Ledibon pills 2,5mg №84

Indications and usage

- treatment of symptoms of estrogen deficiency in postmenopausal women;

- prevention of osteoporosis in postmenopausal women with a high risk of fractures and with intolerance to other groups of drugs used to prevent osteoporosis.

Drug Ledibon^® should be taken after 12 months after the last natural menstruation. If drug Ledibon^® begin to take before the specified time, then increases the likelihood of irregular bleeding / bleeding from the vagina.

Before starting to use the drug Ledibon^® malignant neoplasms of the reproductive system should be excluded, regardless of whether the woman is taking another HRT drug or not, especially in the case of bloody discharge from the genital tract.

When treating drug Ledibon^® No need to add gestagensoderzhaschie drugs.

The recommended dose of the drug - 1 tab. / Day. It is preferable to take the drug at the same time of day, pills should be swallowed with water.

Blisters with Ledibon^® marked 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 passes in the use of the drug when changing blisters or packaging.

If the next pill is missed, the further tactics depend on the time of delay from the scheduled 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 was 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.

In the transition from a cyclic mode of use of the drug for HRT treatment with Ledibon^® must begin the day after the completion of the previous treatment regimen. In the case of transition from the continuous mode of use of the combined drug for HRT, treatment can be started at any time.

Have elderly patients dose adjustment is not required.

This section describes the adverse effects that were reported during 21 placebo-controlled studies (including the Tibolone Effect Assessmenton the incidence of new vertebral fractures in postmenopausal women with osteoporosis (LIFT) [Long Term Intervention on Tibolone]) involving 4079 women who received Tibolone in therapeutic doses (1.25 or 2.5 mg) and 3476 women who received 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.

Gastrointestinal: often (> 1% and <10%) - abdominal pain.

Dermatological: often (> 1% and <10%) - increased hair growth, incl. on the face; infrequently (> 0.1% and <1%) - acne.

From the reproductive system and the mammary gland: often (> 1% and <10%) - vaginal discharge, endometrial thickening, bleeding or vaginal bleeding, pain in the mammary glands, genital itching, vulvovaginal candidiasis, pain in the pelvic region, cervical dysplasia, vulvovaginitis; infrequently (> 0.1% and <1%) - mycosis, breast engorgement, nipple soreness.

Laboratory and instrumental data: often (> 1% and <10%) - an increase in body weight, deviations of the results of a smear from the cervix¹.

¹ Deviation from the normal values ​​of the cytological characteristics of the cervical epithelium.

Most of the side effects were mild. The number of cases of pathology of the cervix (cervical cancer) did not increase with the use of the drug Ledibon^® compared to placebo. Other possible side effects may be (frequency not established): dizziness, headache, migraine; depression; skin rashes,itchy 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).

Risk of developing breast cancer

In women receiving combined therapy (estrogen / progestogen) drugs for more than 5 years, there has been a twofold increase in the diagnosis of 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 level of risk depends on the duration of use.

Table 1. Estimated additional risk of developing breast cancer after 5 years of use (according to the "Research of a million women")

DI - confidence interval;
* - total risk ratio. The risk ratio is not constant, it increases with increasing duration of use.

Risk of endometrial cancer

The highest risk of endometrial cancer was observed in a randomized, placebo-controlled study that included women who were not initially examined for endometrial pathology, so the study design was close to the clinical practice conditions (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 developing ischemic stroke does not depend on the age or duration of the drug intake, but the absolute risk strongly depends on age. The overall risk of ischemic stroke in women taking tibolone will increase with age.

A randomized controlled trial for 2.9 years established a 2.2-fold increase in the risk of stroke in women (mean age 68 years) who took Tibolone 1.25 mg (28/2249) compared with placebo (13/2257). The majority (80%) of strokes were ischemic.

The absolute risk of developing a 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, we 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 associated with the use of drugs for hormone therapy (estrogen-containing drugs, combined (estrogen / progestogen) drugs, Tibolone) were also noted. Prolonged use of drugs
for hormone therapy containing only estrogen 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 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.

