Universal reference book for medicines
Product name: LEDIBON ® (LADYBON ® )

Active substance: tibolone

Type: Antimycotic estrogen preparation

Manufacturer: ZENTIVA (Czech Republic)
Composition, form of production and packaging

Tablets from white to almost white, round, flat, engraved "e" on one side.

1 tab.

tibolone 2.5 mg

Excipients: lactose monohydrate (micronized) - 12.5 mg, lactose monohydrate (lactose directly pressed) - 74.5 mg, potato starch - 9.5 mg, ascorbyl palmitate - 500 μg, magnesium stearate - 500 μg.

28 pcs.
- blisters (1) - packs of cardboard.
28 pcs.
- blisters (3) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Anti-climacteric drug.

When administered orally, tibolone is rapidly metabolized to form three compounds that determine the pharmacodynamic characteristics of the Ledibon ®preparation.
Two metabolites of tibolone (3? -hydroxytibolone and 3? -hydroxytibolone) have estrogen-like activity, while the third metabolite-4-isomer tibolone has gestagen-like and androgen-like activity.
Ledibon ® replenishes estrogen deficiency in postmenopausal women, alleviating the symptoms associated with their deficiency, such as vasomotor disorders ("hot flashes", increased sweating at night), irritability, dryness and discomfort in the vagina, decreased mood and libido and the like.

Ledibon ® prevents the loss of bone mass after menopause or removal of the ovaries.

PHARMACOKINETICS

Absorption and Metabolism

Absorption is high.

Metabolised in the liver with the formation of hydrophilic products, some of which are pharmacologically active.

Excretion

It 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 with a high risk of fracture and with intolerance to other groups of drugs used to prevent osteoporosis.

DOSING MODE

The drug Ledibon ® should be taken after 12 months after the last natural menstruation.
If the drug Ledibon ® start taking before the specified time, then the probability of irregular bloody discharge / bleeding from the vagina increases.
Before starting the use of Ledibon ® , malignant neoplasms of the reproductive system should be excluded, regardless of whether the woman is taking another HRT medication or not, especially if bleeding from the genital tract occurs.

When treating Ledibon ®, there is no need to add gestagen-containing drugs.

The recommended dose of the drug is 1 tablet / day.
It is preferable to take the drug at the same time of day, the tablets should be swallowed with water.
Rules for taking tablets

Blisters with the medicine Ledibon ® are marked with days of the week.
You should start using the drug with a pill given the current day. For example, if the day of reception coincides with Monday, you must take a pill, marked on Monday, from the top of the blister. Next, take the pill, according to the days of the week. Of the next blister pills are taken without missing and breaks. Do not skip the use of the drug when changing blisters or packaging.
Skipping pills

If you missed the next pill, the next tactic depends on the time of delay from the planned reception.
If the pass is less than 12 hours , you must take the missed tablet as soon as possible. If the delay in taking the tablets 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 tablets at the same time to replenish the missed dose.
Transition from a cyclic or continuous regimen of use of the drug for HRT to tibolone

When switching from a cyclic regimen of the drug to HRT, treatment with Ledibon ® should be started the day after the completion of the previous treatment regimen.
In case of transition from a continuous mode of application of the combined preparation for HRT, treatment can be started at any time.
In elderly patients, dose adjustment is not required.

SIDE EFFECT

This section describes the undesirable effects that were recorded during 21 placebo-controlled studies (including the study "Evaluation of the effect of tibolone on the incidence of new vertebral fractures in postmenopausal women with osteoporosis" (LIFT) [Long Term Intervention on Fractures with Tibolone]) with the participation of 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. Below are the undesirable effects that were statistically significantly more frequent with tibolone than with placebo.
From the digestive system: often (> 1% and <10%) - pain in the lower abdomen.

From the skin and subcutaneous tissues: often (> 1% and <10%) - increased hair growth, incl.
on the face; infrequently (> 0.1% and <1%) - acne.
On the part of the reproductive system and breast: often (> 1% and <10%) - vaginal discharge, thickening of the endometrium, spotting or bleeding from the vagina, pain in the mammary glands, genital itching, vulvovaginal candidiasis, pelvic pain, dysplasia cervix, vulvovaginitis;
infrequently (> 0.1% and <1%) - mycosis, engorgement of the mammary glands, soreness of the nipples.
Laboratory and instrumental data: often (> 1% and <10%) - increase in body weight, deviation of the results of a smear from the cervix 1 .

