Pharmacological properties

Pharmacodynamics

action Mechanism. Didrogesteron is a selection gestagen which substitutes some functions of progesterone. As gestagen, didrogesteron only influences only endometrium, a mucous membrane of a vagina and the cervical channel.

Didrogesteron does not oppress an ovulation. It means that the possibility of fertilization of an ovum at non-pregnant at reception of a didrogesteron remains.

Didrogesteron and his metabolites have no thermogene properties. At women in a postmenopause with the kept uterus the replacement therapy by estrogen results in the increased risk of developing a hyperplasia of endometrium and endometrial cancer. Addition of progestogens can prevent excessive risk.

Cyclic addition of a didrogesteron transfers to women at whom endometrium was stimulated estrogen it to a secretion phase.

Didrogesteron has no masculinizing or virilizing properties. Didrogesteron has no anabolic or kortikoidny properties.

Clinical performance and safety

Support of a lyuteinovy phase at use of the auxiliary reproductive technologies (ART). Randomized multicenter study with participation of two parallel groups for comparison of efficiency, safety and shipping of a didrogesteron for oral administration in a dose of 30 mg/days and the intravaginalny micronized progesterone in capsules in a dose of 600 mg/days for maintenance of a lyuteinovy phase at use of technologies of fertilization of in vitro (LOTUS I) is carried out double blind, with double masking.

Main goal of a research — to show to

not smaller efficiency of an oral didrogesteron in comparison with the intravaginalny micronized progesterone in terms of presence of warm reductions at a fruit on the 12th week of a gestation (10th week of pregnancy) — it is reached.

In the studied population of patients the frequency of approach of the pregnancy confirmed on the 12th week of a gestation (10th week of pregnancy) was 37.6 and 33.1% in groups of a didrogesteron and the micronized progesterone respectively. The difference in the frequency of approach of pregnancy between two groups made 4.7 (95% the confidence interval (CI) −1.2; 10.6).

In sample of subjects of a research for safety assessment (1029 subjects of a research who received at least one dose of the studied medicine) the cases of the undesirable phenomena which arose during therapy about which it was reported most often were identical in both studied groups.

a certain number of early abortions / abortions is expected by

Due to the nature of the studied indication and the studied population of patients, especially till 12th week of a gestation (10th week of pregnancy) as the predicted rate of frequency of approach of pregnancy during this period is about 35%.

safety Profile noted in this research answered with

to expected, considering the established profile of safety of a didrogesteron and also the studied population of patients and the studied indication.

Pharmacokinetics. Unlike progesterone, didrogesteron it is not excreted with urine in the form of pregnandiol. Thus, an opportunity to determine secretion of endogenous progesterone by pregnandiol excretion remains.

on average 63% of a dose are removed by

At oral administration with urine. Full removal happens in 72 h. Its main metabolite is 20 - alpha digidrodidrogesteron (DGD), allocated with urine in the state connected with glucuronic acid. The general property of all metabolites is maintaining structure 4.6 - a diene - 3 - it initial substance and absence 17 - alpha hydroxylations that explains absence at a didrogesteron of estrogenic and androgenic effects.

concentration in DGD blood plasma is much higher than

After oral administration of a didrogesteron, than initial substance. The ratio of AUC makes about 30.

Didrogesteron is quickly absorbed by

. The C _max a didrogesteron and DGD is reached in 0.5-2.5 h

Indication

Irregular menstrual cycles; endometriosis; dysmenorrhea; the infertility caused by lyuteinovy insufficiency; support of a lyuteinovy phase at application vrt; the menacing and usual abortion connected with progesteronovy insufficiency.

Dufaston can be applied as cyclic addition to therapy with estrogen at women with an intact uterus:

• for prevention of a hyperplasia of endometrium in the period of a menopause;
• at dysfunctional uterine bleedings;
• at a secondary amenorrhea.

Use

Dose, the scheme and duration of treatment can be adjusted by

depending on weight of violation and the individual clinical answer of the patient.

Irregular menstrual cycles. Duration of a cycle of 28 days can be reached by purpose of 1 tablet Dufaston in day from the 11th to the 25th day of a cycle.

Endometriosis. From 1 to 3 tablets Dufaston a day from the 5th to the 25th day of a cycle or during all cycle. Doses, multiple 10 mg/days, it is necessary to distribute evenly within a day. It is recommended to appoint the maximum dose at the initial stage of treatment.

Dysmenorrhea. From 1 to 2 tablets Dufaston a day from the 5th to the 25th day of a cycle. Doses, multiple 10 mg/days, it is necessary to distribute evenly within a day. It is recommended to appoint the maximum dose at the initial stage of treatment.

