Velledien tablets 2,5mg, no. 28

• treatment of symptoms of estrogen deficiency in postmenopausal women (no earlier than 1 year after the last menstruation at the onset of natural menopause or immediately after surgical menopause);

• prevention of postmenopausal osteoporosis in women at high risk of fractures with intolerance or contraindications to the use of other drugs intended for the treatment of osteoporosis.

The drug is taken orally 1 tablet / day, without chewing, drinking water, preferably at the same time, continuously.

The first pill is taken from the cell of the upper row, marked by the day of the week corresponding to the day of the beginning of the intake. All other tablets are taken sequentially from the wells in the direction of the arrow on the calendar package until all the tablets have been taken.

Start taking Welledien

For the treatment of postmenopausal symptoms, Velledien should be used only for symptoms that adversely affect a woman's quality of life. The reception of the drug Velledien is begun no earlier than 12 months after the last menstruation with the onset of natural menopause. Patients with surgery-related menopause can start taking the drug immediately. In all cases, at least once every 6 months, it is necessary to conduct a thorough assessment of the risk and benefit of treatment and continue using the drug during a period of time when the benefits of therapy outweigh the risk.

Switching to Welledien after another hormone replacement therapy (HRT)

For women with an intact uterus, when switching to Velledien after using another HRT containing only estrogens, it is recommended to first induce menstrual 'withdrawal' bleeding by using a progestogen to eliminate the likely existing endometrial hyperplasia.

When switching from a drug for HRT with a cyclic regimen of taking the drug, Welledien should be started the next day after the end of the use of the progestogen.

If you switch from a continuous HRT combination, you can start taking Welledien at any time.

Violation of the drug intake regimen

If less than 12 hours have passed since the missed pill, the woman should take it as soon as possible on the same day. The next pill is taken at the usual time of the day.

If the delay in taking the pill is more than 12 hours (the interval since the last pill was more than 36 hours), you do not need to take the missed pill, and the next pill must be taken at the usual time.

Tablets are white, round, flat-cylindrical.

1 tab.

tibolone 2.5 mg

Excipients: lactose monohydrate - 69.44 mg, microcrystalline cellulose - 17.36 mg, ascorbyl palmitate - 0.2 mg, corn starch - 10 mg, magnesium stearate - 0.5 mg.

• diagnosed (including in history) breast cancer or suspicion of it and diagnosed (including in history) estrogen-dependent malignant tumors (for example, endometrial cancer) or suspicion of them;

• vaginal bleeding of unknown etiology;

• thrombosis (venous and arterial) and thromboembolism at present or in history (including thrombosis and deep vein thrombophlebitis, pulmonary embolism), coronary artery disease, myocardial infarction, ischemic and hemorrhagic cerebrovascular disorders;

• conditions preceding thrombosis (including transient ischemic attacks, angina pectoris at present or in history);

• identified predisposition to venous or arterial thrombosis, including resistance to activated protein C, protein C deficiency, protein S or antithrombin III deficiency, antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant);

• multiple or severe risk factors for venous or arterial thrombosis, including:

  • complicated lesions of the valvular apparatus of the heart;

  • atrial fibrillation;

  • diseases of the vessels of the brain or coronary arteries;

  • uncontrolled arterial hypertension;

  • extended surgery with prolonged immobilization, extensive trauma;

  • smoking over the age of 35;

  • obesity with a BMI> 30 kg / m2;

• malignant or benign tumors (including liver adenoma) at present or in history;

• liver failure, acute liver disease or a history of liver disease, after which the indicators of liver function tests did not return to normal;

• porphyria;

• otosclerosis that occurred during a previous pregnancy or with the use of hormonal contraceptive drugs in history;

• chronic heart failure (III-IV FC);

• cerebrovascular disorders;

• period less than 1 year after the last menstrual period;

• untreated endometrial hyperplasia;

• pregnancy;

• breastfeeding period;

• rare hereditary diseases (galactose intolerance, lactase deficiency or glucose-galactose malabsorption);

• hypersensitivity to the drug or any of its components.