Table 2. Additional risk of developing venous thromboembolism (VTE) when used for more than 5 years according to the results of the study "Women's Health Initiative"

* In women with a remote uterus

There is a slight increase in the risk of developing coronary heart disease in patients over 60 years of age who receive HRT with combined (estrogen / progestogen) drugs (there is no reason to believe that the risk of developing myocardial infarction when taking tibolone is different from the risk of using 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.

- a period of less than a year after the last menstruation;

- diagnosed (including in history) breast cancer or suspicion of it;

- diagnosed (including in history) malignant estrogen-dependent tumors (for example, endometrial cancer) or suspicion of 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, pulmonary thromboembolism, myocardial infarction, ischemic or hemorrhagic cerebrovascular disorders);

- diagnosed thrombophlebic conditions (for example, deficiency of protein C, protein S or antithrombin III);

- conditions preceding thrombosis (including transient ischemic attacks, angina pectoris), currently or in history;

- severe or multiple risk factors for the development of venous or arterial thrombosis (including atrial fibrillation, complicated valvular heart disease and subacute bacterial endocarditis, uncontrolled arterial hypertension, extended surgery with prolonged immobilization, extensive trauma, obesity (IMT), extensive trauma, obesity (ICT), followed by prolonged immobilization, extensive trauma, obesity (ICT), extensive surgery, prolonged immobilization, extensive trauma, obesity (ICT kg / m²), smoking over the age of 35;

- cardiovascular failure in the stage of decompensation;

- An acute liver disease or liver disease in history, after which the indicators of liver function did not return to normal;

- liver failure;

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

- porphyria;

- Otosclerosis, which occurred during a previous pregnancy or when using hormonal contraceptive drugs in history;

- rare inherited diseases such as galactose intolerance, lapp lactase deficiency, glucose-galactose malabsorption;

- pregnancy;

- lactation period (breastfeeding);

- hypersensitivity to the active substance or to any excipient of the drug.

Carefully

If any of the conditions / diseases listed below are present, observed previously and / or exacerbated during pregnancy or previous hormonal therapy, the patient should be under the close supervision of a physician.These conditions / diseases include:

- cardiovascular failure 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;

- increasing the concentration of cholesterol 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;

- bronchial asthma;

- renal failure;

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

It should be appreciated that these conditions / diseases may recur or worsen during treatment with Tibolone.

Use of the drug Ledibon^® during pregnancy and during breastfeeding is contraindicated. In case of pregnancy, treatment with Ledibon^® must stop immediately.

Contraindicated for use in acute liver disease or liver disease in history, after which the indicators of liver function did not return to normal; liver failure; malignant or benign liver tumors (including liver adenoma) now or in history.

Application for violations of kidney function

WITH caution It should appoint a drug for renal failure.

Use in elderly patients

Have elderly patients dose adjustment is not required.

You should consider the increased risk of dementia in the case of initiation of treatment with tibolone in women over the age of 65 years.

Drug Ledibon^® not intended for use as a contraceptive and does not protect against unwanted pregnancy.

The decision to start the use of the drug Ledibon^® should be based on an “benefit / risk” ratio taking into account all individual risk factors, and in women over 60 years old, the increased risk of stroke can also be taken into account.

For the treatment of postmenopausal symptoms drug Ledibon^® It 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 in a period of time when 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 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 treatability, morbidity and mortality.

Evidence of the relative risk associated with HRT or the use of tibolone for treating premature menopause is 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

Prior to the commencement or resumption of therapy with Ledibon^® Individual and family medical history should be collected.

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 are determined by the patient's individual characteristics, but at least 1 time in 6 months. In particular, the woman should be informed of the need to inform the doctor about changes in the mammary glands.

Examinations, including appropriate imaging techniques, for example, mammography, should be carried out in accordance with the current examination scheme, adapted to the clinical needs of each patient, but at least 1 time in 6 months.

