Dufaston, 10 mg 112 pcs

Pharmacotherapeutic group

Sex hormones. Progestagens. Pregnadine derivatives. Dydrogesterone.

ATC code G03DB01

Pharmacological properties

Pharmacokinetics

Absorption. After oral administration, didrogesterone is rapidly absorbed from the gastrointestinal tract. Time of reaching maximum concentration (Tmax) is from 0.5 to 2.5 hours. The absolute bioavailability of didrogesterone at a dose of 20 mg orally (compared with 7.8 mg intravenously) is 28%.

The table shows the mean pharmacokinetic parameters of didrogesterone (D) and dihydrodihydrogesterone (DDH) after multiple oral doses of 10 mg of didrogesterone.

Didrogesterone 10 mg

*: based on AUC (0-tau)/24

Distribution. With a stable concentration of didrogesterone when administered intravenously, the volume of distribution is about 1400L. Didrogesterone and DDH bind to plasma proteins by more than 90%.

Metabolism. After oral administration, didrogesterone is rapidly metabolized to DDH. The concentration of the main metabolite 20-α-dihydrodihydrogesterone (DDH) peaks about 1.5 hours after a dose. Plasma concentrations of DDH are significantly higher than those of didrogesterone. The AUC (area under the curve) and Cmax (maximum concentration) ratios of DDH and didrogesterone are approximately 40 and 25, respectively. The half-lives of didrogesterone and DDH are on average 5-7 hours and 14-17 hours, respectively. The main feature of all didrogesterone metabolites is the presence of the 4,6-dien-3-1 configuration of the parent compound and the absence of 17-α-hydroxylation. This explains the absence of estrogenic and androgenic effects of didrogesterone.

Excretion. After oral administration of labeled didrogesterone, on average 63% of the dose is excreted with the urine. Total plasma clearance is 6.4 l/min. Complete excretion of didrogesterone occurs after 72 hours. DDH is excreted with urine mainly in the form of glucuronic acid conjugate.

Dose and time dependence. Pharmacokinetics are linear for both single and multiple doses between 2.5 and 10 mg. A comparison of the kinetics of single and multiple doses shows that the pharmacokinetic parameters of D and DD do not change as a result of repeated dosing. Stable concentration is reached after 3 days of treatment.

Pharmacodynamics

Dydrogesterone is a synthesized analogue of progesterone that is active when taken orally. Dufaston® causes complete endometrial secretory transformation in the estrogen-sensitized uterus, thereby protecting the endometrium from hyperplasia and/or cancer, the risk of which is increased with estrogen intake. Dydrogesterone has no estrogenic, androgenic, anabolic or corticoid activity.

Dufaston® does not suppress ovulation. As a consequence, it remains possible to conceive in women of reproductive age who take Dufaston®.

In postmenopausal women with a non-removed uterus, estrogen-based ZGT increases the risk of endometrial hyperplasia and cancer. The addition of progestagen prevents an increase in this risk.

Indications

– menstrual cycle disorder

– endometriosis

– dysmenorrhea

– infertility due to luteal insufficiency

– threatened abortion due to progesterone insufficiency

– habitual pregnancy failure due to progesterone insufficiency

– premenstrual syndrome

Oestrogen therapy in women with an intact uterus may be used cyclically for the following conditions:

– to prevent endometrial hyperplasia during postmenopause

– dysfunctional uterine bleeding

– secondary amenorrhea

Active ingredient

Composition

In 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.

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

How to take, the dosage

The suggested regimens can be adjusted according to the severity of the condition and individual response to treatment.

In irregular menstruation, 1 tablet (10 mg) a day from the 11th to the 25th day. It is possible to achieve a regular 28-day cycle.

Endometriosis – 1 to 3 tablets (10-30 mg) a day from the 5th to the 25th day of the cycle or continuously. The dose of more than 1 tablet a day is divided into several receptions during the day. Treatment should be started with the highest dose.