Carefully

If any of the following conditions / diseases are present, have been observed previously and / or have worsened during pregnancy or previous hormone therapy, the patient should be under close medical supervision. It should be borne in mind that these conditions / diseases may recur or worsen during treatment with Velledien, in particular:

• leiomyoma (uterine fibroma) or endometriosis;

• cardiovascular failure without signs of decompensation;

• the presence of risk factors for estrogen-dependent tumors (for example, breast cancer in first-degree relatives);

• controlled arterial hypertension;

• hypercholesterolemia;

• disorders of carbohydrate metabolism, diabetes mellitus, both in the presence and in the absence of complications;

• cholelithiasis;

• migraine or severe headache;

• systemic lupus erythematosus;

• a history of endometrial hyperplasia;

• epilepsy;

• bronchial asthma;

• renal failure;

• otosclerosis not associated with pregnancy or previous use of hormonal contraceptive drugs.

pharmachologic effect

The drug selectively regulates estrogen-like activity in tissues and is a tissue-selective regulator. Its pharmacodynamic properties are determined by the action of three pharmacologically active metabolites of tibolone: ??3-alpha-hydroxytybolone and 3-beta-hydroxytybolone have estrogen-like activity, the delta-4 isomer is characterized by progestogen-like and weak androgen-like activity.

The drug compensates for the deficiency of estrogen in the postmenopausal period, relieving the symptoms associated with their deficiency - hot flashes, depression, increased sweating at night, headache. It has a positive effect on libido and mood (increases the concentration of central and peripheral opioids). Has a trophic effect on the vaginal mucosa without causing endometrial proliferation. Prevents bone loss after menopause or ovarian removal. Reduces the concentration of phosphates and calcium in blood plasma.

Application during pregnancy and lactation

Taking the drug is contraindicated during pregnancy and during breastfeeding.

Application for violations of liver function

The use of the drug is contraindicated in case of liver failure, acute liver disease or a history of liver disease, after which the indicators of liver function tests did not return to normal.

Application for impaired renal function

With caution: renal failure.

Use in elderly patients

There is evidence of an increased risk of possible dementia in women with the initiation of continuous therapy with HRT preparations containing only estrogens, after the age of 65 years.

special instructions

Velledien is not intended for use as a contraceptive and does not protect against unwanted pregnancies.

The decision to start taking the drug Velledien should be based on the benefit / risk ratio, taking into account all individual risk factors, and in women over 60 years old, the increased risk of stroke should also be taken into account.

For the treatment of postmenopausal symptoms, Velledien should only be prescribed for symptoms that adversely affect quality of life. In all cases, it is necessary to conduct a thorough assessment of the risk and benefit of therapy at least 1 time per year, and you should continue taking the drug Velledien only if the benefits of therapy outweigh the risk.

It is necessary to carefully assess the risk of stroke, the risk of developing breast cancer and endometrial cancer in every woman with an intact uterus (see the section 'Side effects'), taking into account all individual risk factors, the incidence and characteristics of both types of cancer and stroke in terms of curability , morbidity and mortality.

Evidence for the relative risk associated with hormone replacement therapy (HRT) or the use of tibolone for the treatment of premature menopause is limited. However, the benefit / risk ratio in women with premature menopause may be more favorable than in older women because of the lower absolute risk in younger women.

Medical examination / observation

An individual and family medical history should be taken before starting or resuming the use of Velledien.

Physical examination (including examination of the pelvic organs and mammary glands) should be carried out taking into account the history data, absolute and relative contraindications. During the administration of the drug, preventive repeated examinations are recommended, the frequency and nature of which are determined by the individual characteristics of the patient, but at least once every 6 months. In particular, a woman should be informed about the need to inform the doctor about changes in the mammary glands.

Examinations, including appropriate imaging techniques such as mammography, should be performed in accordance with the currently accepted examination schedule, adapted to the clinical needs of each patient, but at least once every 6 months.

Reasons for immediate discontinuation of the drug and immediate medical attention

The drug should be discontinued in case of contraindications and / or in the following conditions / diseases:

• jaundice or worsening liver function;

• a sudden increase in blood pressure, which differs from the usual blood pressure indicators characteristic of the patient;

• the occurrence of a migraine-type headache.

