usually occurs with dydrogesterone.

The use of combination therapy with estrogen and progestogen in postmenopausal women should be limited to the minimum effective dose and the shortest time to achieve the therapeutic goal, and the risks for each woman should be periodically reviewed (see SPECIAL INSTRUCTIONS).

Mode of application. For oral administration. When using high doses, the tablets should be evenly distributed for admission throughout the day.

Children. Due to the lack of data on the safety and effectiveness of the use of Duphaston in children, it is not recommended to prescribe a drug in this category of patients.

Contraindications

• Undiagnosed vaginal bleeding; serious serious liver diseases or the presence of serious liver diseases in the past, if liver function indicators have not returned to normal; contraindications to the use of estrogens should be taken into account when they are used in combination with progestogens such as dydrogesterone; established hypersensitivity to the active substance or any other component of the drug; identified or suspected progestogen-dependent neoplasms (e.g., meningioma).

Treatment to support the luteal phase with ART should be discontinued if abortion / miscarriage is diagnosed.

Side effects

When using dydrogesterone in clinical trials according to indications without estrogen treatment, the following adverse reactions were most often reported: migraine / headache, nausea, menstrual irregularities and pain / tenderness of the mammary glands.

The following adverse reactions were observed with the following frequency in clinical trials of the use of dydrogesterone (n = 3483) for indications without estrogen treatment and for spontaneous reports: often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000).

Neoplasms are benign, malignant and indefinite (including cysts and polyps): rarely - an increase in the size of progestogen-dependent neoplasms (for example, meningiomas) *.

Blood and lymphatic system: rarely - hemolytic anemia *.

Mental disorders: infrequently - depressive mood.

Immune system: rarely - hypersensitivity reactions.

Nervous system: often - headache and migraine; infrequently - dizziness; rarely drowsiness.

Alimentary tract: often - nausea; infrequently - vomiting.

Hepatobiliary system: infrequently - impaired liver function, accompanied by weakness, malaise, jaundice and abdominal pain.

Skin and subcutaneous tissue: infrequently - allergic dermatitis (eg, rash, itching and urticaria); rarely - angioedema *.

Reproductive system and mammary glands: often - menstrual irregularities (including metrorrhagia, menorrhagia, oligo- / amenorrhea, dysmenorrhea and irregular menstruation), pain in the mammary glands / sensitivity of the mammary glands; rarely - swelling of the mammary glands.

General symptoms and local reactions: rarely - edema.

Examination: infrequently - weight gain.

* Adverse reactions from spontaneous reports that are not noted in clinical trials are included in the “rarely” column on the basis that the upper limit of 95% CI frequency is estimated to be no higher than 3 / x, where x = 3483 (total number of subjects observed in clinical trials) .

LOTUS I study on luteal phase support with ART (seePHARMACOLOGICAL PROPERTIES, Pharmacodynamics): the most frequently reported adverse events were vaginal bleeding, nausea, pain during procedures, headache, abdominal pain, and biochemical pregnancy. The only adverse event that occurred during therapy and was noted in both groups was vaginal bleeding, recorded in ≥2% of subjects.

Adverse reactions associated with estrogen-progestogen treatment (see SPECIAL INSTRUCTIONS and instructions for medical use of estrogen preparations):

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

** The use of estrogen monotherapy or combined estrogen-progestogen hormone replacement therapy (HRT) has been associated with a slightly increased risk of ovarian cancer diagnosis (see SPECIFIC INDICATIONS). A meta-analysis of 52 epidemiological studies showed an increased risk of ovarian cancer in women treated with HRT compared to women who had never used HRT (RR 1.43; 95% CI 1.31-1.56). In women aged 50–54 years who used HRT for 5 years, the result showed one additional case in 2000 patients. About 2 out of 2,000 women aged 50–54 years who did not use HRT were diagnosed with ovarian cancer over a 5-year period.

special instructions

Before using dydrogesterone for the treatment of pathological bleeding, the organic cause of the bleeding should be ruled out.

Breakthrough bleeding or spotting may occur in the first months of treatment. If breakthrough bleeding or spotting occurs after some time of treatment or continues after treatment is completed, the cause should be established, including if necessary to exclude malignant neoplasm of the endometrium by means of an endometrial biopsy.

