Dufaston pills 10mg, 28pcs

Composition

1 film-coated tablet contains: Active ingredient: didrogesterone-10.0 mg; Excipients: lactose monohydrate-111.1 mg, hypromellose-2.8 mg, corn starch-14 mg, colloidal silicon dioxide-1.4 mg, magnesium stearate-0.7 mg.

Shell composition:  opadray white Y-1-7000 (hypromellose, polyethylene glycol 400, titanium dioxide (E 171)) – 4 mg

Pharmacological action

Duphaston® (didrogesterone) is an orally active progestogen indicated in all cases of endogenous progesterone deficiency. Didrogesterone promotes the endometrial secretion phase, thereby reducing the risk of endometrial hyperplasia and/or estrogen-induced carcinogenesis.

It has no estrogenic, androgenic, anabolic or glucocorticoid activity.

Didrogesterone is not a contraceptive. The therapeutic effect of taking didrogesterone is achieved without suppressing ovulation.

Pharmacokinetics

Suction

After oral use, didrogesterone is rapidly absorbed. The time to reach_cmax for didrogesterone varies between 0.5 and 2.5 h. The absolute bioavailability of didrogesterone (a dose of 20 mg for oral use compared to intravenous use of 7.8 mg) is 28%.

The table shows the pharmacokinetic parameters of didrogesterone and 20α-dihydrodirogesterone (DHD) after a single dose of 10 mg of didrogesterone:

Distribution

After intravenous use_of didrogesterone, vd at steady state is about 1400 liters. More than 90% of didrogesterone and DHD are bound to plasma proteins.

Metabolism

After oral use, didrogesterone is rapidly metabolized to DHD. With_max the main metabolite of DHD is reached approximately 1.5 hours after taking the drug. The concentration of DHD in the blood plasma is significantly higher than the concentration of didrogesterone. The AUC and_{cmax ratios} of DHD to didrogesterone are about 40 and 25, respectively. The average T_1/2 of didrogesterone and DHD is from 5 to 7 and from 14 to 17 hours, respectively. A common property of all metabolites is the preservation of the 4,6-diene-3-oh configuration of the initial compound and the absence of a 17α-hydroxylation reaction. This explains the lack of estrogenic and androgenic effects of didrogesterone.

Deduction

After oral use of labeled didrogesterone, an average of 63% of the dose is excreted through the kidneys (in the urine). The total plasma clearance is 6.4 l/min. Didrogesterone is completely eliminated from the body after 72 hours. DHD is found in the urine mainly in the form of glucuronic acid conjugates.

Dependence of pharmacokinetic parameters on dose and time

The drug is characterized by linear pharmacokinetics with single and multiple oral use in the dose range from 2.5 mg to 10 mg.

When comparing the pharmacokinetic parameters for single and multiple oral use, it was found that the pharmacokinetics of didrogesterone and DHD do not change as a result of repeated use.

The state of equilibrium is reached 3 days after the start of treatment.

Indications

-endometriosis;

– infertility due to luteal phase insufficiency;

– threatened miscarriage;

– habitual miscarriage;

– premenstrual syndrome;

– dysmenorrhea;

– irregular menstruation;

– secondary amenorrhea;

– dysfunctional uterine bleeding;

– support of the luteal phase in the process of using assisted reproduction methods.

Contraindications

• hypersensitivity to dydrogesterone or other components of the drug;
• diagnosed or suspected progestagens. obesity tumors (e. g., meningioma);
• vaginal bleeding of unknown etiology;
• the liver due to acute or chronic liver diseases in the present or in history (up to normalization in liver function tests);
• malignant tumor of the liver in the present or in the anamnesis;
• galactose intolerance, lactase deficiency, malabsorption syndrome of glucose-galactose;
• lactation;
• porphyria, at present or in the anamnesis;
• the age of 18, in connection with the lack of data on efficacy and safety in adolescent girls under the age of 18;
• spontaneous abortion (miscarriage) or a failed abortion when conducting support the luteal phase in the framework of assisted reproductive technologies (art).

When combined with estrogens

When used as indicated by hormone replacement therapy (HRT):

• untreated endometrial hyperplasia;
• arterial and venous thrombosis, thromboembolism in the present or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, thrombophlebitis, cerebrovascular disorders hemorrhagic and ischemic type);
• identified a predisposition to venous or arterial thrombosis (resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, deficiency of protein C, protein S deficiency, antiphospholipid antibodies (antibodies to cardiolipin, lupus anticoagulant).

With caution

• depression, currently or in the anamnesis;
• conditions that previously appeared or worsened during a previous pregnancy or previous use of sex hormones, such as cholestatic jaundice, herpes during pregnancy, severe pruritus of the skin, otosclerosis.