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

Most side effects were mild.
The number of cases of cervical pathology (cervical cancer) did not increase with the use of the Ledibon ® preparation compared with placebo. Other possible side effects may be (frequency not established): dizziness, headache, migraine; depression; skin rashes, skin itching, seborrheic dermatitis;visual impairment (including blurred vision); gastrointestinal disorders (diarrhea, flatulence); fluid retention in the body, peripheral edema; pain in the joints and muscles; violations of the liver (including increased activity of transaminases).
The risk of developing breast cancer

In women receiving combination therapy (estrogen / progestogen) for more than 5 years, there has been a two-fold increase in the incidence of breast cancer diagnosis.
Any increased risk in patients receiving only estrogen or tibolone is significantly lower than the risk observed in patients receiving combination therapy (estrogen / progestogen) drugs. The level of risk depends on the duration of the application.
Table 1. Estimated additional risk of developing breast cancer after 5 years of use (according to the "Study of a million women")

Age group (years) Additional cases per 1000 patients who had not previously received HRT for a period of 5 years Risk ratio * (95% CI) Additional cases per 1000 patients who received HRT over 5 years (95% CI)

HRT is only estrogen

50-65 9-12 1.2 1-2 (0-3)

Combination therapy (estrogen / gestagen) with drugs

50-65 9-12 1.7 6 (5-7)

Tibolon

50-65 9-12 1.3 3 (0-6)

CI - confidence interval;

total risk ratio.
The ratio of risks is not constant, it increases with the duration of application.
Risk of developing 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 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 observation for 2.9 years, compared with 4 cases of endometrial cancer in the tibolone group (n = 1746), which corresponds to the diagnosis of 0.8 additional cases of cancer endometrium per 1000 women who received tibolone for 1 year in this study.
The risk of developing ischemic stroke

The relative risk of developing ischemic stroke does not depend on the age or duration of the drug, but the absolute risk depends heavily on age.
The overall risk of developing 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 at a dose of 1.25 mg (28/2249) compared with placebo (13/2257).
The majority (80%) of strokes were ischemic.
The absolute risk of stroke depends on age.
Thus, the absolute risk for a period of 5 years is 3 cases per 1,000 women aged 50-59 years and 11 cases per 1000 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 undesirable phenomena associated with the use of drugs for HRT (estrogen-containing drugs, combined (estrogen / gestagen) drugs, tibolone) have been noted.Prolonged use of drugs

for HRT 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 for 2500 patients. This study showed that the relative risk of ovarian cancer when using tibolone is similar to the risk with other HRT medications.
The use of tibolone is associated with an increase in the relative risk of venous thromboembolism (VTE), i.e.
thrombosis of deep veins and thromboembolism of the pulmonary artery, in 1.3-3 times. This phenomenon often occurs during the first year of use.
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"

Age group (years) The incidence of diseases per 1000 women in the placebo group over 5 years Risk ratio (95% CI) Additional cases per 1000 patients who received HRT over 5 years (95% CI)

Only estrogen orally *

50-59 7 1.2 (0.6-2.4) 1 (3-10)

Combination estrogen-gestagen orally

50-59 4 2.3 (1.2-4.3) 5 (1-13)

* In women with a deleted uterus

There is a slight increase in the risk of developing coronary artery disease in patients older than 60 years 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 that of other HRT types);
increased blood pressure;pancreatitis; diseases of the gallbladder (cholelithiasis, cholecystitis); skin diseases: chloasma, erythema multiforme, erythema nodosum, vascular purpura; dementia at the onset of therapy over the age of 65 years.
CONTRAINDICATIONS

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

- diagnosed (including in the anamnesis) breast cancer or suspected of it;

- diagnosed (including in the anamnesis) malignant estrogen-dependent tumors (for example, endometrial cancer) or suspicion of them;

bleeding from the vagina of an unclear etiology;

- untreated endometrial hyperplasia;

- Thrombosis (venous or arterial) and thromboembolism now or in the anamnesis (including thrombosis and deep vein thrombophlebitis, pulmonary embolism, myocardial infarction, ischemic or hemorrhagic cerebrovascular disorders);

- diagnosed thrombophlebitic conditions (eg, deficiency of protein C, protein S or antithrombin III);

- the conditions preceding thrombosis (including transient ischemic attacks, angina pectoris), now or in the anamnesis;

- expressed or multiple risk factors for venous or arterial thrombosis (including atrial fibrillation, complicated heart valve disease and subacute bacterial endocarditis, uncontrolled arterial hypertension, extensive surgery, accompanied by prolonged immobilization, extensive trauma, obesity (BMI> 30 kg / m 2 ), smoking is older than 35 years;

- cardiovascular failure in the stage of 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) at present or in the anamnesis;

- porphyria;

otosclerosis, which occurred during a previous pregnancy or when using hormonal contraceptive drugs in an anamnesis;

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

- Pregnancy;

- the period of lactation (breastfeeding);

- Hypersensitivity to the active substance or to any auxiliary substance of the drug.

