Instructions Duphaston film-coated tablets 10 mg blister No. 14
Composition
active ingredient: dydrogesterone;
1 tablet contains dydrogesterone 10 mg;
excipients: tablet core – lactose monohydrate; hypromellose; corn starch; colloidal anhydrous silicon dioxide; magnesium stearate;
shell: macrogol 400, hypromellose, titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex, film-coated, white tablet with beveled edge, with a score line and marking "155" on one side on both sides of the score line. Diameter - 7 mm.
The score line is intended only to facilitate swallowing and does not divide the tablet into equal doses.
Pharmacotherapeutic group
Hormones of the sex glands and drugs used in pathologies of the reproductive system. Progestogens. Pregnadiene derivatives. ATX code G03D B01.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Dydrogesterone is a selective progestogen that replaces some of the functions of progesterone.
As a progestogen, dydrogesterone exclusively affects the endometrium, the mucous membrane of the vagina and the cervical canal.
Dydrogesterone does not suppress ovulation. This means that the possibility of fertilization of an egg in non-pregnant women when taking dydrogesterone remains.
Dydrogesterone and its metabolites do not have thermogenic properties.
In postmenopausal women with an intact uterus, estrogen replacement therapy increases the risk of endometrial hyperplasia and endometrial cancer. The addition of progestogens may prevent this excess risk.
Cyclical addition of dydrogesterone to women whose endometrium has been stimulated by estrogen puts it into the secretory phase.
Dydrogesterone has no masculinizing or virilizing properties. Dydrogesterone has no anabolic or corticoid properties.
Clinical efficacy and safety
A double-blind, double-masked, randomized, multicenter study with two parallel groups was conducted to compare the efficacy, safety, and tolerability of oral dydrogesterone at a dose of 30 mg per day and intravaginal micronized progesterone capsules at a dose of 600 mg per day for luteal phase support during in vitro fertilization (LOTUS I).
A randomized, open-label, multicenter, two-arm, parallel-group study was conducted to compare the efficacy, safety, and tolerability of oral dydrogesterone 30 mg/day and intravaginal progesterone 8% gel (Crinone) 90 mg/day for luteal phase support during in vitro fertilization (LOTUS II).
The LOTUS I and LOTUS II clinical trials confirmed the following.
The main objective of the studies – to prove the non-inferior efficacy of oral dydrogesterone compared to intravaginal micronized progesterone in terms of the presence of fetal heartbeats at 12 weeks of gestation (10 weeks of pregnancy) – was achieved.
In the study population, the pregnancy rates confirmed at 12 weeks of gestation (10 weeks of pregnancy) were 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 study population (1029 subjects (LOTUS I) and 1030 subjects (LOTUS II) who received at least one dose of study drug), the most commonly reported treatment-emergent adverse events (TEAEs) were identical in both study groups.
Due to the nature of the indication studied and the patient population studied, a certain number of early abortions/miscarriages is expected, especially before the 12th week of gestation (10th week of pregnancy), as the predicted pregnancy rate during this period is about 35%.
The safety profile observed in both LOTUS studies was consistent with what was expected, given the established safety profile of dydrogesterone, as well as the patient population studied and the indication studied.
Pharmacokinetics
Unlike progesterone, dydrogesterone is not excreted in the urine as pregnanediol. Thus, it remains possible to determine endogenous progesterone secretion from pregnanediol excretion.
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-dihydrodydrogesterone (DHD), which is excreted in the urine in a glucuronic acid-bound state. A common property of all metabolites is the preservation of the 4,6-dien-3-one structure of the parent substance and the absence of 17-alpha-hydroxylation, which explains the absence of estrogenic and androgenic effects in dydrogesterone.
After oral administration of dydrogesterone, the plasma concentration of DHD is significantly higher than that of the parent compound. The AUC ratio (area under the plasma concentration curve) is about 30.
