Composition, form of production and packaging
The tablets covered with a film cover of orange-pink color, round, biconcave, with engraving "379" on one side of the tablet.
Estradiol hemihydrate 1.03 mg,
which corresponds to the content of estradiol 1 mg
dydrogesterone 5 mg
Excipients: lactose monohydrate - 114.7 mg, hypromellose - 2.8 mg, corn starch - 14.4 mg, silicon colloidal dioxide - 1.4 mg, magnesium stearate - 0.7 mg.
The composition of the film shell: opedrai OY-8734 orange (hypromellose - 2.844 mg, macrogol 400 - 0.284 mg, titanium dioxide (E171) - 0.8 mg, iron dye oxide yellow (E172) - 0.048 mg, iron dye oxide red (E172) 0.024 mg) 4 mg.
28 pcs. - blisters (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
Estradiol , part of the preparation Femoston В® 1/5 contin, is identical to the endogenous estradiol of a human being, which is the most active estrogen. Estradiol replenishes the deficiency of estrogen in the female body after the onset of menopause and reduces menopausal symptoms during the first weeks of treatment.
Dydrogesterone is a gestagen effective in ingestion and having parenteral progesterone-like activity.
When carrying out hormone replacement therapy (HRT), the inclusion of dydrogesterone provides a full secretory transformation of the endometrium, thereby reducing the increased risk of endometrial hyperplasia under the influence of estrogen.
HRT preparation Femoston В® 1/5 continent prevents loss of bone mass in the postmenopausal period.
The absorption of estradiol depends on the particle size; Micronized estradiol is easily absorbed from the digestive tract.
With the daily use of the drug Femoston В® 1/5 cons C ss estradiol in blood plasma is achieved after about 5 days.
Estrogen can be detected both in bound and free state. About 98-99% of the dose of estradiol binds to plasma proteins, of which 30-52% bind with albumin and about 46-69% - with sex hormone binding globulin (GSHG).
Estrogens are excreted in breast milk.
Estradiol is metabolized in the liver to estrone and estrone sulfate, which have estrogenic activity. Estrone sulfate can undergo intestinal hepatic recirculation.
Estrone and estradiol are excreted in conjugated glucuronic acid state mainly by the kidneys. T 1/2 is 10-16 hours.
After oral administration, it is rapidly absorbed and completely metabolized. The time to reach Cmax for dydrogesterone varies from 30 min to 2.5 h. Cmax 20? -dihydrodrogesterone (DHH) in the blood plasma is reached approximately 1.5 h after the administration of the drug. Bioavailability of dydrogesterone - 28%.
Comparison of pharmacokinetics in single and multiple applications has shown that the pharmacokinetic properties of dydrogesterone and DGD do not change with repeated use.
More than 90% of dydrogesterone and DGD bind to plasma proteins. C ss of dydrogesterone is achieved 3 days after the start of treatment.
The main metabolite of dydrogesterone is 20? -dihydrodrohydrogesterone (DGD). The concentration of DGD in plasma significantly exceeds the initial concentration of dydrogesterone, the ratio of AUC and Cmax DGD to dydrogesterone is about 40 and 25, respectively.
A common characteristic feature of all metabolites of dydrogesterone is the preservation of the configuration of 4,6-dien-3-one of the starting material and the lack of 17? -hydroxylation, which leads to the absence of estrogenic and androgenic activity.
T 1/2 is 5-7 hours for dydrogesterone, 14-17 hours for DGD.
Completely dydrogesterone is withdrawn after 72 hours. On average, 63% of the dose taken is excreted by the kidneys. The total plasma clearance is 6.4 l / min. DGD is determined in urine mainly in the form of glucuronic acid conjugate.
- hormone replacement therapy due to estrogen deficiency in postmenopausal women (no earlier than 12 months after the last menstrual period);
- prevention of postmenopausal osteoporosis in women with a high risk of fractures with intolerance or contraindications to the use of other medications.
The drug is taken orally daily, in a continuous regime of 1 tab. / Day (preferably at the same time of day), regardless of food intake.
When switching from another continuous sequential or cyclic regimen, the patient should complete the current cycle, and then switch to Femoston В® 1/5 continuum.
When switching from a continuous combination regimen of therapy, you can begin taking Femoston В® 1/5 contin on any day.
If the patient misses the next dose, the tablet should be taken within 12 hours after the usual intake time; otherwise the missed tablet should not be taken, the next day you need to take the pill at the usual time. Skipping the drug may increase the probability of breakthrough uterine bleeding.