Carefully

If any of the conditions / diseases listed below are present, previously observed and / or worsened with pregnancy or previous hormone therapy, the patient should be under close medical supervision.
Such 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 immediate relatives (mother, sisters));

- controlled arterial hypertension;

- increase in the concentration of cholesterol in the blood;

- violations of carbohydrate metabolism, diabetes mellitus both in the presence and in the absence of complications;

- cholelithiasis;

- Migraine or severe headache;

- hard currency;

- Endometrial hyperplasia in the anamnesis;

- epilepsy;

- bronchial asthma;

- kidney failure;

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

It should be taken into account that these conditions / diseases can recur or worsen during treatment with tibolone.

PREGNANCY AND LACTATION

The use of Ledibon ® during pregnancy and during breastfeeding is contraindicated.
If pregnancy occurs, treatment with Ledibon ® should be stopped immediately.
APPLICATION FOR FUNCTIONS OF THE LIVER

With caution should prescribe the drug for kidney failure.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindicated in the use of acute liver disease or liver disease in history, after which the liver function indicators did not return to normal;
hepatic insufficiency;malignant or benign tumors of the liver (including liver adenoma) at present or in the anamnesis.
APPLICATION IN ELDERLY PATIENTS

In elderly patients , dose adjustment is not required.

An increased risk of dementia should be considered in cases of initiation of therapy with tibolone in women over the age of 65 years.

SPECIAL INSTRUCTIONS

Ledibon ® is not intended to be used as a contraceptive and does not protect against unwanted pregnancy.

The decision to start Ledibon ® should be based on an assessment of the benefit / risk ratio taking into account all individual risk factors, and women over 60 should also take into account the increased risk of stroke.

For the treatment of postmenopausal symptoms, the Ladybone ® drug should only be prescribed for symptoms that adversely affect the quality of life.
In all cases, a careful assessment of the risks and benefits of therapy should be carried out at least once a year, and Ledibon ® therapy should be continued only at a time when the benefits of therapy exceed the risk. It is necessary to carefully evaluate the risk of stroke, the risk of developing breast cancer and endometrial cancer in every woman with an intact uterus, taking into account all individual risk factors, the incidence and characteristics of both cancers and stroke in terms of healing, morbidity and mortality.
Evidence of the relative risk associated with 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, due to the low absolute risk level in younger women.
Medical Examination / Surveillance

Before initiating or resuming therapy with Ledibon ® , individual and family medical history should be collected.

Physical examination (including examination of pelvic organs and mammary glands) should be performed taking into account the history, absolute and relative contraindications.
During the therapy, 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.
Surveys, including appropriate imaging techniques, such as mammography, should be carried out in accordance with the currently accepted screening scheme, adapted to the clinical needs of each patient, but at least once every 6 months.