Infertility caused by lyuteinovy insufficiency. 1 tablet Dufaston a day from the 14th to the 25th day of a cycle. This treatment should be continued during at least 6 consecutive cycles. It is recommended to continue treatment within the first months of pregnancy in the same doses, as for usual abortion.

Support of a lyuteinovy phase at application of VRT. 1 tablet Dufaston 3 times a day (30 mg/days). Treatment is begun from the date of a fence of oocytes and continued during 10 weeks if pregnancy is confirmed.

Threat of an abortion. Initial dose: 4 tablets Dufaston at once, then on 1 tablet Dufaston each 8 h. Doses, multiple 10 mg/days, it is necessary to distribute evenly within a day. It is recommended to appoint the maximum dose at the initial stage of treatment.

If symptoms do not disappear or again appear during treatment, the dose needs to be raised on 1 tablet Dufaston each 8 h

After disappearance of symptoms an effective dose needs to be kept during 1 week, further it can be lowered gradually. If symptoms appear again, treatment has to be immediately restored with the established effective dosage.

Usual abortion. Treatment needs to be begun before conception. 1 tablet Dufaston a day till 20th week of pregnancy then it is possible to reduce a dose gradually.

If symptoms of threat of termination of pregnancy appear during treatment, then therapy should be continued as it is described in case of abortion threat.

Dysfunctional uterine bleeding. 2 tablets Dufaston within 5–7 days in combination with estrogen.

In several days after the end of such treatment the cancellation bleeding will develop.

for the purpose of prevention of further developing of bleeding Dufaston is appointed on 1 tablet a day from the 11th to the 25th day of a cycle.

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in case of a cystous hemorrhagic metropathia appoint 1 tablet Dufaston a day from the 11th to the 25th day of a cycle.

In certain cases necessary. In several days after the termination of such treatment the cancellation bleeding will develop.

Such treatment should be continued by

during several cycles.

Secondary amenorrhea. For treatment it is at the same time necessary to appoint estrogen. Estrogen is appointed from 1st to the 25th day of a cycle, from the 11th to the 25th day in combination with 1 tablet Dufaston a day.

For creation of prerequisites for the subsequent cycles therapy is begun for the 5th day after the beginning of bleeding by prescribing of estrogen (from the 5th to the 25th day). Dufaston 10 mg are appointed from the 11th to the 25th day.

For prevention of a hyperplasia of endometrium in the period of a menopause. During each 28-day cycle of therapy by estrogen accept only estrogen during the first 14 days and during the next 14 days take 1 or 2 pill, the containing 10 mg of a didrogesteron, in addition to therapy by estrogen. In case of dosing of 10 mg of a didrogesteron 2 times in day of a tablet should be distributed within a day. Cancellation bleeding usually arises at application of a didrogesteron.

Use of combination therapy by estrogen and progestogen at women in a postmenopause needs to limit to a minimal effective dose and the minimum term for achievement therapeutic the purposes and also periodically it is necessary to revise risks for each woman (see. Special INSTRUCTIONS).

Route of administration. For oral administration. At application of high doses of a tablet have to be evenly distributed for reception within a day.

Children. Because of insufficiency of data on safety and efficiency of application of Dufaston for children it is not recommended to appoint medicine of this category of patients.

Contraindication

not diagnosed vaginal bleeding; the available serious diseases of a liver or presence of a serious illness of a liver in the past if indicators of function of a liver were not normalized; it is necessary to consider contraindications to use of estrogen when they are applied in combination with progestogens, such as didrogesteron; the established hypersensitivity to active agent or any other component of medicine; the established or suspected progestagenzavisimy new growths (for example a meningioma).

Treatment for the purpose of support of a lyuteinovy phase at application of VRT should be stopped if the abortion/abortion is diagnosed.

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Side effects

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At application of a didrogesteron in clinical trials according to indications without treatment by estrogen it was most often reported about the following side reactions: migraine/headache, nausea, menstrual violations and pain/sensitivity of mammary glands.

Following side reactions were observed by

with a frequency stated below in clinical trials of application of a didrogesteron (n=3483) according to indications without treatment by estrogen and according to spontaneous messages: often (≥1/100, 1/10); infrequently (≥1/1000, 1/100); seldom (≥1/10,000, 1/1000).

New growth benign, malignant and uncertain (including cysts and polyps): seldom — increase in sizes of progestagenzavisimy new growths (for example meningiomas) *.

Blood and lymphatic system: seldom — hemolytic anemiya*.

