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Active ingredients
Tibolon
Release form
Pills
Composition
1 tablet contains: Active substance: Tibolone 2.5 mg. Adjuvants: lactose monohydrate (micronized) - 12.5 mg, lactose monohydrate (direct compression lactose) - 74.5 mg, potato starch - 9.5 mg, ascorbyl palmitate - 500 μg, magnesium stearate - 500 mcg
Pharmacological effect
Anti-menopausal drug. When ingested, tibolone is rapidly metabolized to form three compounds that determine the pharmacodynamic characteristics of Ledibon. Two metabolites of tibolone (3α-hydroxy-tibolone and 3β-hydroxy-tibolone) have estrogen-like activity, while the third metabolite, the Δ4-isomer of tibolone, has gestagen-like and androgen-like activity. such as vasomotor disorders (hot flashes, excessive sweating at night), irritability, dryness and discomfort in the vagina, decreased mood and libido, and so on. Leadibon prevents loss of stnoy weight after menopause or removal of the ovaries.
Pharmacokinetics
Absorption and metabolism Absorption is high. Metabolized in the liver to form hydrophilic products, some of which are pharmacologically active. Excretion is excreted by the kidneys (including metabolites) and through the intestines.
Indications
- Treatment of symptoms of estrogen deficiency in postmenopausal women; - Prevention of osteoporosis in postmenopausal women who are at high risk of fractures and with intolerance to other groups of drugs used to prevent osteoporosis.
Contraindications
- a period of less than a year after the last menstruation; - diagnosed (including a history of) breast cancer or suspicion of it; - diagnosed (including a history of) malignant estrogen-dependent tumors (eg, endometrial cancer) or suspected them; - bleeding from the vagina of unknown etiology; - untreated endometrial hyperplasia; - thrombosis (venous or arterial) and thromboembolism at present or in history (including thrombosis and deep vein thrombophlebitis, thromboembolism of the pulmonary artery, in case of infarct myocardial infarction, in case of infarction, pulmonary artery thrombosis, deep vein thromboembolism, pulmonary artery) hemorrhoids cerebrovascular disorders); - diagnosed thrombophlebic conditions (for example, deficiency of protein C, protein S or antithrombin III); - conditions that precede thrombosis (includingtransient ischemic attacks, angina), currently or in history - severe or multiple risk factors for venous or arterial thrombosis (including atrial fibrillation, complicated valvular lesions of the heart and subacute bacterial endocarditis, uncontrolled arterial hypertension, advanced operative intervention, accompanied by prolonged immobilization, extensive trauma, obesity (BMI more than 30 kg / m2), smoking over the age of 35 years - cardiovascular insufficiency in herds and decompensation; - acute liver disease or liver disease in history, after which the liver function indicators did not return to normal; - liver failure; - malignant or benign liver tumors (including liver adenoma) now or in history; - porphyria; - otosclerosis that occurred during a previous pregnancy or when using hormonal contraceptive drugs in history; - rare hereditary diseases, such as galactose intolerance, lactase deficiency lapp, glucose-galactose small absorption; - pregnancy; - lactation period (breastfeeding); - hypersensitivity to the active substance or to any excipient of the drug. With care If any of the conditions / diseases listed below are present, observed earlier and / or exacerbated during pregnancy or previous hormone therapy, the patient should be under the close supervision of a physician. Such conditions / diseases include: - cardiovascular insufficiency without signs of decompensation, - the presence of risk factors for estrogen-dependent tumors (for example, the presence of breast cancer in the immediate family (mother, sister)); - controlled arterial hypertension; - increased cholesterol concentration in the blood - disorders of carbohydrate metabolism, diabetes mellitus, both in the presence and in the absence of complications; - cholelithiasis; - migraine or severe headache; - SLE; - endometrial hyperplasia in history; - epilepsy; - br onchial asthma; - renal failure; - otosclerosis, not associated with pregnancy or prior use of hormonal contraceptive drugs. It should be taken into account that these conditions / diseases may recur or worsen during treatment with Tibolone.
Use during pregnancy and lactation
The use of the drug Ledibon during pregnancy and during breastfeeding is contraindicated.In the event of pregnancy, treatment with Ledibon should be immediately discontinued.
