Dufaston, 10 mg 28 pcs

Dufaston^® (dydrogesterone) is an oral progestagen indicated for all cases of endogenous progesterone deficiency. Didrogesterone ensures the onset of the secretion phase in the endometrium, thus reducing the risk of endometrial hyperplasia and/or estrogen-induced carcinogenesis.

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

Dydrogesterone is not a contraceptive. The therapeutic effect against the background of taking didrogesterone is achieved without suppressing ovulation.

Pharmacokinetics

Intake

Didrogesterone is rapidly absorbed after oral administration. The time to reach C_max for didrogesterone varies between 0.5 and 2.5 h. The absolute bioavailability of didrogesterone (20 mg dose for oral versus 7.8 mg intravenous) is 28%.

The table shows the pharmacokinetics of didrogesterone and 20α-dihydrodihydrogesterone (DDH) after a single dose of 10 mg of didrogesterone:

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Distribution

After IV administration of didrogesterone, the V_d in equilibrium is about 1400L. More than 90% of didrogesterone and DDH are bound to plasma proteins.

Metabolism

After oral administration, didrogesterone is rapidly metabolized to DDH. C_max of the main metabolite of DDH is reached approximately 1.5 h after ingestion. Plasma concentrations of DDH are significantly higher than those of didrogesterone. The AUC and C_max ratios of DDH to didrogesterone are about 40 and 25, respectively. The mean T_1/2 of didrogesterone and DDH are 5 to 7 and 14 to 17 h, respectively. A common property of all metabolites is the preservation of the 4,6-dien-3-one configuration of the parent compound and the absence of a 17α-hydroxylation reaction. This explains the absence of estrogenic and androgenic effects of didrogesterone.

After oral administration of labeled didrogesterone on average 63% of the dose is excreted through the kidneys (in the urine). Total plasma clearance is 6.4 L/min. Dydrogesterone is completely eliminated from the body after 72 hours. DDH is detected in the urine mainly in the form of glucuronic acid conjugates.

Dose and time dependence of pharmacokinetic parameters

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

The pharmacokinetics of didrogesterone and DDH are not altered by multiple doses when comparing single and multiple oral doses.

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

Indications

Threatened miscarriage, Menstrual disorders, Premenstrual syndrome, Climax

– Endometriosis;

– Infertility due to insufficient luteal phase;

– threatened miscarriage;

– habitual miscarriage;

– premenstrual syndrome;

– dysmenorrhea;

– irregular menstruation;

– secondary amenorrhea;

– Dysfunctional uterine bleeding;

– Luteal phase support during assisted reproductive techniques.

Active ingredient

Didrogesterone

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 silica – 1.4 mg, magnesium stearate – 0.7 mg.

Contents of coating: white opadray Y-1-7000 (hypromellose, polyethylene glycol 400, titanium dioxide (E171)) – 4 mg.

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How to take, the 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 to fit the patient’s individual clinical response and the degree of pathology within the dosing regimen outlined below:

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

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

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

In habitual miscarriage: 10 mg twice daily until the 20th week of pregnancy, with gradual dose reduction thereafter.

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

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

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

Secondary amenorrhea: estrogen drug 1 time/d from day 1 to day 25 of the cycle along with 10 mg of Dufaston^® 2 times/d from day 11 to day 25 of the menstrual cycle.

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

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

MWH in combination with estrogens: in continuous sequential regimen, 10 mg of didrogesterone per day for 14 consecutive days within a 28-day cycle. At the cyclic scheme of therapy (when estrogens are applied by 21-day courses with 7-day pauses) – on 10 mg didrogesterone a day during last 12-14 days of reception of estrogens. If a biopsy or ultrasound examination indicates an inadequate response to the progestagen drug, the daily dose of didrogesterone should be increased to 20 mg.

If a patient misses a pill, it should be taken as soon as possible, within 12 hours of the usual time of taking it. If more than 12 hours have elapsed, the missed tablet should not be taken, and the next day the tablet should be taken at the usual time. Skipping the medication may increase the chance of “breakthrough” bleeding or “smeary” bleeding.

Luteal phase support during assisted reproductive techniques: 10 mg three times a day from the day of egg retrieval until the 10th week of pregnancy (if pregnancy is confirmed). If the patient missed taking the pill, this pill should be taken as soon as possible and consult a physician.

The use of didrogesterone before menarche is not indicated. The safety and effectiveness of didrogesterone in adolescent girls aged 12 to 18 years has not been established. The currently available limited data do not allow recommendations for a dosing regimen in patients in this age group.

Interaction

In vitro data show that the main pathway for the formation of the main pharmacologically active metabolite of DDH is catalyzed by the aldo-keto reductase 1C (AKR1 C) in the cytosol of human cells. It is then metabolized within the cytosol by cytochrome P450 isoenzymes, predominantly by CYP3A4, resulting in the formation of several minor metabolites.