Mental violations: infrequently — depressive mood.

Immune system: seldom — reactions of hypersensitivity.

Nervous system: often — a headache and migraine; infrequently — dizziness; seldom — drowsiness.

Digestive tract: often — nausea; infrequently — vomiting.

Gepatobiliarnaya system: infrequently — the abnormal liver functions which are followed by weakness, an indisposition, jaundice and an abdominal pain.

Skin and hypodermic fabrics: infrequently — allergic dermatitis (for example rash, an itch and urticaria); seldom — angioneurotic otek*.

Reproductive system and mammary glands: often — menstrual violations (including a metrorrhagia, a menorrhagia, oligo-/an amenorrhea, a dysmenorrhea and irregular periods), mammary gland pain / sensitivity of mammary glands; seldom — a swelling of mammary glands.

General symptoms and local reactions: seldom — hypostases.

Inspection: infrequently — increase in body weight.

* the Side reactions from spontaneous messages which are not noted in clinical trials are included by

in the column "seldom" on the basis of the fact that the upper bound of 95% of D of frequency is estimated not higher than 3/x where x =3483 (total number of subjects of observation in clinical trials).

Research LOTUS I on support of a lyuteinovy phase at application of VRT (see. Pharmacological PROPERTIES, Pharmacodynamics): it was most often reported about such undesirable phenomena: vaginal bleeding, nausea, pain during the procedures, a headache, an abdominal pain and biochemical pregnancy. The vaginal bleeding recorded at ≥2% of subjects was the only undesirable phenomenon which arose during therapy and noted in both groups.

Side reactions associated about estrogen-progestagenovym by treatment (see. Special INDICATIONS and instructions for medical use of medicines of estrogen):

• breast cancer, hyperplasia and carcinoma of endometrium, ovary cancer **;
• venous thrombembolia;
• myocardial infarction, ischemic heart disease, ischemic stroke.

** monotherapy Use by estrogen or the replacement hormonal therapy (RHT) combined estrogen-progestagenovoy was associated by

with a little increased risk of diagnosis of cancer of ovary (see. Special INDICATIONS). The metaanalysis of 52 epidemiological researches showed the increased risk of developing cancer of ovary at the women receiving ZGT in comparison with the women never applying ZGT (RR 1.43; 95% of DI 1.31-1.56). At women at the age of 50–54 years applying ZGT within 5 years, the result showed one additional case on 2000 patients. Ovary cancer for the 5-year period is diagnosed for about 2 of 2000 women at the age of 50–54 years which were not applying ZGT.

Special instructions

before application of a didrogesteron for treatment of pathological bleeding should exclude the organic cause of bleeding.

In the first months of treatment breakthrough bleedings or bloody discharges can arise. If breakthrough bleeding or bloody discharges arise treatments after a while or proceed after the end of treatment, it is necessary to establish the reason, including in case of need to exclude a malignant new growth of endometrium by carrying out a biopsy of endometrium.

If any of the following violations occurs for the first time or worsens at use of medicine, the question of the treatment termination has to be considered:

• very severe headache, migraine or symptoms which can indicate brain ischemia;
• substantial increase of the ABP;
• appearance of a venous thrombembolia.

in case of the usual or menacing abortion needs to define and control viability of a fruit during treatment to be convinced that pregnancy continues and the embryo is alive.

State, demanding control. It is known that sex hormones can influence the next exceptional cases and therefore during pregnancy or at use of sex hormones can develop or worsen: the cholestatic jaundice, herpes of pregnant women, a heavy itch, an otosclerosis, a porphyria, a depression and abnormal indicators of function of a liver caused by an acute or chronic hepatic disease. If any of these states is present or appeared earlier and/or worsened during pregnancy or the previous treatment by hormones, the patient has to be under careful observation. It is necessary to consider that these states can recur or worsen during therapy didrogesterony therefore it is necessary to consider the termination of therapy in such cases.

to Patients with a depression should be in the anamnesis under careful observation. If the heavy depression recurs, treatment didrogesterony should be stopped.

Following cautions concern Dufaston's application according to indications "for prevention of a hyperplasia of endometrium in the period of a menopause". See also preventions in instructions for medical use of medicines of estrogen.

should be applied To knocking over of post-menopausal symptoms of ZGT only in cases when symptoms have negative effect on quality of life. In all cases it is necessary to estimate carefully advantage and risk of ZGT at least 1 time a year. ZGT should be continued only if the advantage exceeds risk.

are limited to

Proof concerning the risks connected with ZGT for treatment of a premature menopause. Thanks to the low level of absolute risk the women of young age between advantage and risk in this group can have more favorable balance, than at women of more advanced age.