When using didrogesterone in combination with estrogens, caution should be exercised in the presence of risk factors for developing thromboembolic conditions, such as angina pectoris, prolonged immobilization, severe forms of obesity (body BMI more than 30 kg/m2), elderly age, extensive surgical interventions, systemic lupus erythematosus, cancer; in patients receiving anticoagulant therapy; with endometriosis, uterine fibroids; with a history of endometrial hyperplasia; liver adenoma; diabetes mellitus with or without vascular complications; arterial hypertension; bronchial asthma; epilepsy; migraine or severe headache in the anamnesis; cholelithiasis; chronic renal failure; in the presence of a history of risk factors for the development of estrogen-dependent tumors (for example, relatives of the 1st line of kinship with breast cancer).

Side effects

In clinical studies, the following symptoms were most common in patients treated with didrogesterone alone: headache/migraine, nausea, menstrual irregularities, and breast tenderness/sensitivity.

In clinical studies, as well as during post-marketing use (spontaneous reports), the following adverse effects were observed with the use of didrogesterone alone, with the frequency indicated below (number of reported cases/number of patients): often (≥1/100 to <1/10); infrequently (≥1/1000 to <1/100); rarely (≥1/10,000 to

From the hematopoietic system:  rarely-hemolytic anemia.

Mental disorders:  infrequently – depression.

From the immune system:  rarely – hypersensitivity reactions.

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

From the gastrointestinal tract:  often – nausea; infrequently-vomiting.

Liver and biliary tract disorders:  infrequently-liver function disorders (with jaundice, asthenia or malaise, abdominal pain).

Skin and subcutaneous tissue disorders:  infrequently-allergic dermatitis (for example, rash, pruritus, urticaria); rarely – angioedema.

From the genitals and breast:  often – menstrual disorders (including metrorrhagia, menorrhagia, oligo – / amenorrhea, dysmenorrhea and irregular menstrual cycle); soreness/sensitivity of the mammary glands; rarely-swelling of the mammary glands.

Neoplasms:  rarely-an increase in the size of progestogen-dependent neoplasms (for example, meningioma).

Other services:  rarely-edema; infrequently-weight gain.

When using some progestogens in combination with estrogens as part of hormone replacement therapy, the following undesirable effects were noted: : breast cancer, endometrial hyperplasia, endometrial cancer, ovarian cancer; venous thromboembolism; myocardial infarction, coronary heart disease, ischemic stroke.

In a randomized double-blind study with two parallel groups to study the oral use of didrogesterone in comparison with intravaginal use of micronized progesterone to support the luteal phase during the use of assisted reproduction methods, it was shown that the incidence of the most frequent adverse events that occurred during treatment was comparable in both groups. Most frequently encountered (at least 5% in one of the treatment groups, regardless of the drug): vaginal bleeding, nausea, pain during the procedure, headache, abdominal pain, biochemical pregnancy.The only adverse event that occurred during treatment, with a frequency of ≥2% of patients in each of the groups, was vaginal bleeding.

Termination of pregnancy is possible at an early stage (especially before the 10th week of pregnancy) – the frequency of pregnancy during ART procedures is on average about 35%.

The safety profile observed in this study is consistent with that expected, given the well-studied safety profile of didrogesterone and the patient population.

Interaction

Data obtained in vitro show that the main pathway of formation of the main pharmacologically active metabolite of DHD is carried out under the catalytic action of aldo-keto reductase 1C (AKR1C) in the cytosol of human cells. Then, inside the cytosol, a metabolic transformation occurs with cytochrome P 450 isoenzymes, mainly with the help of CYP3A4, resulting in the formation of several minor metabolites.

The substrate for transformation by the CYP3A4 isoenzyme is the main active metabolite of DHD. The metabolism of didrogesterone and DHD can be accelerated by the combined use of substances that are inducers of cytochrome 450 enzymes, such as anticonvulsants (for example, phenobarbital, phenytoin, carbamazepine), antibacterial and antiviral drugs (for example, rifampicin, rifabutin, nevirapine, efavirenz) and herbal preparations containing, for example, St. John’s wort. Ritonavir and nelfinavir, known as strong inhibitors of cytochrome P450 enzymes, have enzyme-reducing properties when co-administered with steroids.

From a clinical point of view, increased metabolism of didrogesterone may reduce its effectiveness.

The results of in vitro studies show that didrogesterone and DHD in clinically significant concentrations do not inhibit or induce cytochrome P450 enzymes that metabolize drugs.

How to take, course of use and dosage

The drug is taken orally.

The break line is only intended to make it easier to break the tablet and easier to swallow, not to divide it into equal doses.

The duration of therapy and doses can be adjusted based on the individual clinical response of the patient and the severity of the pathology within the dosage regimen of the drug presented below:

Endometriosis: 10 mg 2-3 times / day from the 5th to the 25th day of the menstrual cycle or continuously.