Dydrogesterone is rapidly absorbed. The maximum concentration of dydrogesterone and DHD is reached after 0.5-2.5 hours.
Indication
Irregular menstrual cycles; endometriosis; dysmenorrhea; infertility caused by luteal insufficiency; luteal phase support during assisted reproductive technologies (ART); threatened and habitual miscarriage associated with progesterone insufficiency.
Duphaston® can be used as a cyclical adjunct to estrogen therapy in women with an intact uterus:
for the prevention of endometrial hyperplasia during menopause; for dysfunctional uterine bleeding; for secondary amenorrhea.
Contraindication
Undiagnosed vaginal bleeding; severe liver disease or a history of severe liver disease if liver function tests have not returned to normal; contraindications for estrogens should be considered when used in combination with progestogens such as dydrogesterone; known hypersensitivity to the active substance or to any of the other ingredients of the product; known or suspected progestogen-dependent neoplasms (e.g. meningioma).
Luteal phase support treatment during assisted reproductive technologies (ART) should be discontinued if abortion/miscarriage is diagnosed.
Interaction with other medicinal products and other types of interactions
In vitro data indicate that the main metabolic pathway leading to the major pharmacologically active metabolite, 20α-dihydrodydrogesterone (DHD), is catalyzed by aldoketoreductase 1C (AKR 1C) in the human cytosol. In addition to cytosolic metabolism, metabolic transformations are mediated by cytochrome P450 (CYP) isoenzymes, almost exclusively CYP3A4, which leads to the formation of 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 by concomitant administration of substances that induce cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), antimicrobials (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 to be potent inhibitors of cytochrome enzymes and exhibit enzyme-inducing properties when used concomitantly with steroid hormones. Clinically increased metabolism of dydrogesterone may result in decreased 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.
Application features
Before starting the use of dydrogesterone for the treatment of pathological bleeding, an organic cause of the bleeding should be excluded.
Breakthrough bleeding or spotting may occur during the first months of treatment. If breakthrough bleeding or spotting continues after some time of treatment or continues after the end of treatment, the cause should be established, including, if necessary, the exclusion of endometrial malignancy by endometrial biopsy.
If any of the following disorders occur for the first time or worsen during use of the drug, discontinuation of treatment should be considered:
extremely severe headache, migraine or symptoms that may indicate cerebral ischemia; significant increase in blood pressure; occurrence of venous thromboembolism.
In the case of habitual or threatened miscarriage, fetal viability should be determined and checked during treatment to ensure that the pregnancy is ongoing and the embryo is alive.
Conditions requiring supervision
The following rare conditions are known to be influenced by sex hormones and may therefore occur or worsen during pregnancy or with the use of sex hormones: cholestatic jaundice, herpes gestationis, severe pruritus, otosclerosis, porphyria, depression and abnormal liver function tests caused by acute or chronic liver disease. If any of these conditions are present or have occurred previously and/or have worsened during pregnancy or previous hormone treatment, the patient should be closely monitored. It should be borne in mind that these conditions may recur or worsen during dydrogesterone therapy, and discontinuation of therapy should be considered in such cases.
Patients with a history of depression should be closely monitored. If severe depression recurs, dydrogesterone treatment should be discontinued.
The following precautions apply to the use of Duphaston® for the indication “for the prevention of endometrial hyperplasia during menopause”
See also the precautions in the instructions for medical use of estrogen preparations.
Evidence regarding the risks associated with hormone replacement therapy for the treatment of premature menopause is limited. Due to the low absolute risk in younger women, the balance of benefits and risks in this group may be more favorable than in older women.