Endometrial hyperplasia and cancer

Observational data have shown an increased risk of developing endometrial hyperplasia or cancer in women taking tibolone. The risk of developing endometrial cancer increases with the duration of drug use.

Tibolone can increase the thickness of the endometrium, as measured by transvaginal ultrasound.

During the first months of taking tibolone, there may be 'breakthrough' bleeding and spotting.

When spotting / bleeding occurs while taking Velledien, which

- lasts more than 6 months from the start of taking the drug,

- start 6 months after the start of taking the drug and continue even after its withdrawal,

a woman needs to see a doctor - this may be a sign of endometrial hyperplasia.

Mammary cancer

Evidence-based clinical research data on the risk of breast cancer with tibolone are contradictory and further research is required.

The Million Women Study found a significant increase in breast cancer risk with 2.5 mg tibolone (see the Side Effects section). This risk became apparent after several years of using the drug and increased with an increase in the duration of use, returning to the initial level after several years (more often after 5 years) after discontinuation of the drug.

These results were not confirmed in a study using the General Practice (GPRD) Database.

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Long-term (at least 5-10 years) estrogen replacement monotherapy was associated with a slight increase in the risk of ovarian cancer.

Several studies, including the Women's Health Initiative (WHI) study, suggest that long-term combination HRT therapy may have a similar or slightly lower risk.

The Million Women Study showed that the relative risk of ovarian cancer with tibolone was similar to that associated with other types of HRT.

Venous thromboembolism

HRT preparations containing only estrogens, or combined HRT preparations containing estrogen and gestagen, can increase the risk of VTE (deep vein thrombosis or pulmonary embolism) by 1.3-3 times, especially during the first year of using HRT drugs (see . section 'Side effects').

There are insufficient data on the increased risk of VTE with the use of tibolone, but a slight increase in risk compared with women who did not take tibolone cannot be ruled out.

Patients with known thrombophilic conditions have an increased risk of developing VTE and the use of Velledien may increase this risk, therefore the use of the drug in this population of patients is contraindicated (see section 'Contraindications').

Risk factors for the development of VTE are estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI> 30 kg / m2), pregnancy and the puerperium, systemic lupus erythematosus and cancer.

Particular attention should be paid to preventive measures to prevent the development of thrombosis, VTE in the postoperative period. It is recommended to discontinue therapy with Velledien 4-6 weeks before surgery if long-term adherence to bed rest is expected in the future. Treatment should not be resumed until the woman has regained physical activity.

Women with no history of VTE, but who have first-degree relatives who have a history of thrombosis at a young age, may be offered screening (the woman should be informed that screening reveals only a part of thrombophilic conditions). If a thrombophilic condition is identified, which is separate from thrombosis in relatives, or a serious disorder (for example, a deficiency of antithrombin III, protein S, protein C, or a combination of disorders), Velledien is contraindicated.

Before prescribing tibolone to women receiving anticoagulants, the physician should carefully assess the benefit / risk ratio of using HRT or tibolone.

If VTE develops after starting treatment, the drug should be discontinued. A woman should be informed about the need for immediate medical attention if symptoms of potential thromboembolism appear (pain and unilateral edema of the lower limb, sudden chest pain, shortness of breath).

Coronary heart disease

In randomized controlled trials, there was no evidence of protection against myocardial infarction in women with or without coronary artery disease who received HRT with combined drugs (estrogen / progestogen) or drugs for HRT containing only estrogen. In epidemiological studies using the GPRD database, there was no evidence of protection against myocardial infarction in postmenopausal women who received tibolone.

Vellediene or any other HRT medication should not be used to prevent cardiovascular disease.

Ischemic stroke

Taking tibolone increases the risk of ischemic stroke starting from the first year of use (see the 'Side effects' section). The absolute risk of stroke is strictly dependent on age, and, therefore, this effect of tibolone is greater the greater the age.