Medical examination / further medical observation. Before ZGT or at its restoration after a break it is necessary to collect the full personal and family anamnesis. Considering data of the anamnesis and also a contraindication and caution to administration of drug, it is necessary to perform objective examination of the patient (including inspection of bodies of a basin and survey of mammary glands). During treatment it is recommended to perform periodic inspections which frequency and character depend on specific features of the patient. Zhenshchin it is necessary to inform about what changes in mammary glands they have to report to the doctor or the nurse (see below "Breast cancer"). Inspection of mammary glands, including the corresponding methods of visualization, for example mammography, should be carried out according to the operating practice of screening taking into account individual clinical needs of the patient.

Hyperplasia and carcinoma of endometrium. Women with an intact uterus have a risk of developing of a hyperplasia and carcinoma of endometrium increases at long monotherapy by estrogen. Depending on duration of treatment and a dose of estrogen the risk can be from 2 to 12 times higher, than at the women who are not accepting estrogen. After the therapy termination by estrogen this risk remains at least within 10 years. Addition of progestogens, such as didrogesteron, cyclically within not less than 12 days a month / the 28-day cycle or in the form of a constant of the therapy combined estrogen-progestagenovoy at women with the kept uterus can prevent the excessive risk associated with ZGT only estrogen.

Breakthrough bleedings and bloody discharges can arise within the first months of treatment. If breakthrough bleedings or bloody discharges arise after purpose of therapy for some time or if they proceed also after the end of treatment, further inspection is shown. It can mean that it is necessary to carry out an endometrium biopsy to exclude malignancy.

Breast cancer. All available data confirm the increased risk of developing a breast cancer at the women accepting the therapy combined estrogen-progestagenovuyu, and, perhaps, even at application of ZGT only estrogen. This risk depends on duration of application of ZGT.

therapy Combined estrogen-progestagenovaya: randomized placebo - the controlled research Women's Health Initiative (WHI) and epidemiological researches showed the increased risk of a breast cancer at the women accepting ZGT estrogen-progestagenovuyu within 3 or more years. After the treatment termination this increased risk remains at least within 5 years. ZGT, is especially oestrogenic-progestagenovaya combination therapy, increases density of mammography images that can negatively affect radiological detection of a breast cancer.

ovary Cancer. Cancer of an ovary arises much less often than a breast cancer. The epidemiological data obtained as a result of the wide metaanalysis showed, the risk at the women accepting monotherapy by estrogen or an estrogen combination with progestogen as ZGT is a little increased; this risk is shown within 5 years of application and decreases after the therapy termination over time. Some other researches, including WHI, showed that application of the combined ZGT can be connected with the same or a little lower risk (see. Side EFFECTS).

Venous thrombembolia. ZGT is connected with 1.3-3-fold increase in risk of a venous thrombembolia, that is deep vein thrombosis or pulmonary embolism. Emergence of such event is more probable on the first year of ZGT, than later.

Patients with the known trombofilichesky states have the increased risk of developing a venous thrombembolia, and ZGT can increase this risk. Therefore ZGT is contraindicated to this group of patients.

Conventional risk factors of a venous thrombembolia is use of estrogen, advanced age, extensive surgical interventions, a long immobilization, obesity (body mass index of 30 kg/m ² ), pregnancy / a puerperal period, a system lupus erythematosus and cancer. There is no consensus of rather possible role of a varicosity in developing of a venous thrombembolia.

As well as at all patients during the postoperative period, preventive measures needs to consider

for prevention of a venous thrombembolia after surgical intervention. If planned surgery demands a further long immobilization, it is recommended to stop temporarily ZGT for 4–6 weeks before operation. Until the woman restores full mobility, it is not necessary to resume treatment.

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to Women without venous thrombembolia in the personal anamnesis, but in the presence in the anamnesis at relatives of the first degree of thrombosis at young age it is possible to offer screening after careful discussion of its restrictions (only a part of trombofilichesky defects can come to light when screening). If the established trombofilichesky defect is connected with thrombosis at family members or the defect is connected with serious anomaly (for example insufficiency of antithrombin, a protein of S or protein With or a combination of defects), ZGT is contraindicated.

At the women who are already receiving continuous anticoagulating therapy should weigh advantage and risk of ZGT carefully.