Reasons for immediate discontinuation of therapy and immediate medical attention.

Therapy should be discontinued if contraindications are detected and / or in the following conditions / diseases:

- jaundice or impaired liver function;

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

- The occurrence of headaches such as migraines.

Endometrial hyperplasia and cancer

Data from randomized controlled clinical trials are controversial, 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 can increase the thickness of the endometrium, as measured by transvaginal ultrasound.

Breakthrough bleeding and bloody discharge may occur during the first months of treatment.

With the appearance of bleeding / bleeding during the use of the drug Ledibon^®that continue for more than 6 months from the start of the drug or start 6 months after the start of the drug and continue even after the patient has discontinued the use of the drug Ledibon^®, you need to consult a doctor - this may be a sign of endometrial hyperplasia.

Mammary 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 needed.

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 combination drugs for HRT may have a similar or slightly lower risk. The study of a million women showed 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

HRT preparations containing only estrogen, or combination drugs containing estrogen and progestogen, may increase the risk of venous thromboembolism (VTE) (ie, deep vein thrombosis or pulmonary embolism) 1.3–3 times, especially during the first years of use.

According to an epidemiological study using the UK database, the risk of developing VTE associated with the use of tibolone was lower than the risk associated with traditional drugs for HRT, but due to the fact that at that time only a small proportion of women took Tibolone, eliminate a slight increase in risk compared with women who did not take Tibolone.

Patients with known thrombophilic conditions have an increased risk of developing VTE, and taking tibolone may increase this risk, so the use of the drug in this population of patients is contraindicated.

Risk factors for VTE are estrogen use, advanced age, extensive surgery, long-term immobilization, obesity (BMI> 30 kg / m²), pregnancy and 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 surgery. 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 detected, which is isolated from thrombosis in relatives, or a serious disorder (for example, an antithrombin deficiency, protein S, protein C or a combination of disorders), use Ledibon^® contraindicated.

For women who are already receiving treatment with anticoagulants, careful consideration is needed of the benefit / risk ratio of HRT or tibolone.

If after the start of treatment develops VTE, the use of the drug should be discontinued.The patient should be informed of the need to immediately consult a doctor if symptoms of potential thromboembolism appear (for example, pain and unilateral edema of the lower limb, sudden chest pain, shortness of breath).

Ischemic Heart Disease (CHD)

In randomized controlled trials, no evidence of protection against myocardial infarction has been obtained in women with or without coronary artery disease who received HRT with a combination of drugs (estrogen / gestagen) or drugs 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.

Ischemic stroke

Tibolone therapy increases the risk of ischemic stroke, 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, you should not take the drug until the doctor confirms the safety of continuing HRT, since such headaches can be an early diagnostic sign of a possible stroke.

Other states

According to available data, the use of tibolone led to a significant dose-dependent decrease in HDL cholesterol (from -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 VLDL was also reduced.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 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.

Tibolone treatment results in a very small reduction in thyroxin-binding globulin (TSH) and total T₄. The concentration of total T₃ does not change. Ledibon^® reduces the concentration of globulin that binds sex hormones (SHBG), whereas the concentrations of corticosteroid binding globulin (CGC) and circulating cortisol do not change.

You should consider the increased risk of dementia in the case of initiation of treatment with tibolone in women over the age of 65 years.

Against the background of the use of the drug Ledibon^® There is a possibility of fluid retention. In this regard, careful monitoring of patients with heart or kidney failure.

Influence on ability to drive motor transport and control mechanisms

No negative effect of the drug on concentration of attention and reaction, ability to drive vehicles and other mechanisms was noted.

While taking a large number of pills drug Ledibon^® the patient must consult a doctor.

Symptoms: malaise, nausea, or vaginal bleeding.

Treatment: symptomatic.

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 pharmacokinetic interactions in the treatment of 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 estrogens and gestagens can lead to a decrease in their clinical effect and a change in the profile of uterine bleeding.

The drug should be stored out of the reach of children at a temperature not higher than 25 ° C.