Ledibon® (Ladybon®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTibolonTibolon
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  • Velleriene
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    VALEANT, LLC     Russia
  • Ledibon®
    pills inwards 
    SANOFI RUSSIA, CJSC    
  • Livial®
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    Organon, N.V.     Netherlands
    • Dosage form: & nbsppills
    Composition:

    Active substance: 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 - 0.5 mg, magnesium stearate - 0.5 mg.

    Description:From white to almost white flat round tablets, engraved "e" on one side.
    Pharmacotherapeutic group:Estrogen
    ATX: & nbsp

    G.03.C.X.01   Tibolon

    Pharmacodynamics:

    When taken orally tibolone It is rapidly metabolized with the formation of three compounds that determine the pharmacodynamic characteristics Ledibon® preparation. Two metabolites of tibolone (3α-hydroxytibolone and 3β- hydroxytibolone) have estrogen-like activity, while the third metabolite - Δ4-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, etc.).Ledibon® prevents the loss of bone mass after menopause or removal of the ovaries.

    Pharmacokinetics:

    After oral administration tibolone quickly absorbed. As a result of rapid metabolism, the concentrations of tibolone in the plasma are very low. The maximum plasma concentrations of metabolites of 3α-hydroxytibolone and 3β-hydroxytibolone are higher, but cumulation does not occur. The concentration of the Δ4 isomer in the plasma is very low. Therefore, a number of pharmacokinetic parameters can not be determined.

    Tibolone excretion mainly occurs in the form of conjugated metabolites (mainly sulphated). Part of the drug is excreted by the kidneys, most of it is excreted through the intestine. Eating does not have any noticeable effects on the degree of absorption. The pharmacokinetic parameters of tibolone and its metabolites are independent of renal function.

    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.
    Contraindications:
    • Pregnancy and the period of breastfeeding.
    • Period less than a year after the last menstruation.
    • Diagnosed (including in anamnesis) breast cancer or suspected of it.
    • Diagnosed (including in the anamnesis) malignant estrogen-dependent tumors (eg, endometrial cancer) or suspicion of them.
    • Bleeding from the vagina is unclear etiology.
    • Untreated hyperplasia of the endometrium.
    • Thrombosis (venous or arterial) and thromboembolism now or in history (including deep vein thrombosis and thrombophlebitis, pulmonary embolism, myocardial infarction, ischemic or hemorrhagic cerebrovascular disorders).
    • Diagnosed thrombophilic conditions (eg, protein C deficiency, protein S or antithrombin III) (see section "Special instructions").
    • 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 (body mass index> 30 kg / m), smoking over the age of 35).
    • Cardiovascular failure in the stage of decompensation.
    • Acute liver disease or liver disease in an anamnesis, after which the liver function indicators did not return to normal.
    • Liver failure.
    • Malignant or benign tumors of the liver (including, adenoma of the liver) now or in the anamnesis.
    • Porphyria.
    • Otosclerosis, which occurred during previous pregnancy or with the use of hormonal contraceptive preparations in the anamnesis.
    • Installed hypersensitivity to the active substance or to any auxiliary substance of the drug.
    • Rare hereditary diseases: intolerance to galactose, deficiency of lactase Lappa or glucose-galactose malabsorption.
    Carefully:If any of the following conditions / diseases are present, has been observed earlier and / or worsened during pregnancy or previous hormone therapy, the patient should be under close medical supervision. Such conditions / diseases include:

    leiomyoma (uterine fibroid) and / or endometriosis;

    cardiovascular insufficiency without signs of decompensation;

    presence of risk factors estrogen-dependent tumors (for example, the presence of breast cancer in close relatives (mother, sisters));

    controlled arterial hypertension;

    increase in concentration 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;

    systemic lupus erythematosus;

    endometrial hyperplasia in the anamnesis;

    epilepsy;

    bronchial asthma;

    kidney failure;

    otosclerosis, not associated with bVariability or previous use of hormonal contraceptives.

    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 breastfeeding is contraindicated. In case of pregnancy, treatment with Ledibon® should be stopped immediately.
    Dosing and Administration:

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

    The dose of the drug is one tablet per day. Dose adjustment with age is not required. Tablets should be swallowed by washing with water, preferably on the same day. Blisters with the drug Ledibon® are marked with days of the week. Start taking the medication with taking the pill, which is marked 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 allow skipping in the drug when changing blisters or packages.