If the venous thrombembolia develops after the beginning of therapy, administration of medicament should be stopped. Patients should be informed that they need to see immediately a doctor at emergence of potential thromboembolic symptoms (for example painful hypostasis of a leg, a sudden stethalgia, short wind).

an ischemic heart disease. In randomized controlled studies proofs of protection against a myocardial infarction at women with or without ischemic heart diseases receiving the therapy combined estrogen-progestagenovuyu or ZGT only estrogen are not revealed.

therapy Combined estrogen-progestagenovaya: the relative risk of emergence of an ischemic heart disease at ZGT is slightly increased. As the basic absolute risk of an ischemic heart disease substantially depends on age, the quantity of additional cases of an ischemic heart disease because of use of estrogen-progestagenov is very insignificant at healthy women at the time of approach of a menopause, but will increase in more advanced age.

Ischemic stroke. The therapy combined estrogen-progestagenovaya and monotherapy by estrogen is associated with 1-1.5-fold increase in risk of an ischemic stroke. The relative risk does not change with age or time from the moment of approach of a menopause. However, as the basic risk of a stroke substantially depends on age, the general risk of a stroke at the women accepting ZGT increases with age.

Excipients. This medicine contains lactoses monohydrate. Patients with rare hereditary forms of intolerance of a galactose, insufficiency of lactase or a syndrome of glyukozo-galaktozny malabsorption should not use this drug.

Use during pregnancy and feeding by a breast

Pregnancy. By calculations, more than 9 million pregnant women accepted didrogesteron. Still proofs of harmful effects of a didrogesteron at application during pregnancy are not revealed.

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In literature described the research which showed that use of some progestogens can be connected with the increased risk of a hypospadias. But as still it is not confirmed in other researches, it is impossible to be defined finally concerning a role of progestogens in development of a hypospadias. Clinical trials in which the limited number of women were treated didrogesterony in the early stages of pregnancy did not show increase in risk. There are no other epidemiological data yet.

In preclinical trials of embriofetalny and post-natal development the effects corresponded to a pharmacological profile. Adverse effects arose only when medicine influence considerably exceeded the maximum exposure for the person.

Didrogesteron can be applied during pregnancy according to accurate indications.

feeding Period breast. There are no data on penetration of a didrogesteron into breast milk. Researches on penetration of a didrogesteron into breast milk were not conducted.

Experience of use of other progestogens specifies that progestogens and their metabolites get to breast milk in small quantities. It is unknown whether there is a risk for the child therefore didrogesteron it is not necessary to apply during feeding by a breast.

Fertility. There are no proofs that didrogesteron in therapeutic doses reduces fertility.

Ability to influence speed of response at control of vehicles or other mechanisms. Dufaston has insignificant impact on ability to drive the car and to work with machines and mechanisms.

Infrequently didrogesteron can cause small drowsiness and/or dizziness, especially in the first several hours after reception. Therefore it is necessary to drive the car or to work with mechanisms with care.

Interaction

Data of the researches in vitro demonstrate that the main way of metabolism thanks to which the active metabolite main pharmacological dgd is formed is catalyzed by aldoketoreductase 1c (akr 1c) in cytosol of the person. along with cytosolic metabolism the metabolic transformations are carried out by isoenzymes of p450 (CYP) cytochrome, almost exclusively cyp isoenzyme 3a4 that leads to formation of several insignificant metabolites. the main active metabolite dgd is substrate for metabolic transformation by means of cyp 3a4. therefore metabolism of a didrogesteron and dgd can accelerate at a concomitant use of the substances inducing enzymes of p450 cytochrome such as antikonvulsant (for example phenobarbital, Phenytoinum, carbamazepine), antimicrobial medicines (for example rifampicin, rifabutin, not Virapinum, efavirenz) and the phytomedicines containing a St. John's wort (hypericum perforatum), a sage or a ginkgo of a bilob.

Ritonavir and nelfinavir, known as strong inhibitors of enzymes of cytochrome, show enzyme - the inducing properties at simultaneous application with steroid hormones. Clinically increased metabolism of a didrogesteron can lead to decrease in effect.

Research in vitro was shown that didrogesteron and DGD in clinically significant concentration do not suppress and do not induce enzymes of P450 cytochrome, the medicines participating in metabolism.

Overdose

Symptoms. didrogesteron is medicine with very hypotoxicity. symptoms which can theoretically arise in case of overdose — nausea, vomiting, drowsiness and dizziness. cases when the overdose of a didrogesteron led to harmful consequences are known (the maximum daily dose accepted by the person made 360 mg).

Treatment. Specific treatment is not required. In case of overdose the symptomatic treatment can be considered.

Storage conditions

does not demand special storage conditions.

Duphaston Compendium — UADUSTO170331