If you experience unexplained migraine headaches with or without visual impairment, see your doctor as soon as possible. In this case, the drug should not be taken until the doctor confirms the safety of continuing HRT, since such headaches can be an early diagnostic sign of a possible stroke.

Other conditions

ѕо имеющимс¤ данным применение тиболона приводило к значительному дозозависимому снижению холестерина Ћѕ¬ѕ (липопротеинов высокой плотности) (с 16.7% при дозе 1.25 мг до 21.8% при дозе 2.5 мг после 2 лет применени¤).

—нижалась обща¤ концентраци¤ триглицеридов и липопротеинов. —нижение концентрации общего холестерина и холестерина ЋѕќЌѕ (липопротеинов очень низкой плотности) не ¤вл¤лось дозозависимым.  онцентраци¤ холестерина ЋѕЌѕ (липопротеинов низкой плотности) не измен¤лась.  линическое значение этих данных пока неизвестно.

Ёстрогены могут вызывать задержку жидкости, поэтому пациентки с сердечной или почечной недостаточностью должны находитьс¤ под тщательным наблюдением врача.

?енщины с уже имеющейс¤ гипертриглицеридемией должны находитьс¤ под тщательным наблюдением врача во врем¤ терапии тиболоном, т.к. редкие случаи значительного повышени¤ концентрации триглицеридов в плазме крови, способствующие развитию панкреатита, отмечались во врем¤ терапии эстрогенами при данном состо¤нии.

ѕрием тиболона может вызвать незначительное снижение концентрации в плазме крови тироксинсв¤зывающего глобулина (“—v) и общего “4.  онцентраци¤ общего “3 не измен¤етс¤. “иболон снижает концентрацию глобулина, св¤зывающего половые гормоны (v—ѕv), но не вли¤ет на концентрацию кортикостероидсв¤зывающего глобулина ( v—) и свободного кортизола.

ѕрименение препаратов дл¤ «v“ не улучшает когнитивную функцию. »меютс¤ данные о повышенном риске возможного развити¤ деменции у женщин при начале непрерывной терапии препаратами дл¤ «v“, содержащими только эстрогены, в возрасте после 65 лет (см. раздел 'ѕобочное действие').

¬ли¤ние на способность к вождению автотранспорта и управлению механизмами

Ќе отмечено какого-либо действи¤ тиболона на концентрацию внимани¤ и способность управл¤ть транспортными средствами и другими механизмами.

ѕередозировка

ќстра¤ токсичность тиболона у животных очень низка¤, поэтому токсических симптомов можно не ожидать, даже если пациентка прин¤ла несколько таблеток одновременно.

—имптомы: в случа¤х острой передозировки могут развитьс¤ тошнота, рвота и влагалищное кровотечение.

Ћечение: антидот неизвестен. –екомендована симптоматическа¤ терапи¤.

Ћекарственное взаимодействие

“иболон усиливает фибринолитическую активность крови, что может привести к усилению противосвертывающего действи¤ антикоагул¤нтов, в частности варфарина, поэтому доза варфарина должна быть соответствующим образом откорректирована по ћЌќ (международное нормализованное отношение).

ќдновременное применение тиболона и антикоагул¤нтов необходимо контролировать, особенно в начале и в конце лечени¤ тиболоном.

—уществует лишь ограниченна¤ информаци¤ относительно фармакокинетического взаимодействи¤ при лечении тиболоном. »сследование in vivo продемонстрировало, что совместное применение с тиболоном в небольшой степени вли¤ет на фармакокинетику субстрата цитохрома –4503ј4 мидазолама. »сход¤ из этого, возможно наличие лекарственного взаимодействи¤ с другими субстратами CYP3A4. Ћекарственные препараты-индукторы CYP3A4 (барбитураты, карбамазепин, производные гидантоина, рифампицин) при одновременном применении могут повышать метаболизм тиболона и, следовательно, повли¤ть на его терапевтический эффект.

Preparations containing St. John's wort (Hypericum perforatum) can increase the metabolism of estrogens and progestogens through the induction of the isoenzyme CYP3A4. Increased metabolism of estrogens and progestogens can lead to a decrease in their clinical effect and a change in the profile of uterine bleeding.