If any of the following disorders occurs for the first time or worsens with the use of the drug, discontinuation of treatment should be considered:

• very severe headache, migraine, or symptoms that may indicate cerebral ischemia;
• a significant increase in blood pressure;
• the appearance of venous thromboembolism.

In the case of a habitual or threatening abortion, it is necessary to determine and monitor the viability of the fetus during treatment to ensure that the pregnancy continues and the embryo is alive.

Conditions requiring control. It is known that the following rare cases can be affected by sex hormones, and therefore, during pregnancy or when sex hormones are used, it can develop or worsen: cholestatic jaundice, herpes pregnant women, severe itching, otosclerosis, porphyria, depression and abnormal liver function indicators caused by acute or chronic liver disease. If any of these conditions is present or appeared earlier and / or worsened during pregnancy or the previous hormone treatment, the patient should be closely monitored. It must be borne in mind that these conditions may recur or worsen during treatment with dydrogesterone, so discontinuation of therapy in such cases should be considered.

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

The following warnings relate to the use of Duphaston according to the indications "for the prevention of endometrial hyperplasia during menopause." See also warnings in instructions for medical use of estrogen preparations.

To relieve postmenopausal symptoms, HRT should be used exclusively in cases where the symptoms negatively affect the quality of life. In all cases, it is necessary to carefully evaluate the benefits and risks of HRT at least 1 time per year.HRT should only be continued if the benefit outweighs the risk.

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

Medical examination / further medical supervision. Before starting HRT or when it is restored after a break, it is necessary to collect a complete personal and family history. Given the history, as well as contraindications and warnings for taking the drug, an objective examination of the patient should be carried out (including examination of the pelvic organs and examination of the mammary glands). During treatment, it is recommended to conduct periodic examinations, the frequency and nature of which depend on the individual characteristics of the patient. Women should be informed of any changes in the mammary glands that they should report to the doctor or nurse (see below “Breast Cancer”). Examination of the mammary glands, including appropriate imaging methods, such as mammography, should be carried out in accordance with current screening practice, taking into account the individual clinical needs of the patient.

Hyperplasia and endometrial carcinoma. In women with an intact uterus, the risk of hyperplasia and endometrial carcinoma increases with prolonged estrogen monotherapy. Depending on the duration of treatment and the dose of estrogen, the risk can be from 2 to 12 times higher than in women not taking estrogen. Once estrogen therapy is discontinued, this risk persists for at least 10 years. The addition of progestogens, such as dydrogesterone, cyclically for at least 12 days per month / 28-day cycle or as a constant combination of estrogen-progestagen therapy in women with a preserved uterus can prevent the excessive risk associated with HRT only with estrogens.

Breakthrough bleeding and spotting can occur during the first months of treatment. If breakthrough bleeding or spotting occurs after the appointment of therapy for some time, or if they continue after the end of treatment, a further examination is indicated. This may mean that an endometrial biopsy is necessary to rule out malignancy.

Mammary cancer. All available data indicate an increased risk of developing breast cancer in women taking combined estrogen-progestogen therapy, and possibly even with HRT alone with estrogens. This risk depends on the duration of HRT use.

Combined estrogen-progestogen therapy: A Women’s Health Initiative (WHI) randomized, placebo-controlled study and epidemiological studies showed an increased risk of breast cancer in women taking estrogen-progestagen HRT for 3 or more years. After discontinuation of treatment, this increased risk persists for at least 5 years. HRT, especially estrogen-progestogen combination therapy, increases the density of mammographic images, which can adversely affect the radiological detection of breast cancer.

Ovarian cancer Ovarian cancer occurs much less frequently than breast cancer. Epidemiological data obtained as a result of extensive meta-analysis showed a slightly increased risk in women taking estrogen monotherapy or a combination of estrogen with a progestogen like HRT; this risk manifests itself within 5 years of use and decreases with time after discontinuation of therapy. Several other studies, including WHI, have shown that combined HRT may be associated with the same or slightly lower risk (see ADVERSE EFFECTS).

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

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

Commonly recognized risk factors for venous thromboembolism are estrogen use, old age, extensive surgery, prolonged immobilization, obesity (body mass index 30 kg / m²), pregnancy / postpartum period, systemic lupus erythematosus and cancer. There is no consensus on the possible role of varicose veins in the occurrence of venous thromboembolism.