In clinical studies, the most common cases of patients receiving estradiol / dydrogesterone combination therapy were headache, abdominal pain, mammary tension / tenderness, and back pain.
In clinical trials (n = 4929), the following adverse events were observed with a developmental frequency indicated below (number of reported cases / number of patients): very often (from 1/10); often (from 1/100 to 1/10); infrequently (from 1/1000 to 1/100), rarely (from 1/10 000 to 1/1000), very rarely (<1/10 000).
From the nervous system: very often - headache; often - migraine, dizziness.
From the side of the psyche: often - depression, nervousness; infrequently - a change in libido.
From the side of the cardiovascular system: infrequently - increased blood pressure, venous thromboembolism; rarely - myocardial infarction.
From the digestive system: very often - pain in the abdomen; often - flatulence, nausea, vomiting; infrequently - gallbladder disease, a violation of the liver, sometimes in combination with jaundice, asthenia, malaise, abdominal pain.
From the side of the reproductive system and mammary glands: very often - the tension / soreness of the mammary glands; often spotting spotting, metrorrhagia, copious menstrual bleeding, meager or no menstrual like bleeding, acyclic spotting, painful menstruation-like bleeding, abdominal pain, altered vaginal secretion, vaginal candidiasis; infrequently - an increase in the size of the leiomyoma, an increase in mammary glands, premenstrual-like syndrome.
From the urinary system: infrequently - cystitis.
From the musculoskeletal system: very often - pain in the back (waist).
Dermatological reactions: rarely - vascular purpura.
From the immune system: infrequently - hypersensitivity to the drug or any of the components of the drug; often - allergic reactions, such as urticaria, skin rash and itching; rarely - angioedema.
On the part of the body as a whole: often - asthenic conditions (weakness, malaise, fatigue), peripheral edema.
Other: often - weight gain; infrequently, weight loss.
Other side effects caused by treatment with a combination of estrogen and progestogen (including estradiol / dydrogesterone).
Benign, malignant and unspecified neoplasms: for example, endometrial cancer, ovarian cancer, meningioma.
From the hemopoietic system: hemolytic anemia.
On the part of the immune system: systemic lupus erythematosus.
On the part of the nervous system: the risk of dementia in women starting to use drugs for HRT at the age of over 65, chorea, provocation of epileptic seizures.
From the side of the organ of vision: intolerance of contact lenses, increased curvature of the cornea.
Dermatological reactions: chloasma and / or melasma, which can persist after discontinuation, erythema multiforme, erythema nodosum.
From the musculoskeletal system: cramps in the muscles of the lower limbs.
From the cardiovascular system: arterial thromboembolism.
From the urinary system: incontinence.
On the part of the reproductive system and mammary glands: fibrocystic mastopathy, erosion of the cervix.
Congenital and hereditary disorders: worsening of the course of concomitant porphyria.
From the side of metabolism: hypertriglyceridemia.
From the digestive system: pancreatitis (in patients with hypertriglyceridemia).
On the part of laboratory indicators: an increase in the content of thyroid hormones.
- lactation period;
- diagnosed or suspected breast cancer;
- diagnosed or suspected estrogen-dependent malignant neoplasms (eg, endometrial cancer);
- diagnosed or suspected progestogen-dependent neoplasms (eg, meningioma);
bleeding from the vagina of an unclear etiology;
- untreated endometrial hyperplasia;
- thromboembolic diseases at present or in the anamnesis (including thrombosis, deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic and hemorrhagic cerebrovascular disorders);
- multiple or expressed factors of arterial or venous thrombosis associated with a congenital or acquired predisposition, for example, protein C deficiency, protein S deficiency, antithrombin III deficiency, antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant), angina pectoris, prolonged immobilization, severe forms of obesity (BMI over 30 kg / m 2), cerebrovascular disease or coronary artery, transient ischemic attacks, complicated lesion valve the Machine and the heart, atrial fibrillation;
- Acute or chronic liver diseases at present or in the anamnesis (before normalization of laboratory parameters of liver function), incl. malignant liver tumors;
- galactose intolerance, lactase deficiency, glucose malabsorption / galactose syndrome;
- Hypersensitivity to the components of the drug.
The use of the preparation Femoston 1/5 continuum should be discontinued if the following conditions occur:
- Jaundice and / or liver dysfunction;
- uncontrolled arterial hypertension;
- first appeared on the background of the use of drugs for HRT migraine-like headache.