Medical examination/follow-up
Before starting hormone replacement therapy or when it is resumed after a break, a complete personal and family history should be taken. Taking into account the history, as well as contraindications and precautions for taking the drug, an objective 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 the individual characteristics of the patient. Women should be informed about what changes in the breasts they should report to their doctor or nurse (see Breast cancer below). Breast examination, including appropriate imaging methods, such as mammography, should be performed in accordance with 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 is increased with long-term estrogen monotherapy. Depending on the duration of treatment and estrogen dose, the risk may be 2 to 12 times higher than in women not taking estrogen. After estrogen therapy is stopped, 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 continuous combined estrogen-progestogen therapy in women with an intact uterus may prevent the excess risk associated with estrogen-only hormone replacement therapy.
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting occurs after therapy has been initiated for some time, or if it persists after treatment has ended, further investigation is indicated. This may indicate that an endometrial biopsy is necessary to rule out malignancy.
Breast cancer
All available evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen therapy and possibly even in women taking estrogen-only HRT. This risk depends on the duration of HRT use.
Combined estrogen-progestogen therapy: The Women's Health Initiative (WHI) randomised placebo-controlled trial and epidemiological studies have shown an increased risk of breast cancer in women taking estrogen-progestogen hormone replacement therapy for 3 or more years. This increased risk persists for up to 5 years after stopping treatment. Hormone replacement therapy, particularly combined estrogen-progestogen therapy, increases the density of mammographic images, which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much less common than breast cancer. Epidemiological data from a large meta-analysis have shown a slightly increased risk in women using estrogen-only or combined estrogen-progestogen hormone replacement therapy; this risk becomes apparent within 5 years of use and decreases over time after discontinuation of therapy. Some other studies, including the WHI, have shown that the 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. This event is more likely to occur in the first year of hormone replacement therapy than later.
Patients with known thrombophilic states are at increased risk of venous thromboembolism, and hormone replacement therapy may further increase this risk. Therefore, hormone replacement therapy is contraindicated in this group of patients.
Generally recognized risk factors for venous thromboembolism include estrogen use, older age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus regarding the possible role of varicose veins in the occurrence of venous thromboembolism.
Women with no personal history of venous thromboembolism but a first-degree relative with a history of thrombosis at a young age may be offered screening after careful discussion of its limitations (only a subset of thrombophilic defects may be detected by screening). If the identified thrombophilic defect is associated with thrombosis in a family member or the defect is associated with a serious abnormality (e.g., antithrombin, protein S, or protein C deficiency, or a combination of defects), hormone replacement therapy is contraindicated.
In women already receiving continuous anticoagulant therapy, the benefits and risks of hormone replacement therapy should be carefully weighed.
If venous thromboembolism develops after initiation of therapy, the drug should be discontinued. Patients should be informed that they should seek medical attention immediately if they experience potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden chest pain, shortness of breath).
Coronary heart disease
Randomized controlled trials have found no evidence of protection against myocardial infarction in women with or without coronary heart disease receiving combined estrogen-progestogen therapy or estrogen-only hormone replacement therapy.
Combined estrogen-progestagen therapy: the relative risk of coronary heart disease during hormone replacement therapy is slightly increased. Since the baseline absolute risk of coronary heart disease is largely age-dependent, the number of additional cases of coronary heart disease due to estrogen-progestagen use is very small in healthy women at the time of menopause, but will increase with older age.
Ischemic stroke
Combined estrogen-progestogen therapy and estrogen monotherapy 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, because the baseline risk of stroke is largely age-dependent, the overall risk of stroke in women taking HRT increases with age.
Excipients
This medicinal product contains lactose monohydrate. Patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Ability to influence reaction speed when driving vehicles or other mechanisms
Duphaston® has a negligible effect on the ability to drive and use machines.
Dydrogesterone may rarely cause mild drowsiness and/or dizziness, especially in the first few hours after administration. Therefore, caution should be exercised when driving or operating machinery.
Use during pregnancy or breastfeeding
Pregnancy
It is estimated that more than 9 million pregnant women have taken dydrogesterone. To date, there is no evidence of harmful effects of dydrogesterone when used during pregnancy.