Reasons for immediate withdrawal of therapy and immediate medical attention

Therapy should stop in case of contraindications and / or under the following conditions / diseases:
- jaundice or deterioration in liver function;
- a sudden increase in blood pressure, which differs from the usual indicators of blood pressure, characteristic of the patient;
- the occurrence of headache such as migraine.
Hyperplasia and endometrial cancer
Data from randomized controlled clinical trials are contradictory, but observational studies data showed an increased risk of hyperplasia or endometrial cancer in women taking tibolone. These studies showed that the risk of endometrial cancer increases with increasing duration of use of the drug. Tibolone may increase endometrial thickness, measured by transvaginal ultrasonography.
During the first months of treatment may experience breakthrough bleeding and spotting.
When bleeding / bleeding during treatment Ledibon preparation ® , which extend more than 6 months from the start of the drug or starting at 6 months after initiation of drug and continues even after the patient has stopped the use Ledibon preparation ® , seek medical advice - this may be a sign of endometrial hyperplasia.
Breast cancer
data from different clinical studies in terms of evidence-based medicine in relation to the risk of developing breast cancer when taking tibolone 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 substitution monotherapy was associated with a slight increase in the risk of developing ovarian cancer. Some studies, including the study on "Women's Health Initiative" (WHI) [Women's Health Initiative], suggest that prolonged treatment with combination therapy for hormone replacement therapy may have the same or a slightly lower risk. In "explore the millions of women," it has been shown that the relative risk of developing ovarian cancer when used tibolone was similar to the risk associated with the use of other types of HRT.
venous thromboembolism
Formulations for HRT containing only estrogen or combined preparations containing estrogen and progestogen may increase the risk of venous thromboembolism (VTE) (i.e., deep vein thrombosis or pulmonary embolism) in 1.3-3 times, especially during the first year of application.
According to epidemiological studies using databases Britain the risk of VTE associated with tibolone was lower than the risk associated with conventional HRT, but due to the fact that at that time only a small proportion of women taking tibolone, should not be eliminate the slight increase in risk compared with women not taking tibolone.
Patients with known thrombophilic states have an increased risk of VTE, and receiving tibolone may increase this risk, so the use of drugs of this population is contraindicated patients.
Risk factors are VTE use of estrogens, older age, major surgery, prolonged immobilization, obesity (BMI> 30 kg / m 2 ), pregnancy and puerperium, SLE and cancer. Patients after surgery is necessary to pay special attention to preventive measures for the prevention of venous thromboembolism in the postoperative period. If necessary, prolonged immobilisation after surgery recommended temporary discontinuation of drug Ledibon ®4-6 weeks prior to surgery. Treatment should not be reopened as long as women are not motor activity recovers. Women who have an indication of a history of VTE is missing, but who have first-degree relatives with a history indication of thrombosis at young age, screening may be offered (a woman should be informed that only a portion of thrombophilic states detected by screening). If detected thrombophilic state which is separated from relatives thrombosis or severe disorder (e.g., Antithrombin deficiency, protein S, protein C or a combination of disorders), using the product Ledibon ® is contraindicated.
For women who are already receiving anticoagulant treatment require careful consideration of the benefit / risk of HRT or tibolone.
If, after the start of treatment is developed VTE, use of the drug should be discontinued. The patient should be informed about the need for immediate treatment to the doctor with symptoms of a potential thromboembolic events (eg, pain and unilateral lower limb edema, sudden chest pain, shortness of breath).
Coronary heart disease (CHD)
in randomized controlled trials have not produced evidence of protection against myocardial infarction in women with or without coronary artery disease who were receiving HRT combination therapy (estrogen / progestogen) or preparations containing estrogen only.
Epidemiological studies using GPRD database was not obtained evidence of protection against myocardial infarction in postmenopausal women who received tibolone.
Ischemic Stroke
Therapy Tibolone increases the risk of ischemic stroke from the first year of application. The absolute risk of stroke is strongly dependent on age, and, therefore, the effect of tibolone is greater the older age. If you have any unexplained migraine headaches with or without visual impairment, you must immediately consult a doctor. In this case, should not take the drug as long as doctor does not confirm the safety of continuation of HRT, such as headaches may be an early diagnostic sign of a possible stroke.
other conditions
According to reports, the use of tibolone resulted in a significant dose-dependent reduction 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).
Also decreased the total concentration of triglycerides and VLDL. Decrease in total cholesterol and VLDL cholesterol was not dose-dependent. LDL cholesterol concentrations did not change. The clinical implications of these findings is still unknown.
Women with pre-existing hypertriglyceridemia should be under close medical supervision during the use of the drug Ledibon ® , as rare cases of a significant increase in plasma concentrations of triglycerides, contributing to the development of pancreatitis observed during estrogen therapy for a given condition.
Tibolone treatment leads to a very small reduction thyroxine binding globulin (TBG) and total T 4 . The concentration of total T 3 is not changed. Ledibon ® reduces the concentration of binding globulin sex hormones (SHBG) whereas the concentration kortikosteroidsvyazyvayuschego globulin (CBG) and circulating cortisol are not changed.
Should be considered at increased risk of developing dementia in the case of tibolone initiating therapy in women over the age of 65 years.
Against the background of the drug Ledibon ® there is a possibility of water retention. In this regard, the need for careful monitoring of the patients with heart or renal failure.
Impact on the ability to drive vehicles and manage mechanisms

Not noted any adverse effects of the drug on the concentration and reaction ability to drive vehicles and other mechanisms.
OVERDOSE

When simultaneous administration of the drug tablets large number Ledibon ® patient should seek medical attention.
Symptoms: malaise, nausea or vaginal bleeding.
Treatment: symptomatic.
DRUG INTERACTION

Tibolone enhances fibrinolytic activity of blood that can lead to increased anticoagulant action of anticoagulants, particularly warfarin, the warfarin dose should therefore be appropriately adjusted by MHO. The simultaneous use of tibolone and anticoagulants must be controlled, particularly at the beginning and end of drug treatment Ledibon ® .
There is limited information regarding pharmacokinetic interactions with tibolone treatment. In vivo study demonstrated that the simultaneous application of tibolone in a small degree affects the pharmacokinetics of midazolam CYP3A4 substrate. Accordingly, the possible presence of drug interactions with other substrates of CYP3A4. Drugs - inducers of CYP3A4, such as barbiturates, carbamazepine, hydantoins and rifampicin may enhance the metabolism of tibolone and thus affect its therapeutic effect. Preparations containing St. John's wort (Hypericum perforatum), may enhance the metabolism estrogen and progestogen through induction of isoenzyme CYP3A4.Increased metabolism of estrogen and progestogen can lead to a decrease in their clinical effect and change in the profile of uterine bleeding.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 25 ° C.
Shelf life - 2 years.
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