With caution, HRT in postmenopausal women is prescribed if, at the present time or in a history, they have been diagnosed with:
- uterine leiomyoma, endometriosis;
- the presence of risk factors for the occurrence of estrogen-dependent tumors (for example, I degree of heredity of breast cancer);
- arterial hypertension;
- benign liver tumors;
- diabetes mellitus, both in the presence of vascular complications, and in cases of their absence;
- a migraine or an intense headache;
- systemic lupus erythematosus;
- Endometrial hyperplasia in the anamnesis;
- bronchial asthma;
PREGNANCY AND LACTATION
The drug is contraindicated in pregnancy and during breastfeeding.
At the onset of pregnancy against the background of treatment with the drug Femoston В® 1/5, the continuum therapy should be stopped immediately.
APPLICATION FOR FUNCTIONS OF THE LIVER
Estrogens can cause fluid retention, which can adversely affect the condition of patients with impaired renal function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated in acute or chronic diseases of the liver at present or in the anamnesis (before normalization of laboratory parameters of liver function), incl.malignant liver tumors.
Use of the drug should be discontinued if there is jaundice and / or a violation of liver function.
With caution should be used in benign tumors of the liver.
APPLICATION IN ELDERLY PATIENTS
The experience of using the drug in women over 65 is limited.
There are reports of an increased risk of developing dementia in women who started using HRT (combined or estrogen-only) after 65 years.
The drug is prescribed only in the presence of symptoms adversely affecting the quality of life. Therapy should be continued until the benefits of taking the drug exceed the risk of side effects. The experience of using the drug in women over 65 is limited.
Before the appointment or resumption of therapy with the drug Femoston В® 1/5 contin, it is necessary to collect a complete medical and family history and conduct a general and gynecological (including mammary glands) examination of the patient in order to identify possible contraindications and conditions requiring compliance with precautions. During treatment with the preparation of Femoston В® 1/5, it is recommended to conduct periodic examinations, the frequency and nature of which are determined individually, but not less than 1 time in 6 months. It is advisable to conduct a mammogram for additional examination of the mammary glands. Women should be informed of any possible changes in the mammary glands that are required to inform the attending physician.
The use of estrogens can affect the results of the following laboratory tests: the determination of glucose tolerance, the study of the functions of the thyroid and liver.
The risk of developing hyperplasia and endometrial cancer in patients with estrogen alone depends on the dose and duration of treatment and is increased 2 to 12 times compared to the absence of treatment; the risk may remain elevated for 10 years after discontinuation of therapy.
Cyclic use of progestogen (at least for 12 days of the 28-day cycle) or the use of continuous combined HRT in women with a preserved uterus can prevent increased risk of hyperplasia and endometrial cancer as a result of estrogen use.
For the purpose of timely diagnosis, it is advisable to perform ultrasound screening, if necessary, conduct a histological (cytological) study.
Bloody discharge from the vagina
In the first months of treatment with the drug, breakthrough bleeding and / or acyclic menstrual-like bloody discharge from the vagina may be noted. If such bleeding occurs some time after the initiation of therapy or continues after the cessation of treatment, their cause should be established. It is possible to conduct an endometrial biopsy to exclude a malignant neoplasm.
HRT is associated with a 1.3-3-fold risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This phenomenon is most likely during the first year of HRT.
In the presence of thromboembolic complications in relatives of the first degree of kinship at a young age, as well as with a habitual miscarriage in a history, it is necessary to conduct a study of hemostasis. If the patient is taking anticoagulants, the expediency of prescribing the preparation of Femoston В® 1/5 continuum in terms of benefit / risk ratio should be carefully evaluated. Until the completion of a thorough assessment of the possible development of thromboembolism or the onset of anticoagulant therapy, the preparation of FemostonВ® 1/5 continuum should not be prescribed.
If a patient's family member is diagnosed with a thrombophilic condition and / or if the defect is severe or severe (eg, deficiency of antithrombin III, protein S or C, and a combination of defects), the preparation Femoston В® 1/5 is contraindicated.
Since patients with diagnosed thrombophilic conditions have an increased risk of developing venous thromboembolism, the use of the drug Femoston В® 1/5 continuum, which increases this risk, is contraindicated.
In most cases, risk factors for VTE include: estrogen use, advanced age, extensive surgery, prolonged immobilization, obesity (BMI> 30 kg / m 2 ), pregnancy or the postpartum period, systemic lupus erythematosus and malignant neoplasms. There is no consensus on the possible role of varicose veins in the development of VTE.
To prevent VTE after surgical intervention in all postoperative patients, it is necessary to consider the issue of conducting preventive measures.