    When treated with Ladybot® there is no need to add gestagen containing preparations.

    If the next pill is missed, further tactics depend on the time of delay from the scheduled time of reception. If less than one tablet was missed 12 hours, it is necessary to take the missed tablet as soon as possible. If the delay in taking the tablets 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 two tablets at the same time to replenish the missed dose!

    Transition from a cyclic or continuous regimenhormonal therapy (HRT) for tibolone

    When switching from a cyclical regimen of the drug to HRT, treatment with Ledibon® should begin the day after the completion of the previous treatment regimen. In case of transition from a continuous regimen of taking a combined drug for HRT, treatment can be started at any time.

    Side effects:

    This section describes the undesirable effects that were recorded during 21 placebo-controlled study (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]) c participation 4079 women receiving therapeutic doses (1.25 or 2.5 mg) of tibolone, and 3,476 women receiving placebo. The duration of treatment in these studies was from 2 months to 4.5 years. Below are the undesirable effects that were statistically significantly more frequent with tibolone than with placebo.

    Table 2. Side effects of tiblonol (2.5 mg)

    System-Organ Class

    Often (> 1% and <10%)

    Infrequently (>0.1% and <1%)

    Violations from side of the gastrointestinal tract

    Lower abdominal pain

    Violations from skin and subcutaneous tissue

    Growth hair, including on the face

    Acne

    Violations from the side of the reproductive system and mammary glands

    Allocations from vagina, thickening of the endometrium, spotting or bleeding from the vagina, pain in the mammary glands, genital itching, candidiasis vulvovaginitis, pain in the pelvis, cervical dysplasia, vulvovaginitis

    Mycosis, breast engorgement, soreness of the nipples

    Laboratory and instrumental data

    An increase in body weight, deviation of the results of a smear from the cervix1

    Deviation from normal values cytological characteristics of the cervical epithelium.

    BMost side effects were mild. Number of cases of cervical pathology (cervical cancer) ne was increased when taking Ledibon® as 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;

    • liver dysfunction (including increased activity of transaminases).

    The risk of developing breast cancer

    In women receiving therapy combined (estrogen / gestagen) drugs for more than 5 years, there was 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 / gestagen) drugs.

    The level of risk depends on duration of use.

    Table 3.The estimated additional risk of developing breast cancer after 5 years of use (according to the "Study of a million women".

    Agegroup

    (years)

    Additional cases per 1000 patients who had not received HRT for the 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 developing 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 (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 group receiving tibolone (n = 1746), which corresponds to the diagnosis of 0.8 additional cases of endometrial cancer per 1000 women who received tibolone for 1 year in this study (see section "Special instructions").

    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 general risk of developing ischemic stroke in women receiving tibolone, will increase with age (see section "Special instructions").

    Randomized controlled

    The study for 2.9 years has established 2,2-fold increase in the risk of stroke in women (mean age 68 years) who took 1.25 mg of tibolone (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 within 5 years, we can expect about 4 additional cases for 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 preparations combined (estrogen / gestagen) drugs, tibolone) Prolonged use of drugs for HRT that contain only estrogen, and combined (estrogen / progestogen) drugs was associated with a slight increase in the risk of developing ovarian cancer. According to the "Study of a million women" [Million Women Study] HRT in for 5 years resulted in 1 additional case of cancer for 2500 patients. This study showed that the relative risk of ovarian cancer when taking tibolone is similar to the risk of using other drugs for HRT.

    Reception 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 (see section "Special instructions").

    Table 4. Additional risk of developing venous thromboembolism (VTE) when used for more than 5 years based on the results of the study "Initiative

    Age

    naya

    Group

    (years)

    The incidence of diseases per 1000 women in the placebo group over 5 years

    Oto

    the

    risks

    (95%

    DI)

    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)

    The combination of estrogen-p

    eogestin orally

    50-59

    4

    2,3 (1,2- 4.3)

    5 (1-13)

    * In women with a deleted uterus.