Dysmenorrhea – 1-2 tablets (10-20 mg) per day from the 5th to the 25th day of the cycle. The dose of more than 1 tablet a day should be divided into several doses during the day. Treatment should be started with the highest dose. Treatment should be continued for 6 months continuously.

Infertility due to luteal insufficiency – 1 tablet (10 mg) a day from the 14th to the 25th day of the cycle. The treatment should be continued continuously for at least 6 consecutive cycles. If pregnancy occurs, it is recommended to continue treatment for the first months according to the scheme recommended for habitual abortion.

Threatened abortion due to progesterone insufficiency – initial dose: 4 tablets (40 mg) once, then 1 tablet (10 mg) every 8 hours until symptoms disappear. Treatment should be started with the highest dose. If symptoms continue or relapse during treatment, the dose should be increased by 1 tablet (10 mg) every 8 hours. Continue treatment at the effective dose for 1 week after symptoms have disappeared; then gradually reduce. In case of subsequent relapse of symptoms, treatment should be continued with the effective dose achieved earlier.

Pregnancy failure due to progesterone insufficiency – 1 tablet (10 mg) daily until the 20th week of pregnancy; then the dose may be gradually reduced. Treatment should be started before conception. If symptoms of threatened abortion occur, treatment should be continued accordingly.

Dysfunctional uterine bleeding

To stop bleeding, 1 tablet (10 mg) 2 times a day for 5-7 days. Blood loss is significantly reduced within a few days. Several days after discontinuation of treatment intense bleeding withdrawal is possible. The patient should be warned about it.

The subsequent intense bleeding can be prevented by prescribing prophylactically 1 tablet (10 mg) per day from days 11 to 25 of the cycle, if necessary in combination with estrogens, for 2-3 cycles. After that the treatment can be stopped to make sure that regularity of cycles is restored.

Secondary amenorrhea – 1-2 tablets (10-20 mg) per day from the 11th to the 25th day of the cycle to achieve endometrial secretory transformation as a result of adequate stimulation with endogenous or exogenous estrogens.

To prevent endometrial hyperplasia in the postmenopausal period, in combination with continuous estrogen administration, 1-2 tablets (10-20 mg) per day for 14 consecutive days in a 28-day cycle. If it is necessary to take 2 tablets a day, the dose is divided into two doses. Withdrogesterone withdrawal bleeding is possible.

The combination therapy with estrogens and progestagens should be carried out using the minimum effective dose of hormones and for the shortest course comparable with the treatment goals and risks for each woman, with regular reassessment of risks and benefits.

Premenstrual syndrome: 1 tablet (10 mg) 2 times daily from day 11 to day 25 of the cycle.

Children and adolescents under 18 years of age: No relevant data on the use of didrogesterone before menarche.

The safety and effectiveness of didrogesterone in adolescents aged 12-18 years has not been established.

For oral use. If higher doses are prescribed, the tablets should be taken in several doses throughout the day.

Interaction

The data from in vitro studies indicate that the main metabolic pathway leads to the formation of the main pharmacologically active metabolite, 20-alpha-dihydrodihydrogesterone (DDH), which is catalyzed by aldo-keto reductase 1C (AKR 1C) in the human cytosol. The following metabolic transformation is performed by cytochrome P450 system isoenzymes (CYPs), almost exclusively by CYP3A4 isoenzyme, resulting in various minor metabolites. The main active metabolite of DDH is a substrate for metabolic transformation by CYP3A4 isoenzymes. Therefore, the metabolism of didrogesterone and DDH may be increased when concomitant administration of drugs that increase the synthesis of cytochrome system enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, Carbamazepine), some tuberculostatics and antivirals (e.g., rifampicin, rifabutin, nevirapine, efavirenz), and herbal products containing extracts of Hypericum perforatum, sage, or ginkgo biloba.

Ritonavir and nelfinavir, known to be powerful cytochrome enzyme inhibitors, in contrast, show enzyme inducer properties when taken concomitantly with steroids.