In the case of prolonged immobilization after surgery (for 4-6 weeks), it is recommended to stop the use of the drug Femoston В® 1/5 continuum and should not be resumed until the woman fully recovered mobility. If VTE develops after the initiation of therapy, the drug should be discontinued and patients should be informed that they should immediately consult a doctor if there is any symptom that indicates the development of thromboembolism (eg, tenderness or swelling of the lower limbs, sudden pain in the chest, shortness of breath).
Breast Cancer and Ovarian Cancer
In women receiving long-term HRT with estrogen alone or estrogen / progesterone complex, the incidence of breast cancer diagnosis increases, which returns to baseline within 5 years after cessation of therapy.
The increase in this risk depends on the duration of HRT use. In women taking combined estrogen-gestagenic HRT for more than 5 years, the risk of developing breast cancer may increase by 2 times.
Against the background of HRT, there may be an increase in the density of breast tissue during mammography, which can make it difficult to diagnose breast cancer.
Ovarian cancer is much less common than breast cancer. Long-term use (at least 5-10 years) of estrogen in monotherapy with HRT is associated with a slight increase in the risk of ovarian cancer. Some studies, including the WHI, indicate that combination HRT may in the same or a lesser extent, increase the risk of this disease.
The risk of ischemic stroke
Combination therapy with estrogen and progestin or estrogen-only therapy is associated with an increased relative risk of ischemic stroke by 1.5 times. The risk of hemorrhagic stroke when receiving HRT does not increase.
The relative risk does not depend on age or length of therapy, but the baseline risk is strongly dependent on age, so the overall risk of stroke in women receiving HRT will increase with age.
Coronary heart disease (CHD)
The relative risk of CAD during use of combined HRT (estrogen + progestin) significantly increases. Due to the fact that the absolute risk of CAD is strongly dependent on age, the number of additional cases of coronary heart disease due to receive a combined HRT in healthy premenopausal women is very low, but it increases with age.
Estrogens may cause fluid retention, which may adversely affect the condition of patients with impaired renal and cardiac function.
Women with hypertriglyceridemia, against the background of HRT in very rare cases there may be a significant increase in plasma concentrations of triglycerides, which contributes to the development of pancreatitis.
Estrogens increase the content of thyroid-binding globulin, resulting in an overall increase in the concentration of circulating thyroid hormones (T3 concentration of free hormones T4 and is usually not changed). Concentrations of other binding proteins in serum (transcortin, globulin, sex hormone binding) can also be increased, which increases the concentration of circulating corticosteroids and sex hormones. The concentrations of free or biologically active hormones do not change. May increase the plasma concentrations of other proteins (substrate angiotensinogen / renin,? -1-antitrypsin, ceruloplasmin).
HRT does not improve cognitive function. There have been reports of an increased risk of dementia among women who started HRT (combined or estrogen-only) after 65 years.
Preparation Femoston В® 1/5 continuum is not contraceptive.
Impact on the ability to drive vehicles and manage mechanisms
Caution should be exercised in the management of vehicles and mechanisms, taking into account the risk of adverse reactions in the nervous system.
Estradiol and dydrogesterone - substances with low toxicity.
Symptoms may be nausea, vomiting, tension of the mammary glands, dizziness, abdominal pain, drowsiness / fatigue, withdrawal bleeding.
Treatment: symptomatic therapy.
Estrogenic and gestagenic action of the drug Femoston В® 1/5 continuum can be reduced while the use of drugs, inducers of microsomal liver enzymes (CYP2B6, CYP3A4, CYP3A5, CYP3A7): anticonvulsant (phenobarbital, carbamazepine, phenytoin) and antimicrobials (rifampicin, rifabutin, nevirapine , efavirenz); with herbal preparations containing St. John's wort (Hypericum perforatum); with ritonavir and nelfinavir. Amplification metabolism estrogen and progestogen can clinically manifest reduction effect of the drug and the change in the intensity of bleeding from the vagina.
Estrogens may affect the metabolism of other drugs due to competitive binding to cytochrome P450 enzyme systems involved in their cleavage. This should be considered for drugs with a narrow therapeutic action profile such as tacrolimus and cyclosporine A (CYP3A4, CYP3A3), fentanyl (CYP3A4) and theophylline (CYP1A2) as This kind of interaction can lead to an increase in the plasma concentration of the above formulations to the toxic level. In this connection it may require careful monitoring of the patient for a long period of time, and possibly reducing the dose of tacrolimus, fentanyl, cyclosporin A and theophylline.
Studies on the interaction with other drugs has not been conducted.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of the reach of children, at a temperature of no higher than 30 В° C. Shelf life - 3 years.