A study has been reported in the literature that suggests that the use of some progestogens may be associated with an increased risk of hypospadias. However, as this has not been confirmed in other studies, it is not possible to definitively determine the role of progestogens in the development of hypospadias. Clinical trials in which a limited number of women were treated with dydrogesterone in early pregnancy did not show an increased risk. No other epidemiological data are available.
In preclinical studies of embryofetal and postnatal development, effects were consistent with the pharmacological profile. Adverse effects occurred only at exposures significantly in excess of the maximum human exposure.
Dydrogesterone can be used during pregnancy for clear indications.
Breastfeeding period
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 unknown whether there is a risk to the child, therefore dydrogesterone should not be used during breastfeeding.
Fertility
There is no evidence that dydrogesterone in therapeutic doses reduces fertility.
Method of administration and doses
The following dosage regimens are recommended for treatment with Duphaston®. The dosage, 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 cycle length of 28 days can be achieved by prescribing 1 Duphaston® tablet per day from the 11th to the 25th day of the cycle.
Endometriosis
1 to 3 Duphaston® tablets per day from the 5th to the 25th day of the cycle or throughout the cycle. Doses in multiples of 10 mg per day should be distributed evenly throughout the day. It is recommended to prescribe the highest dose at the initial stage of treatment.
Dysmenorrhea
1 to 2 tablets of Duphaston® per day from the 5th to the 25th day of the cycle. Doses in multiples of 10 mg per day should be distributed evenly throughout the day. It is recommended to prescribe the highest dose at the initial stage of treatment.
Infertility caused by luteal insufficiency
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 for a habitual miscarriage.
Luteal phase support during assisted reproductive technologies (ART)
1 Duphaston® tablet 3 times a day (30 mg per day). Treatment begins on the day of oocyte collection and continues for 10 weeks if pregnancy is confirmed.
Threatened miscarriage
Initial dose: 4 tablets of Duphaston® at once, then 1 tablet of Duphaston® every 8 hours. Doses in multiples of 10 mg per day should be evenly distributed throughout the day. It is recommended to prescribe the highest dose at the initial stage of treatment.
If symptoms persist or recur during treatment, the dose should be increased by 1 Duphaston® tablet every 8 hours.
After symptoms have resolved, the effective dose should be maintained for one week, after which it can be gradually reduced. If symptoms recur, treatment should be resumed immediately at the dosage that has proven effective.
Habitual miscarriage
Treatment should be started before conception. 1 Duphaston® tablet per day until the 20th week of pregnancy, after which the dose can be gradually reduced.
If symptoms of threatened abortion appear during treatment, treatment should be continued as described in the case of threatened miscarriage.
Dysfunctional uterine bleeding
2 Duphaston® tablets per day for 5-7 days in combination with estrogen.
A few days after the end of such treatment, withdrawal bleeding will appear.
To prevent further bleeding, Duphaston® should be prescribed 1 tablet per day from the 11th to the 25th day of the cycle.
In case of cystic hemorrhagic metropathy, prescribe 1 Duphaston® tablet per day from the 11th to the 25th day of the cycle.
In some cases, it may be necessary to administer estrogen during the first half of the cycle. A few days after stopping this treatment, withdrawal bleeding will occur.
This treatment should be continued for several cycles.
Secondary amenorrhea
For treatment, estrogen must be prescribed simultaneously. Estrogen should be prescribed from the 1st to the 25th day of the cycle, from the 11th to the 25th day in combination with 1 Duphaston® tablet per day.
To create the prerequisites for subsequent cycles, therapy should be started on the 5th day after the onset of bleeding by administering estrogens (from the 5th to the 25th day). Duphaston® 10 mg should be administered from the 11th to the 25th day.
To prevent endometrial hyperplasia during menopause
During each 28-day cycle of estrogen therapy, take estrogen alone for the first 14 days, and for the next 14 days, take 1 or 2 tablets containing 10 mg of dydrogesterone in addition to estrogen therapy. In the case of a dosage of 10 mg of dydrogesterone 2 times a day, the tablets should be taken throughout the day. Withdrawal bleeding usually occurs during the use of dydrogesterone.