Infertility (due to luteal phase insufficiency): 10 mg/day from the 14th to the 25th day of the cycle. Treatment should be carried out continuously for at least six consecutive cycles. In the first months of pregnancy, it is recommended to continue treatment according to the scheme described in the usual miscarriage.

Threatened miscarriage: 40 mg once, then 10 mg every 8 hours until symptoms disappear.

Habitual miscarriage: 10 mg 2 times / day until the 20th week of pregnancy, followed by a gradual reduction in the dose.

Premenstrual syndrome: 10 mg 2 times / day from the 11th to the 25th day of the menstrual cycle.

Dysmenorrhea: 10 mg 2 times / day from the 5th to the 25th day of the menstrual cycle.

Irregular menstruation: 10 mg 2 times / day from the 11th to the 25th day of the menstrual cycle.

Secondary amenorrhea: estrogenic drug 1 time/day from the 1st to the 25th day of the cycle together with 10 mg of Duphaston® 2 times/day from the 11th to the 25th day of the menstrual cycle.

Dysfunctional uterine bleeding (to stop the bleeding): 10 mg 2 times / day for 5 or 7 days.

Dysfunctional uterine bleeding (to prevent bleeding): 10 mg 2 times / day from the 11th to the 25th day of the menstrual cycle.

HRT combined with estrogens: with a continuous sequential regimen – 10 mg of didrogesterone per day for 14 consecutive days within a 28-day cycle. With a cyclic therapy scheme (when estrogens are used in 21-day courses with 7-day breaks) – 10 mg of didrogesterone per day for the last 12-14 days of taking estrogens. If a biopsy or ultrasound examination indicates an insufficient response to a progestogen drug, the daily dose of didrogesterone should be increased to 20 mg.

If the patient missed taking the pill, it should be taken as early as possible, within 12 hours after the usual intake time. If more than 12 hours have passed, the missed pill should not be taken, and the next day it is necessary to take the pill at the usual time. Skipping the drug may increase the likelihood of “breakthrough” bleeding or “spotting” spotting.

Support of the luteal phase in the process of using assisted reproduction methods: 10 mg 3 times / day, starting from the day of egg collection and up to the 10th week of pregnancy (if pregnancy is confirmed). If the patient missed taking a pill, this pill should be taken as early as possible and consult a doctor.

The use of didrogesterone before menarche is not indicated. The safety and efficacy of didrogesterone in adolescent girls aged 12-18 years have not been established. Currently available limited data do not allow us to make recommendations on the dosage regimen in patients of this age group.

Overdose

Data on drug overdose cases are limited. Didrogesterone was well tolerated after oral use (the maximum described daily dose was 360 mg).

Symptoms: theoretically, clinical manifestations of drug overdose are possible – nausea, vomiting, dizziness and drowsiness.

Treatment: There is no specific antidote, and treatment should be symptomatic.

Special instructions

Before starting treatment with Duphaston® for abnormal uterine bleeding, it is necessary to determine the cause of bleeding. With prolonged use of the drug, periodic examinations of a gynecologist are recommended, the frequency of which is set individually, but at least once every six months. In the first months of treatment for abnormal uterine bleeding, “breakthrough” bleeding or “smearing” spotting may occur. If “breakthrough” bleeding or” spotting ” spotting occurs after a certain period of taking the drug or continues after a course of treatment, you should contact your doctor and conduct an appropriate additional examination, if necessary, do an endometrial biopsy to exclude neoplasms in the endometrium.

When prescribing didrogesterone in combination with estrogens for the purpose of hormone replacement therapy (HRT), you should carefully read the contraindications and special instructions related to the use of estrogens.

HRT should be used to treat menopausal symptoms that adversely affect the patient’s quality of life. The benefit/risk ratio of HRT should be evaluated annually. Therapy should be continued as long as the potential benefit outweighs the potential risk.

There are limited data on the risks associated with HRT in the treatment of premature menopause. Due to the low absolute risk in young women, the benefit/risk ratio for them may be more favorable compared to that in older women.

Medical examination

A complete individual and family history should be collected before starting the use of a combination of didrogesterone and estrogen (for HRT). An objective examination (including pelvic and mammary examination) should be performed to identify possible contraindications and conditions that require precautionary measures.

During treatment, it is recommended to periodically monitor individual tolerance to HRT. The patient should be informed about what changes in the mammary glands she should report to the doctor. (see “Breast cancer”). Studies that include mammography should be conducted in accordance with generally accepted screening, taking into account individual characteristics and the clinical picture.

Endometrial hyperplasia and cancer

In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases with long-term estrogen monotherapy.

Cyclical use of progestogens, including didrogesterone (at least for 12 days of a 28-day cycle), or the use of a consistent combined HRT regimen in women with a preserved uterus may prevent an increased risk of endometrial hyperplasia and cancer with estrogen monotherapy.