As with all patients in the postoperative period, preventive measures should be considered to prevent venous thromboembolism after surgery. If planned surgical intervention requires further long-term immobilization, it is recommended to temporarily discontinue HRT 4–6 weeks before surgery. Until the woman regains full mobility, treatment should not be resumed.

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

In women already receiving ongoing anticoagulant therapy, the benefits and risks of HRT should be carefully weighed.

If venous thromboembolism develops after initiation of therapy, the drug should be discontinued. Patients should be informed that they should immediately consult a doctor if potential thromboembolic symptoms occur (for example, painful leg swelling, sudden chest pain, shortness of breath).

Ischemic heart disease. In randomized controlled trials, there was no evidence of protection against myocardial infarction in women with or without coronary artery disease receiving combined estrogen-progestogen therapy or HRT with estrogens only.

Combined estrogen-progestogen therapy: the relative risk of coronary heart disease with HRT is slightly increased. Since the basic absolute risk of coronary heart disease is largely dependent on age, the number of additional cases of coronary heart disease due to the use of estrogen-progestogen is very small in healthy women at the time of menopause, but will increase at an older age.

Ischemic stroke. Combined estrogen-progestogen therapy and estrogen monotherapy are associated with a 1–1.5-fold increased risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, since the underlying risk of stroke is highly dependent on age, the overall risk of stroke in women taking HRT increases with age.

Excipients. This medicine contains lactose monohydrate. Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use this drug.

Use during pregnancy and lactation

Pregnancy. According to estimates, more than 9 million pregnant women took dydrogesterone. There is still no evidence of the harmful effects of dydrogesterone when used during pregnancy.

The literature describes a study showing that the use of certain progestogens may be associated with an increased risk of hypospadias.But since so far this has not been confirmed in other studies, it is impossible to finally determine the role of progestogens in the development of hypospadias. Clinical studies in which a limited number of women were treated with dydrogesterone in early pregnancy did not show an increased risk. There are no other epidemiological data yet.

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

Dydrogesterone can be used during pregnancy for clear indications.

The period of breastfeeding. There is no data on the penetration of dydrogesterone into breast milk. Studies on the penetration 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 quantities. It is not known whether there is a risk for the baby, therefore didrogesterone should not be used during lactation.

Fertility. There is no evidence that dydrogesterone in therapeutic doses reduces fertility.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Duphaston has a negligible effect on the ability to drive a car and work with machines and mechanisms.

Infrequently, dydrogesterone may cause slight drowsiness and / or dizziness, especially in the first few hours after ingestion. Therefore, you must be careful when driving or operating machinery.

Interactions

In vitro studies indicate that the main metabolic pathway, which forms the main pharmacologically active metabolite of DGD, is catalyzed by aldoketoreductase 1c (akr 1c) in human cytosol. Along with cytosolic metabolism, metabolic transformations are carried out by isoenzymes of cytochrome p450 (cyp), almost exclusively by isoenzyme cyp 3a4, which leads to the formation of several minor metabolites. The main active metabolite, DGD, is a substrate for metabolic conversion using cyp 3a4. therefore, the metabolism of dydrogesterone and DGD can be accelerated while taking substances that induce cytochrome p450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), antimicrobial drugs (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and peripreforate (hyperfum) , sage or ginkgo biloba.

Ritonavir and nelfinavir, known as potent inhibitors of cytochrome enzymes, exhibit enzyme-inducing properties when used with steroid hormones. Clinically increased metabolism of dydrogesterone can lead to a decrease in effect.

In vitro studies have shown that didrogesterone and DHD in clinically significant concentrations do not inhibit and do not induce cytochrome P450 enzymes involved in drug metabolism.

Overdose

Symptoms dydrogesterone is a drug with very low toxicity. symptoms that theoretically can occur in case of an overdose are nausea, vomiting, drowsiness, and dizziness. There are known cases when an overdose of dydrogesterone led to harmful consequences (the maximum daily dose taken by a person was 360 mg).

Treatment. No specific treatment is required. In case of an overdose, symptomatic treatment may be considered.

Storage conditions

It does not require special storage conditions.

Duphaston Compendium - UADUSTO170331