The use of combined estrogen-progestogen therapy in postmenopausal women should be limited to the lowest effective dose and for the shortest duration necessary to achieve the therapeutic goal, and the risks for the individual woman should be periodically reviewed (see Precautions).
Method of application
For oral administration.
When using higher doses, the tablets should be evenly distributed throughout the day.
Children
Due to insufficient data on the safety and efficacy of Duphaston® in children, it is not recommended to prescribe the drug to this category of patients.
Overdose
Symptoms
Dydrogesterone is a drug with very low toxicity. Symptoms that may theoretically occur in case of overdose are nausea, vomiting, drowsiness and dizziness. There are no known cases when an overdose of dydrogesterone has led to harmful effects (the maximum daily dose taken by a person was 360 mg).
Treatment
No specific treatment is required. In case of overdose, symptomatic treatment may be considered.
Adverse reactions
When dydrogesterone was used in clinical trials for indications without estrogen treatment, the following adverse reactions were most frequently reported: vaginal bleeding, migraine/headache, nausea, vomiting, abdominal pain, menstrual disorders, and breast pain/tenderness.
The following adverse reactions were observed with the following frequencies in clinical trials of dydrogesterone (n=3483) in indications without estrogen treatment, in two company-sponsored interventional clinical trials of luteal phase support in assisted reproductive technologies (ART) with dydrogesterone (n=1036) and from spontaneous reporting. The frequency of adverse reactions is based on the most conservative approach: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000).
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Rare: increase in the size of progestogen-dependent neoplasms (e.g. meningioma)*.
Blood and lymphatic system
Rare: hemolytic anemia*.
Mental disorders
Uncommon: depressed mood.
Immune system
Rare: hypersensitivity reactions.
Nervous system
Common: headache and migraine.
Uncommon: dizziness.
Rare: drowsiness.
Digestive tract
Common: nausea, vomiting, abdominal pain.
Uncommon: liver function abnormalities accompanied by weakness or malaise, jaundice and abdominal pain.
Skin and subcutaneous tissue
Uncommon: allergic dermatitis (e.g. rash, itching and urticaria).
Rare: angioedema*.
Reproductive system and mammary glands
Very common: vaginal bleeding.
Common: menstrual disorders (including metrorrhagia, menorrhagia, oligo-/amenorrhea, dysmenorrhea and irregular menstruation), breast pain/tenderness.
Rare: swelling of the mammary glands.
General disorders and local reactions
Rare: edema.
Examination
Uncommon: weight gain.
*Adverse reactions from spontaneous reports not observed in clinical trials were assigned to the frequency “rare” based on the fact that the upper limit of the 95% confidence interval of the expected frequency is estimated to be no higher than 3/x, where x=3483 (total number of subjects observed in clinical trials).
Adverse reactions associated with estrogen-progestogen treatment (see also the section "Special instructions for use" 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.
** - Use of oestrogen-only or combined oestrogen-progestagen hormone replacement therapy (HRT) has been associated with a slightly increased risk of ovarian cancer (see section 4.4). A meta-analysis of 52 epidemiological studies has shown an increased risk of ovarian cancer in women using HRT compared with women who have never used HRT (RR 1.43; 95% CI 1.31-1.56). In women aged 50-54 years who have used HRT for 5 years, the result was one additional case per 2000 patients. In women aged 50-54 years who have not used HRT, about 2 in 2000 women were diagnosed with ovarian cancer over a 5-year period.
Expiration date
5 years.
Storage conditions
Does not require any special storage conditions. Keep out of the reach of children.
Packaging
14 tablets in a blister; 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
Abbott Biologicals B.V., Netherlands.
Location of the manufacturer and its business address
Weerweg 12, 8121 AA Olst, Netherlands.