The substrate for transformation by CYP3A4 isoenzyme is the main active metabolite of DDH. Metabolism of didrogesterone and DDH can be accelerated by co-administration of substances that are inducers of cytochrome 450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), antibacterial and antiviral drugs (e.g. rifampicin, rifabutin, nevirapine, efavirenz) and herbal medicines containing, for example, St John’s wort. Ritonavir and nelfinavir, known to be strong cytochrome system enzyme inhibitors, in contrast, have enzyme-inducing properties when used together with steroids.

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

The results of in vitro studies show that didrogesterone and DDH in clinically relevant concentrations do not inhibit or induce cytochrome system enzymes that metabolize drugs.

Special Instructions

Before starting treatment with Dufaston^® for abnormal uterine bleeding, the cause of the bleeding should be investigated. During long-term use of the drug, periodic examinations by a gynecologist are recommended, the frequency of which is determined individually, but not less than once every six months. During the first months of treatment of abnormal uterine bleeding, “breakthrough” bleeding or “smeary” bloody discharge may occur. If breakthrough bleeding or “oozing” occurs after a period of taking the drug or continues after treatment, you should contact your physician and have an appropriate additional exam, and if necessary take an endometrial biopsy to rule out an endometrial mass.

If dihydrogesterone is used in combination with estrogens for hormone replacement therapy (HRT), the contraindications and special indications associated with estrogen use should be carefully read.

MHT should be prescribed to treat menopausal symptoms that adversely affect a patient’s quality of life. The benefit/risk ratio of ongoing MHT should be evaluated annually. Therapy should be continued as long as the potential benefit exceeds the potential risk.

Limited data are available on the risks associated with MHT in the treatment of premature menopause. Because of the low absolute risk in younger women, their benefit/risk ratio may be more favorable than that of older women.

Medical examination

A full individual and family history should be taken before starting a combination of didrogesterone and estrogen (for ZGT). An objective examination (including pelvic and breast examinations) should be performed to identify possible contraindications and conditions that require precautions.

A periodic monitoring of individual tolerance to ZHT is recommended during treatment. The patient should be informed about which changes in the mammary glands she should report to her doctor. (See Breast Cancer). Investigations that include mammography should be performed according to common screening, taking into account individual characteristics and the clinical picture.

Hyperplasia and endometrial cancer

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

Cyclical use of progestagens, including didrogesterone (for at least 12 days of a 28-day cycle), or use of a sequential combination regimen of ZGT in women with an intact uterus may prevent the increased risk of endometrial hyperplasia and cancer with estrogen monotherapy.

Breast cancer

The evidence suggests that the risk of breast cancer is increased in women who have received ZGT with estrogen-progestogen and possibly also with estrogen monotherapy. The level of risk depends on the length of time on MHT. Results of epidemiological research 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 MHT. The risk increases after about 3 years of use, with a return to the mean value within a few (usually five) years after the end of therapy.

An increase in breast tissue density on mammography can be observed with MHT, especially with combined estrogen and progestagen therapy, which can make breast cancer difficult to diagnose.

Ovarian cancer

Ovarian cancer is much less common than breast cancer.

Epidemiologic data from a large-scale meta-analysis suggest a slightly increased risk for women receiving ZGT as estrogen monotherapy or combined estrogen and progestagen therapy. An increase in this risk becomes apparent with a duration of therapy of more than 5 years, and after discontinuation of therapy the risk gradually decreases over time. The results of several other studies, including the WHI, suggest that combined HRT is associated with a similar or slightly lower risk of ovarian cancer.

Venous thromboembolism

MGT is associated with a 1.3-3-fold increased risk of venous thromboembolism (VTE), that is, deep vein thrombosis or pulmonary embolism. The likelihood is higher in the first year of MST than in subsequent years. Patients with diagnosed thrombophilia have an increased risk of venous thromboembolism, and MHT may increase the risk. For this reason, ZGT is contraindicated in these patients.

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

If prolonged immobilization is necessary after surgical interventions, the use of ZGT drugs should be stopped 4 to 6 weeks before surgery; resumption of the drug is possible after full restoration of a woman’s motor activity.

Women with no history of VTE but with an indication of a family history of thrombosis at a young age in close relatives may be offered screening after detailed counseling about possible limitations and shortcomings of therapy (screening reveals only a portion of hereditary defects of the hemostatic system).

If thrombophilia associated with thrombosis is identified in family members or if there is a severe defect (e.g., deficiency of antithrombin III, protein C, protein S, or a combination of defects), VHST is contraindicated.

If the patient is taking anticoagulants, the benefit/risk of prescribing ZGT should be carefully evaluated. Until a thorough evaluation of possible thromboembolic factors or initiation of anticoagulant therapy has been completed, MHT should not be prescribed. If thrombosis develops after initiation of therapy, MHT should be stopped.

You should see your doctor urgently if you have any of the symptoms suggestive of a possible thromboembolism (pain or swelling of the lower extremities, sudden chest pain, shortness of breath, visual disturbances).

