Instructions Duphaston film-coated tablets 10 mg blister No. 20
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 synthetic progesterone with orally bioavailable properties that induces secretory transformation of the endometrium in the estrogen-stimulated uterus. It provides protection against the increased risk of endometrial hyperplasia and/or cancer induced by estrogens. Dydrogesterone has no estrogenic, androgenic, anabolic or corticoid properties.
Dydrogesterone does not inhibit ovulation. This means that the possibility of fertilization of the egg in women of reproductive age when taking dydrogesterone remains.
In postmenopausal women with an intact uterus, estrogen replacement therapy carries 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-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 study with two parallel groups 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) techniques.
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
Absorption
After oral administration of dydrogesterone in the form of film-coated tablets, it is rapidly absorbed. Maximum plasma concentrations (Cmax) of about 3.2 ng/ml for the parent substance dydrogesterone and 57 ng/ml for its active metabolite 20-alpha-dihydrodydrogesterone (DHD) are reached 0.5–1.5 hours after administration. The total exposure over time (AUC) is about 9.1 and 220 ng.h/ml for dydrogesterone and DHD, respectively.
After a single dose, food delays the peak plasma concentration of dydrogesterone by approximately 1 hour, resulting in a decrease in peak plasma concentration of dydrogesterone by approximately 20%, without affecting the extent of exposure to dydrogesterone and DHD.
The observed effect of simultaneous food intake on the peak plasma concentration of dydrogesterone is considered to be clinically insignificant. Therefore, Duphaston film-coated tablets can be taken regardless of meals.
Distribution
After oral administration of dydrogesterone, the apparent volume of distribution is significant and is approximately 22,000 L. More than 90% of dydrogesterone and DHD are bound to plasma proteins.
After oral administration, dydrogesterone is rapidly metabolized to DHD. The concentration of the main active metabolite DHD reaches a peak after the same time as dydrogesterone. The plasma concentration of DHD is significantly higher than that of the parent compound. The ratio of DHD AUC and Cmax to dydrogesterone AUC and Cmax is about 25 and 20, respectively. The mean terminal half-life of both dydrogesterone and DHD is about 15 hours. A common property of all characteristic metabolites is the preservation of the 4,6-dien-3-one structure of the parent compound and the absence of 17-alpha-hydroxylation, which explains the absence of estrogenic and androgenic effects in dydrogesterone.
Breeding
After oral administration, an average of 63% of the dose is excreted in the urine. The apparent total clearance of dydrogesterone from plasma in the body is high and is approximately 20 l/min. Complete elimination occurs after 72 hours. DHD is excreted in the urine mainly as a glucuronic acid conjugate.
Dose and time dependence
Single and multiple dose pharmacokinetics are linear over the oral dose range of 2.5–20 mg. Comparison of single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD do not change with repeated dosing. Steady-state conditions are usually reached after 3 days of treatment.
Indication
- Irregular menstrual cycles;
- endometriosis;
- dysmenorrhea;
- infertility caused by luteal insufficiency;
- support of the luteal phase when using assisted reproductive technologies (ART);
- threatened and habitual miscarriage associated with progesterone deficiency.
Duphaston can be used as a cyclical adjunct to estrogen therapy in women with an intact uterus:
- to prevent endometrial hyperplasia during menopause;
- with dysfunctional uterine bleeding;
- with secondary amenorrhea.
Contraindication
- Undiagnosed vaginal bleeding;
- have serious liver disease or have had serious liver disease in the past if liver function tests have not returned to normal;
- contraindications for estrogens should be considered if used in combination with progestogens such as dydrogesterone;
- established hypersensitivity to the active substance or to any other component of the drug;
- established 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 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.
Application features
Before starting the use of 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 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;
- the appearance 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.
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.
For the treatment of postmenopausal symptoms, hormone replacement therapy should be used only when symptoms negatively affect quality of life. In all cases, the benefits and risks of hormone replacement therapy should be carefully assessed at least annually. Hormone replacement therapy should only be continued if the benefits outweigh the risks.
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 or estrogen-only HRT. This risk depends on the duration of use of HRT.
Combined estrogen-progestogen therapy: The Women's Health Initiative (WHI) randomized placebo-controlled trial and a meta-analysis of prospective epidemiological studies have shown an increased risk of breast cancer in women taking estrogen-progestogen hormone replacement therapy, which becomes apparent after approximately 3 (range 1 to 4) years. The results of a large meta-analysis have shown that after stopping treatment, this increased risk decreases over time and that the time taken to return to baseline risk depends on the duration of previous use of hormone replacement therapy. If such therapy has been continued for more than 5 years, this risk may persist for 10 years or more.
Hormone replacement therapy, particularly estrogen-progestogen combination therapy, increases the density of mammographic images, which may adversely affect the radiological detection of breast 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.
As in all postoperative patients, prophylactic measures should be considered to prevent venous thromboembolism after surgery. If elective surgery requires prolonged immobilization, it is recommended that hormone replacement therapy be temporarily discontinued 4-6 weeks prior to surgery. Treatment should not be resumed until the woman is fully ambulatory.
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.
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.
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.
The ability to influence the reaction speed when driving vehicles or other mechanisms.
Duphaston has a negligible influence 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.
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 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 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
1 Dufaston tablet 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 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 reappear 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
To stop bleeding, 2 tablets of Duphaston are prescribed per day for 5–7 days. Blood loss is significantly reduced within a few days. A few days after the end of such treatment, withdrawal bleeding will occur, which the patient should be warned about.
To prevent further heavy uterine bleeding, Duphaston should be prescribed 1 tablet per day from the 11th to the 25th day of the cycle, if necessary in combination with estrogen for 2–3 cycles. After this, treatment can be stopped to check the normalization of the patient's cycle.
Secondary amenorrhea
1 to 2 tablets of Duphaston per day from the 11th to the 25th day of the cycle to ensure optimal secretory transformation of the endometrium, adequately stimulated by endogenous or exogenous estrogen.
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 consistent with the therapeutic goals and risks for the individual woman, and the appropriateness of such treatment should be reviewed periodically (see Precautions).
Method of application
For oral administration.
When using higher doses, the tablets should be evenly distributed throughout the day.
Children.
Dydrogesterone is not used before the onset of menstruation. The safety and effectiveness of dydrogesterone in adolescents aged 12 to 18 years have not been established.
Overdose
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 the non-estrogenic indication, 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,
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.
Hepatobiliary system
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 having ovarian cancer diagnosed (see section 4.4). A meta-analysis of 52 epidemiological studies showed an increased risk of ovarian cancer in women who used HRT compared with women who had never used HRT (RR 1.43; 95% CI 1.31-1.56). In women aged 50-54 years who had used HRT for 5 years, the result was one extra case per 2000 patients. In women aged 50-54 years who had 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 or 20 or 28 tablets in a blister; 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
Abbott Biologicals BV, The Netherlands.
Location of the manufacturer and address of its place of business
Veerweg 12, 8121 AA Olst, The Netherlands.