    • An insignificant increased risk of development ischemic heart disease patients older than 60 years receiving HRT 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 types of HRT.
    • Increase in 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 (see section "Special instructions")
    Overdose:

    When taking a large number of Ledibon® tablets, you should consult a doctor.

    The main symptoms are: a feeling of malaise, nausea, or vaginal bleeding. Treatment: symptomatic.

    Interaction:

    Tibolon strengthens the fibrinolytic activity of the blood, which can lead to an increase in the anticoagulant effect of anticoagulants, in particular warfarin, so the dose of warfarin should be appropriately adjusted by INR (international normalized ratio). The simultaneous use of tibolone and anticoagulants should be monitored, especially at the beginning and at the end of treatment with Ledibon®. There is only limited information on pharmacokinetic interaction at treatment with tibolone. Study in vivo demonstrated that the joint application with tibolone in a small degree affects the pharmacokinetics substrate of cytochrome P450 3A4 midazolam.

    Based on this, it is possible that drug interactions with other substrates CYP3A4. Medications-inducers CYP3A4, such as barbiturates, carbamazepine, hydantoins and rifampicin, can increase metabolism tibolone and thus affect its therapeutic effect. Preparations, containing St. John's wort (Hypericum perforatum), can strengthen metabolism of estrogens and progestins by induction of isoenzyme CYP3A4. Increased metabolism Estrogen and progestin can lead to decrease their clinical effect and change the profile of the uterus bleeding.

    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, Ledibon® is necessary appoint only 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."Side effect"), considering all individual risk factors, incidence and specificity of both types of cancer and stroke in terms of healing, morbidity and mortality. Evidence of 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, due to the low absolute risk level in younger women.

    Medical Examination / Follow-up 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 1 times in 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 mammograms, should be performed in accordance with the currently accepted screening scheme, adapted to the clinical needs of each patient, but at least 1 times in 6 months. Reasons for immediate discontinuation of therapy and immediate medical attention Therapy should be discontinued if contraindications and / or following conditions / diseases:

    • jaundice or worsening of liver function;
    • a sudden increase in blood pressure, which differs from the usual indices of blood pressure characteristic of the patient;
    • occurrence of a headache type migraine.
    • Hyperplasia and endometrial 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 (see also the "Side effect" section). These studies have shown that the risk of developing endometrial cancer increases with an increase in the duration of the drug, tibolone can increase the thickness of the endometrium measured by transvaginal ultrasound.

    During the first months of treatment, observed "breakthrough" bleeding and spotting.

    When bloody discharge / bleeding during the use of the drug Ladybin®,

    • which continue 6 months from the beginning of the drug,
    • start through 6 months after started using Ledibon® and continues even after How the patient stopped using Ladybin®,
    Mr.It is necessary to consult a doctor - this may be a sign of endometrial hyperplasia.

    Mammary cancer

    Data from different clinical trials from the point of view of evidence-based medicine regarding the risk of developing breast cancer when taking tibolone is controversial, and further research is required.

    Ovarian Cancer

    Ovarian cancer is widespread less than breast cancer.

    Long-term (not less than 5-10 years) substitution monotherapy with estrogens was associated with a slight increase in the risk of ovarian cancer.

    Some studies, including study "Health Initiative women " (WHI) [Women's Health Initiative], suggest that prolonged therapy with combined drugs for HRT may have a similar or slightly lower risk.

    In the "Study of a million women" was It was shown that the relative risk of developing ovarian cancer with tibolone was similar to the risk associated with the use of other types of HRT.

    Venous thromboembolism ZGT preparations containing only estrogens or combination preparations containing estrogen and progestogen may increase the risk of venous thromboembolism (VTE) (ie, deep vein thrombosis or pulmonary embolism) by 1.3 to 3 times, in features during the first year of use (see section "Side effect").

    According to an epidemiological study using UK databases, the risk of developing VTE related to taking tibolone was lower than that associated with conventional HRT drugs, but due to the fact that at that time only a small proportion of women were taking tibolone, we can not exclude a slight increase in risk compared to women who did not take tibolone. Patients with known thrombophilic states have an increased risk of developing VTE, and taking tibolone may increase this risk, so the use of the drug by this population Patients are contraindicated (see section "Contraindications").