Dosage and administration
The drug Ledibon should be taken after 12 months after the last natural menstruation. If you start taking Ledibon before the specified time, then the likelihood of irregular bleeding / bleeding from the vagina increases. Before you start using Ledibon, you should rule out malignant neoplasms of the reproductive organs, regardless of whether the woman takes another HGT drug or not, especially if you have bleeding discharge from the genital tract. When treating with Ledibon, there is no need to add gestagen-containing preparations. The recommended dose of the drug is 1 tab./day It is preferable to take the drug at the same time of day, pills should be swallowed with water. Tablets administration rules Blisters with Ledibon are marked with days of the week. You should start using the drug with the pill, marked the current day. For example, if the reception day coincides with Monday, then it is necessary to take a pill marked Monday from the top row of the blister. Then you should take pills according to the days of the week. From the next blister, pills are taken without any passes or breaks. Do not allow skips in the use of the drug when changing blisters or packaging. Skip taking pills If you miss the next pill, further tactics depend on the time of delay from the planned reception. If the pass is less than 12 hours, you must take the missed pill as soon as possible. If the delay in taking the pills is more than 12 hours, you should skip the reception, and take the next pill at the usual time. It is not recommended to take 2 pills at the same time to replenish the missed dose. Switching from cyclic or continuous use of the drug for HRT to tibolone When switching from cyclic use of the drug for HRT, treatment with Ledibon should be started the next day after the completion of the previous treatment regimen. In the case of transition from a continuous mode of use of the combined drug for HRT, treatment can be started at any time. Elderly patients do not need dose adjustment.
Side effects
This section describes the adverse effects that were reported during 21 placebo-controlled studies (including the study Assessing the effect of Tibolone on the incidence of new vertebral fractures in postmenopausal women with osteoporosis (LIFT) [Long Term Intervention on Fractures with Tibolone]) 4,079 women receiving tibolone at therapeutic doses (1.25 or 2.5 mg) and 3,476 women receiving placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. The following are undesirable effects that were statistically significantly more frequent with Tibolone than with placebo. From the digestive system: often (more than 1% and less than 10%) - pain in the lower abdomen. From the side of the skin and subcutaneous tissues: often (more 1% and less than 10%) - increased hair growth, incl. on the face; infrequently (more than 0.1% and less than 1%) - acne. From the reproductive system and mammary gland: often (more than 1% and less than 10%) - vaginal discharge, thickening of the endometrium, bleeding or bleeding from the vagina, pain in the mammary glands , genital pruritus, vulvovaginal candidiasis, pain in the pelvic region, cervical dysplasia, vulvovaginitis; infrequently (more than 0.1% and less than 1%) - mycosis, breast engorgement, nipple soreness. Laboratory and instrumental data: often (more than 1% and less than 10%) - an increase in body weight, deviations of the results of a smear from the cervix1.1 Deviation from normal values of the cytological characteristics of the cervical epithelium. Most of the side effects were mild. The number of cases of cervical disease (cervical cancer) did not increase with the use of Ledibon compared with placebo. Other possible side effects may be (frequency not established): dizziness, headache, migraine; depression; skin rashes, itching of the skin, seborrheic dermatitis; visual impairment (including blurred vision); gastrointestinal disorders (diarrhea, flatulence); fluid retention, peripheral edema; pain in the joints and muscles; abnormal liver function (including increased transaminase activity). The risk of developing breast cancer In women receiving combined therapy (estrogen / gestagen) with drugs for more than 5 years, there has been a twofold increase in the frequency of diagnosing breast cancer. Any increased risk in patients receiving only estrogen or tibolone is significantly lower than the risk observed in patients receiving therapy with combined (estrogen / gestagen) drugs.The risk level depends on the duration of use. The risk of endometrial cancer The highest risk of developing endometrial cancer was observed in a randomized, placebo-controlled study that included women who were not initially examined for endometrial pathology, thus the design of the study was close to the clinical practice (LIFT study, mean age 68 years). In this study, there were no cases of endometrial cancer diagnosed in the placebo group (n = 1773) after follow-up for 2.9 years, compared with 4 cases of endometrial cancer in the tibolone group (n = 1746), which corresponds to a diagnosis of 0.8 additional cases of cancer endometrium per 1000 women who received tibolone for 1 year in this study. Risk of ischemic stroke The relative risk of ischemic stroke does not depend on the age or duration of the drug, but the absolute risk strongly depends on age. The overall risk of developing ischemic stroke in women taking Tibolone will increase with age. A randomized controlled study for 2.9 years found a 2.2-fold increase in the risk of stroke in women (mean age 68 years) who took Tibolone at a dose of 1.25 mg (28/2249 ) compared with placebo (13/2257). Most (80%) strokes were ischemic. The absolute risk of stroke depends on age. Thus, the absolute risk over a period of 5 years is 3 cases per 1,000 women aged 50–59 years and 11 cases per 1,000 women aged 60–69 years. For women taking Tibolone for 5 years, you can expect about 4 additional cases per 1000 patients aged 50-59 years and 13 additional cases per 1000 patients aged 60-69 years. Other adverse events related to the use of drugs for hormone therapy (estrogen-containing drugs, combined (estrogen / gestagen) drugs, tibolone) were also noted. Prolonged use of drugs for estrogen-only drugs and combined (estrogen / progestogen) drugs was associated with a slight increase in the risk of ovarian cancer. According to the Million Women Study [Million Women Study], HRT for 5 years resulted in 1 additional case of cancer per 2500 patients. This study showed that the relative risk of ovarian cancer when using tibolone is similar to the risk of using other drugs for HRT. The use of Tibolone is associated with an increase in the relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis and pulmonary thromboembolism, 1.3-3 times.This phenomenon often occurs during the first year of the drug. There is a slight increase in the risk of developing coronary artery disease in patients over 60 years of age who receive HRT with combined (estrogen / gestagen) drugs (there is no reason to believe that the risk of myocardial infarction when taking Tibolone is different from the risk of use of other types of HRT); increased blood pressure; pancreatitis; gallbladder disease (cholelithiasis, cholecystitis); skin diseases: chloasma, erythema multiforme, erythema nodosum, vascular purpura; dementia at the start of therapy at the age of 65 years.