Ischemic Heart Disease (CHD)

Data from randomized controlled trials suggest no protective effect against the development of myocardial infarction in women with and without CHD receiving ZHT as combined estrogen and progestogen therapy or estrogen monotherapy.

The relative risk of CHD is slightly increased during combination MHT. The absolute risk of CHD depends on age. The number of cases of CHD on MHT is lower in healthy women near the age of natural menopause; however, it increases in subsequent years.

Ischemic stroke

Combination therapy with estrogens and progestogens or estrogens alone is associated with a 1.5-fold increased risk of ischemic stroke. The relative risk does not change with age and is independent of the timing of menopause. However, the incidence of stroke is age-dependent, and the overall risk of stroke in women receiving MHT will increase with age.

Auxiliary substances

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

Impact on driving and operating machinery

Dufaston ^® has little effect on driving and operating machinery. Caution should be exercised when driving vehicles and operating machinery, given the possibility of adverse reactions from the nervous system (light drowsiness and/or dizziness, especially in the first hours of administration).

Contraindications

• high sensitivity to didrogesterone or other drug components;
• diagnosed or suspected progestagen-dependent neoplasms (e.g., meningioma);
• bloods from vaginal bleeding of unclear etiology;
• liver function abnormalities due to current or history of acute or chronic liver disease
• disorders of liver function due to current or history of acute or chronic liver disease (until normalization of liver function tests);
• malignant liver tumors, current or history;
• Galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;period of breastfeeding;
• porphyria, current or history;
• spontaneous abortion (miscarriage) or failed miscarriage with luteal phase support under assisted reproductive technology (ART).

In combination with estrogens

When used with indicated hormone replacement therapy (HRT):

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

With caution

• depression, current or history;
• Conditions that have previously appeared or worsened during prior pregnancy or previous use of sex hormones, such as cholestatic jaundice, herpes in pregnancy, severe skin itching, otosclerosis.

When using didrogesterone in combination with estrogens, caution should be exercised if there are risk factors for thromboembolic conditions such as angina pectoris, prolonged immobilization, severe obesity (BMI over 30 kg/msup>2), advanced age, major surgery, systemic lupus erythematosus, cancer; in patients receiving anticoagulant therapy; with endometriosis, uterine myoma; A history of endometrial hyperplasia; adenoma of the liver; diabetes with or without vascular complications; arterial hypertension; bronchial asthma; epilepsy; a history of migraine or severe headache; gallstone disease; chronic renal insufficiency; and a history of risk factors for estrogen-related tumors (for example, first-line relatives with breast cancer).

Side effects

In clinical trials in patients receiving therapy with didrogesterone alone, the most common adverse effects were: headache/migraine, nausea, menstrual irregularities, and breast soreness/sensitivity.

In clinical trials as well as in post-marketing use (spontaneous reports), the following adverse effects have been observed with the use of didrogesterone alone with the frequency of development indicated below (number of cases/number of patients reported): Frequent (≥1/100 to < 1/10); infrequent (≥1/1000 to < 1/100); rare (≥1/10,000 to < 1/1000).

Hematopoietic system: rare – hemolytic anemia.

Mental disorders: infrequent – depression.

The immune system: rarely – hypersensitivity reactions.

Nervous system disorders: frequent – migraine/headache; infrequent – dizziness; rarely – drowsiness.

Gastrointestinal system: frequently – nausea; infrequently – vomiting.

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

Skin and subcutaneous tissue disorders: infrequent – allergic dermatitis (e.g., rash, itching, urticaria); rarely – Quincke’s edema.

Gender and mammary gland disorders: often – menstrual cycle disorders (including metrorrhagia, menorrhagia, oligo/amenorrhea, dysmenorrhea and irregular menstrual cycle); pain/sensitivity of the breast; rarely – swelling of the breast.

New growths: rare – increase in size of progestagen-dependent neoplasms (e.g., meningioma).

Others: rare – edema; infrequent – increase in body weight.

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

In a randomized, double-blind, double-group parallel study of oral versus intravaginal administration of micronized progesterone to support the luteal phase during assisted reproduction, the incidence of the most frequent adverse events occurring during treatment was shown to be comparable in both groups. The most frequent ones (at least 5% in one treatment group, regardless of the drug) were: vaginal bleeding, nausea, pain during the procedure, headache, abdominal pain, and biochemical pregnancy. The only adverse event that occurred during treatment, with a frequency of ≥2% of patients in each group, was vaginal bleeding.

Possible early pregnancy termination (especially before 10 weeks’ gestation) – the rate of pregnancy development with ART procedures averages about 35%.

The safety profile observed in this study is as expected, given the well-studied safety profile of dydrogesterone and the patient population.

Overdose

There are limited data on cases of drug overdose. Dydrogesterone was well tolerated after oral administration (maximum daily dose described was 360 mg).

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

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