Breast cancer

Available evidence suggests that the risk of breast cancer is increased in women receiving HRT with oestrogen-progestogen medications, and possibly also with oestrogen monotherapy. The level of risk depends on the duration of HRT. The results of the epidemiological study and the WHI(Women’s Health Initiative Study) confirm an increased risk of breast cancer in women taking medications containing a combination of estrogen and progesterone as part of HRT. The risk increases after about 3 years of use, but returns to the average value within a few (usually five) years after the end of therapy.

When taking HRT medications, especially when combined with oestrogens and progestogens, there may be an increase in breast tissue density during mammography, which may make it difficult to diagnose breast cancer.

Ovarian cancer

Ovarian cancer is significantly less common than breast cancer.

Epidemiological data obtained from a large-scale meta-analysis indicate a slight increase in risk for women receiving HRT in the form of estrogen monotherapy or combined therapy with estrogens and progestogens. An increase in this risk becomes apparent when the duration of therapy is more than 5 years, and after its termination, the risk gradually decreases over time. Results from several other studies, including WHI, indicate that combined HRT is associated with a similar or slightly lower risk of ovarian cancer.

Venous thromboembolism

HRT is associated with a 1.3-to 3-fold increased risk of venous thromboembolism( VTE), i. e. deep vein thrombosis or pulmonary embolism. The probability is higher in the first year of HRT than in subsequent years. Patients with diagnosed thrombophilia have an increased risk of developing venous thromboembolism, and HRT may increase the risk. For this reason, HRT is contraindicated in such patients.

Risk factors for venous thromboembolism include estrogen use, advanced age, extensive surgery, prolonged immobilization, obesity (BMI >30 kg / m2), pregnancy, the postpartum period, systemic lupus erythematosus, and cancer. There are no definitive data on the possible role of varicose veins in the development of venous thromboembolism.

If prolonged immobilization is necessary after surgical interventions, you should stop taking HRT medications 4-6 weeks before the operation, and resume taking the drug is possible after the woman’s motor activity is fully restored.

Women who do not have a history of VTE, but indicate the presence of a family history of thrombosis at a young age in the next of kin, after detailed consultation about possible limitations and disadvantages of therapy, screening may be offered (during screening, only a part of hereditary hemostatic system defects is detected).

If a family member has thrombophilia associated with thrombosis, or if there is a severe defect (for example, a lack of antithrombin III, protein C, protein S, or a combination of defects), HRT is contraindicated.

If the patient is taking anticoagulants, the benefit/risk of HRT should be carefully evaluated. HRT medications should not be prescribed until a thorough assessment of possible thromboembolic factors is completed or anticoagulant therapy is initiated. If thrombosis develops after starting therapy, HRT should be discontinued.

It is necessary to immediately consult a doctor in case of any of the symptoms that indicate a possible thromboembolism (soreness or swelling of the lower extremities, sudden chest pain, shortness of breath, visual impairment).

Coronary heart disease (CHD)

Data obtained in randomized controlled trials indicate that there is no protective effect against the development of myocardial infarction in women with and without CHD who receive HRT in the form of combined therapy with estrogens and progestogens or monotherapy with estrogens.

The relative risk of developing CHD is slightly increased during combined HRT. The absolute risk of CHD depends on age. The number of cases of CHD associated with HRT is lower in healthy women at the age close to the onset of natural menopause, however, it increases in subsequent years.

Ischemic stroke

Combined therapy with oestrogens and progestogens or oestrogens alone is associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age and does not depend on the time of menopause. However, the incidence of stroke depends on age, and the overall risk of stroke in women receiving HRT will increase with age.

Auxiliary substances

The drug contains lactose monohydrate. Patients with rare hereditary problems such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicine.

Influence on the ability to drive motor vehicles and manage mechanisms

Duphaston® it has little effect on the ability to drive vehicles and mechanisms. Caution should be exercised when driving vehicles and mechanisms, taking into account the possibility of adverse reactions from the nervous system (light drowsiness and / or dizziness, especially in the first hours of use).

Form of production

28 tablets of 10 mg in a blister of aluminum foil and PVC film, not coated or coated with PVDC, packed in a cardboard pack.

Storage conditions

In a dark place at a temperature of 0 to 30 °C. Keep out of reach of children.

Expiration date

The drug is stable for 5 years after release, provided that it is stored at a temperature of 0 to 30 °C in its original and undamaged packaging. The drug should not be used later than the date indicated on the package.

Active ingredient

Didrogesterone

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For postmenopausal women, For women of childbearing age, For women, For women in the menopausal period, For women planning pregnancy

Indications

Threatened Miscarriage, Premenstrual Syndrome, Menopause, Menstrual Disorders