Overdose
While taking a large number of pills of drug Ledibon, the patient should consult a doctor. Symptoms: malaise, nausea, or vaginal bleeding. Treatment: symptomatic.
Interaction with other drugs
Tibolone increases blood fibrinolytic activity, which can lead to increased anticoagulant action of anticoagulants, in particular of warfarin, therefore, the dose of warfarin should be adjusted accordingly by MHO. The simultaneous use of tibolone and anticoagulants must be controlled, especially at the beginning and at the end of treatment with Ledibon. There is only limited information regarding the pharmacokinetic interaction with treatment with tibolone. An in vivo study demonstrated that concomitant use with tibolone to a small extent affects the pharmacokinetics of the CYP3A4 substrate midazolam. Based on this, drug interactions with other CYP3A4 substrates are possible. Medicinal products — CYP3A4 inducers, such as barbiturates, carbamazepine, hydantoins, and rifampicin, can increase Tibolone metabolism and thus affect its therapeutic effect. Drugs containing Hypericum perforatum (Hypericum perforatum) can enhance the metabolism of estrogens and gestagens through the induction of the CYP3A4 isoenzyme. Increased metabolism of estrogen and gestagen may lead to a decrease in their clinical effect and a change in the profile of uterine bleeding.
special instructions
The drug Ledibon is not intended for use as a contraceptive and does not protect against unwanted pregnancy. Decision on the beginning of the use of the drug Ledibon should be based on an assessment of 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, Ledibon should be prescribed only for symptoms that adversely affect the quality of life. In all cases, it is necessary to conduct a thorough assessment of the risk and benefits of therapy at least once a year, and therapy with Ledibon should be continued only during the period of time when the benefits of therapy exceed the risk. It is necessary to carefully evaluate the risk of developing stroke, the risk of developing breast and endometrial cancer in each woman with an intact uterus, taking into account all individual risk factors, the incidence and characteristics of both types of cancer and stroke in terms of cure, morbidity and mortality. associated with HRT or the use of tibolone for the treatment of premature menopause are limited. However, the benefit / risk ratio in women with premature menopause may be more favorable than in older women due to the lower absolute risk level in younger women. Medical examination / observation Before initiating or resuming treatment with Ledibon, individual and family medical history. Physical examination (including examination of the pelvic organs and mammary glands) should be carried out taking into account the data of anamnesis, absolute and relative contraindications. During therapy, preventive follow-up examinations are recommended, the frequency and nature of which is determined by the patient's individual characteristics, but at least 1 time in 6 months. In particular, the woman should be informed about the need to report to the doctor about changes in the mammary glands. Surveys, including appropriate imaging techniques, such as mammography, should be conducted in accordance with the current examination scheme adapted to the clinical needs of each patient, but not less 1 time in 6 months. The reasons for the immediate cancellation of therapy and immediate treatment to the doctor. The therapy should be stopped if a contraindication is detected and / or in the following conditions / for Olevanov: - jaundice or deterioration of liver function, - a sudden increase in blood pressure, characterized by the usual indicators of blood pressure,typical for the patient; - the occurrence of migraine-type headache. Hyperplasia and endometrial cancer These randomized controlled clinical trials are contradictory, but observational studies have shown an increased risk of developing hyperplasia or endometrial cancer in women taking Tibolone. These studies have shown that the risk of developing endometrial cancer increases with increasing duration of drug use. Tibolone may increase the thickness of the endometrium, as measured by transvaginal ultrasound. Breakthrough bleeding and bleeding may occur during the first months of treatment. If bleeding / bleeding occurs during the application of the drug Ledibon, which lasts more than 6 months from the start of the drug or starts after 6 months after the start of the drug and continue even after the patient has discontinued the use of the drug Ledibon, it is necessary to consult a doctor - this can be recognized Aktoma endometrial hyperplasia. Breast cancer The data from different clinical studies from the point of view of evidence-based medicine regarding the risk of developing breast cancer when taking Tibolone is contradictory, and further research is required. 