    Risk factors for the development of VTE are the use of estrogens, advanced age, extensive surgical intervention, prolonged immobilization, obesity (body mass index (BMI)> 30 kg / m2), pregnancy and the postpartum period, systemic lupus erythematosus and cancer. Patients after the surgical interventions it is necessary to pay special attention to preventive measures for the prevention of VTE in the postoperative period. If necessary prolonged immobilization after surgery, a temporary discontinuation of Ledibon® was recommended 4-6 weeks before surgery. Treatment should not be resumed until the woman's motor activity is restored. Women who have no history of VTE, but who have relatives of the first degree of kinship who have a history of thrombosis at a young age, can be offered screening inform the woman that screening reveals only a part of the thrombophilic conditions). If a thrombophilic condition is identified that is isolated from the thrombosis of relatives, or a serious violation (for example, deficiency of antithrombin III, protein S, protein C or a combination of disorders), taking Ledibon® is contraindicated.

    For women who are already receiving anticoagulant treatment, tA careful consideration of the benefit / risk ratio of HRT or tibolone is required.

    If VTE develops after the beginning of treatment, the drug should be stopped. Patients should be informed of the need for immediate medical attention if symptoms of potential thromboembolism (eg, pain and unilateral swelling of the lower limb, sudden chest pain, shortness of breath) appear. Ischemic heart disease (CHD)

    In randomized controlled trials, evidence of protection against myocardial infarction was not obtained in women with or without CHD who received HRT with combined drugs (estrogen / progestogen) or preparations containing only estrogen.

    In epidemiological studies using the base GPRD There was no evidence of protection against myocardial infarction in postmenopausal women who received tibolone. Ischemic stroke Therapy with tibolone increases the risk of ischemic stroke, starting from the first year of use (see section "Side effect"). Absolute risk of stroke depends strictly on age, and, consequently, this effect of tibolone is greater, the greater the age. If you experience unexplained migraine headaches with or without vision impairment, you should contact your doctor as soon as possible. In this case, you can not take the drug until the doctor confirms the safety of continuation of HRT, since such headaches can be an early diagnostic sign of a possible stroke.

    Other states

    • According to available data, admission tibolone led to a significant dose-dependent decrease HDL cholesterol (high-density lipoprotein) (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 overall concentration of triglycerides and VLDL. Reducing the concentration of total cholesterol and VLDL cholesterol (very low density lipoproteins) was not dose-dependent.Concentrations of LDL cholesterol (low density lipoproteins) did not change. The clinical significance of this data not yet known.
    • Women with an existing hypertriglyceridemia should be under close supervision of the doctor during therapy with tibolone, since rare cases of a significant increase in the level of triglycerides in the blood plasma, contributing to the development pancreatitis, were noted during estrogen therapy in this condition.
    • Treatment with tibolone leads to a very small decrease in thyroxine-binding globulin (TSH) and total T4. The level of total T3 does not change. Ledibon® lowers the level of sex hormone binding globulin (SHBG), whereas levels corticosteroid-binding globulin (CSG) and circulating cortisol do not change.
    • An increased risk of dementia should be considered in cases of initiation of therapy with tibolone in women over the age of 65 years.
    • Against the background of taking Ledibon ® there is a possibility of fluid retention. In this regard, careful monitoring of patients with cardiac or renal insufficiency is necessary.
    Effect on the ability to drive transp. cf. and fur:

    No negative action of the drug on concentration of attention and reaction, ability to govern vehicles and other mechanisms.

    Form release / dosage:Tablets 2.5 mg.
    Packaging:For 28 tablets in a blister of PVC / PVDC / AI. For 1 or 3 blisters are placed in a cardboard box together with instructions for medical use.
    Storage conditions:

    At a temperature of no higher than 25 ° C, in the original packaging. Keep out of the reach of children!

    Shelf life:

    2 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-005344/09
    Date of registration:01.07.2009 / 01.08.2017
    Expiration Date:Unlimited
    The owner of the registration certificate:SANOFI RUSSIA, CJSCSANOFI RUSSIA, CJSC
    Manufacturer: & nbsp
    ZENTIVA, k.s. Czech Republic
    Representation: & nbspSanofi Russia, JSCSanofi Russia, JSCRussia
    Information update date: & nbsp06.03.2018
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