The clinical significance of increased metabolism of didrogesterone is a decrease in efficacy.

In vitro studies have shown that didrogesterone and DDH in therapeutic concentrations do not inhibit or induce cytochrome enzymes.

Special Instructions

Before you start taking Dufaston to treat uterine bleeding, you must rule out an organic cause.

Sometimes breakthrough bleeding can occur during the first months of treatment. If breakthrough bleeding or bleeding occurs after a period of time on the drug or continues after treatment, the cause should be determined, and an endometrial biopsy should be taken to rule out malignant changes in the endometrium.

Conditions requiring discontinuation of therapy

If any of the conditions listed below occur in the first days of treatment or increase in severity, discontinuation should be considered:

– exceptionally severe headache, migraine, or symptoms suggestive of cerebral ischemia

– significant increase in blood pressure

– signs of venous thromboembolism.

In case of threatened abortion or habitual miscarriage, the progression of the pregnancy and the viability of the embryo or fetus should be monitored.

Conditions that require close monitoring

It is known that some rare conditions may be dependent on sex hormones and may occur or worsen during pregnancy and while taking medications containing sex hormones. These include: cholestatic jaundice, pregnancy herpes, severe itching, otosclerosis, and porphyria.

Patients with a history of depression need close monitoring. If there are signs of depression, Duphaston should be discontinued.

Contraindications

– Consider the contraindications for estrogens when used in combination with progestagens such as didrogesterone

– Vaginal bleeding of unspecified etiology

– Serious liver function problems present or in the history before normalization of liver tests

– Hypersensitivity to oestrogens or other drug components

Hypersensitivity to dydrogesterone or other drug components

Diagnosed or suspected progestogen- or estrogen-dependent malignancies (such as meningioma).

Side effects

The undesirable adverse reactions most frequently reported during clinical trials in patients using didrogesterone for the indication without estrogen were: metrorrhagia, breast soreness/sensitivity, migraine/headache.

The following adverse reactions (with frequency) were observed in clinical trials with dydrogesterone (n=3483) in indication without estrogen and were reported spontaneously.

– very common (≥ 1/10);

– frequent (≥ 1/100 to <1/10);

– infrequent (≥ 1/1000 to <1/100);

– infrequent (≥ 1/10000 to <1/1000)

Benign, malignant, and unspecified neoplasms (including cysts and polyps): Rarely, an increase in the size of progestagen-dependent neoplasms, (e.g., meningioma)*.

Blood and lymphatic system disorders: rare – hemolytic anemia*.

Immune system disorders: rare – hypersensitivity.

Psychiatric disorders: infrequent – depression.

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

Hematopoietic and lymphatic system disorders – hypersensitivity.

Gastrointestinal disorders: frequently – nausea; infrequently – vomiting.

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

Skin and subcutaneous tissue disorders: infrequent – allergic dermatitis (e.g., rash, itching, urticaria); rarely – angioedema*.

Gender and mammary gland disorders: often – menstrual disorders (including metrorrhagia, menorrhagia, oligo/amenorrhea, dysmenorrhea and irregular menstruation). Soreness/sensitivity of the mammary glands; rarely – swollen mammary glands.

General disorders and disorders at the injection site: rarely – edema.

Impact on the results of laboratory and instrumental studies: infrequent – increase in body weight.

* Unwanted adverse reactions from spontaneous reports that have not been observed in clinical trials have been classified as “rare” based on the fact that the upper limit of the 95% confidence interval of the frequency estimate does not exceed 3/x, where x =3483 (total number of subjects in clinical trials).

Unwanted adverse reactions that may occur during estrogen-progestagen therapy (see also the section on “Special Precautions” as well as information in the instructions for medical use of estrogen):

– breast cancer, endometrial hyperplasia, endometrial cancer, ovarian cancer;

– venous thromboembolism;

– myocardial infarction, ischemic heart disease, ischemic stroke.

Overdose