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. Some studies, including the Women's Health Initiative (WHI) study, suggest that long-term therapy with HRT combination drugs may have a similar or slightly lower risk. In a study of a million women, it was shown that the relative risk of developing ovarian cancer when using tibolone was similar to the risk associated with the use of other types of HRT. Venous thromboembolism The drugs for HRT containing only estrogen, or combination drugs containing estrogen and gestagen can increase the risk of venous thromboembolism (VTE) (i.e., deep vein thrombosis or pulmonary thromboembolism) 1.3-3 times, especially during the first year of use. According to epidemiological studies using the UK database, the risk of developing VTE associated with the use of tibolone was lower than the risk associated with conventional drugs for hormone replacement therapy, but due to the factthat at that time only a small proportion of women took tibolone, 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 taking tibolone may increase this risk, therefore use of the drug in this population patients are contraindicated. The risk factors for the development of VTE are the use of estrogen, advanced age, extensive surgery, prolonged immobilization, obesity (BMI is e 30 kg / m2), pregnancy and the postpartum period, SLE and cancer. In patients after surgical interventions, special attention should be paid to preventive measures to prevent VTE in the postoperative period. If necessary, prolonged immobilization after surgery recommended the temporary cessation of the use of the drug Ledibon 4-6 weeks before the operation. Treatment should not be resumed until the woman has restored physical activity. Women who have a history of VTE with no history, but who have first-degree relatives, who have a history of thrombosis at a young age, may be screened (a woman should be informed that only part of thrombophilic conditions are detected during screening). If a thrombophilic condition is found that is isolated from thrombosis in relatives or a serious disorder (for example, an antithrombin deficiency, protein S, protein C or a combination of disorders), Ledibon is contraindicated. For women who are already receiving treatment with anticoagulants, careful consideration of the ratio benefit / risk of using HRT or tibolone. If VTE develops after the start of treatment, the use of the drug should be discontinued. The patient should be informed about the need to immediately see a doctor if symptoms of potential thromboembolism appear (eg, pain and unilateral edema of the lower limb, sudden chest pain, shortness of breath). Ischemic heart disease (CHD) No evidence of protection against myocardial infarction has been obtained in randomized controlled studies women with or without IHD,who received hormone therapy with combined drugs (estrogen / progestogen) or drugs containing only estrogen. In epidemiological studies using the GPRD database, no evidence of protection against myocardial infarction in postmenopausal women who received tibolone was obtained. starting from the first year of use. The absolute risk of stroke is strictly dependent on age, and, consequently, this effect of tibolone is the greater, the older the age. If you experience unexplained migraine-like headaches with or without visual impairment, you should see a 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 conditionsAccording to available data, the use of Tibolone led to a significant dose-related decrease in HDL cholesterol (with -16.7% at a dose of 1.25 mg to -21.8% at a dose of 2.5 mg after 2 years of use). The total concentration of triglycerides and VLDLP also decreased. The decrease in total cholesterol and VLDL cholesterol was not dose-dependent. Concentrations of LDL cholesterol did not change. The clinical significance of this data is not yet known. Women with already existing hypertriglyceridemia should be under the close supervision of a physician during the use of Ledibon, because rare cases of a significant increase in plasma triglyceride concentrations contributing to the development of pancreatitis were noted during estrogen therapy in this condition. Treatment with Tibolone leads to a very small decrease in thyroxin-binding globulin (TSH) and total T4. The concentration of total T3 does not change. Ledibon reduces the concentration of sex hormone-binding globulin (SHBG), while the concentrations of corticosteroid-binding globulin and circulating cortisol do not change. The increased risk of dementia should be taken into account in case of initiation of tibolone therapy in women over 65 years of age. There is a possibility of fluid retention.In this regard, careful monitoring of patients with cardiac or renal insufficiency is necessary. Impact on the ability to drive vehicles and control mechanismsNo negative effect of the drug on concentration and reaction, ability to drive vehicles and other mechanisms is noted.