Buy Livial pills 2.5 mg, 28 pcs
  • Buy Livial pills 2.5 mg, 28 pcs

Tibolon

Schering-Plough
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2019-09-19
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Clinical Pharmacology

LIVIAL - a drug for the treatment of menopausal syndrome that does not cause regular withdrawal bleeding. Stabilizes the work of the hypothalamic-pituitary system in menopause, which is achieved due to the estrogenic, progestogenic and weak androgenic properties of the drug.
Tibolone is rapidly metabolized to three compounds that provide the pharmacological action of Livial. Two metabolites, 3α-OH-tibolone and 3β-OH-tibolone, have predominantly estrogenic activity, and the third, the δ4 isomer of tibolone, has progestogenic and weak androgenic activity.
Livial has a specific effect for different types of tissues. This is an estrogenic effect on the vagina, bone tissue and temperature-controlled centers in the brain (correction of hot flashes); Predominantly progestogenic effect on the mammary glands. Livial does not cause endometrial proliferation due to local conversion to the δ4-isomer, which has progestogenic and androgenic activity. Rare cases of bloody discharge when taking Livial are usually the result of endometrial atrophy. Livial helps to reduce the concentration of cholesterol, triglycerides in the blood plasma and increase the fibrinolytic activity of the blood. Livial improves mood and increases libido.

Indications

Symptoms of natural or surgical menopause; prevention of osteoporosis with estrogen deficiency.

Composition

1 tablet contains:

Active substance: Tibolone 2.5 mg;

Excipients: potato starch, magnesium stearate, ascorbyl palmitate, lactose, purified water.

Tibolon is marketed under different brands and generic names, and comes in different dosage forms:

Brand nameManufacturerCountryDosage form
Livial Schering-Plough USA pills
Tibolone Zentiva KS Czech pills

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Tibolon

Dosage and Administration

Tibolone should be taken 12 months after the last natural menstruation. If Tibolone begin to take before the specified time, then increases the likelihood of irregular bleeding / bleeding from the vagina. Before starting the Tibolone 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.

The dose of the drug - one tablet per day.

Dose adjustment based on age is not required. Tablets should be swallowed with water, preferably on the same day.

Blisters with Tibolone marked days of the week. Start taking 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 take the pills according to the days of the week. From the next blister, the tablets are taken without any passes or interruptions. Do not allow skips in the reception of the drug when changing blisters or packaging.

When treating Tibolone No need to add gestagenic drugs.

If the next pill is missed, the subsequent tactic depends on the late arrival time from the scheduled reception time. If less than 12 hours have passed since the tablet was missed, it is necessary to take the missed tablet 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.

Do not take two tablets at the same time to replenish the missed dose!

Transition from a cyclic or continuous regimen of a drug for hormone replacement therapy (HRT) to tibolone

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

Adverse reactions

This section describes the undesirable effects that were recorded 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) involving 4079 women who received therapeutic doses (1.25 or 2.5 mg) of tibolone, 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.

Table 2. Side effects of tibolone (2.5 mg)

System organ class

Often (> 1% and <10%)

Infrequently (> 0.1% and <1%)

Violations of the gastrointestinal tract

Lower abdominal pain

 

Violations of the skin and subcutaneous tissue

Strengthening hair growth, including on the face

Acne

Disorders of the reproductive system and mammary glands

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

Mycosis, breast engorgement, nipple soreness

Laboratory and instrumental data

Weight gain, abnormal cervical smear results1

 

1Deviation 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 when taking the Tibolone compared to placebo.

Other possible side effects may be (frequency not set):

  • dizziness, headache, migraine;

  • depression;

  • skin rash, 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).

Breast Cancer Risk

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

Age

Group (years)

Additional cases for 1000 patients who have not previously received HRT, over a period of 5 years

Attitude

risk *

(95% CI)

Additional cases for 1000 patients receiving HRT over 5 years (95% CI)

HRT only estrogen

50-65

9-12

1,2

1-2 (0-3)

Therapy with combined (estrogen / gestagen) drugs

50-65

9-12

1,7

6 (5-7)

Tibolon

50-65

9-12

1,3

3 (0-6)

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, thus 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 endometrial cancer per 1000 women who received tibolone for 1 year in this study (see section "Special Instructions").

Risk of ischemic stroke

The relative risk of developing 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 ischemic stroke in women taking tibolone will increase with age (see the section "Special Instructions").

A randomized controlled trial of 2.9 years found a 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 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 noted. The prolonged use of drugs for hormone therapy containing only estrogen and combined (estrogen / gestagen) drugs was associated with a slight increase 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 taking Tibolone is similar to the risk of using other drugs for HRT.

Tibolone administration is associated with an increase in the relative risk of venous thromboembolism (VTE), i.e. deep vein thrombosis and pulmonary embolism, 1.3-3 times. This phenomenon occurs more often during the first year of the drug use (see section "Special instructions").

Table 4. Additional risk of developing venous thromboembolism (VTE) when used for more than 5 years according to the results of the Women's Health Initiative.

Age

Group (years)

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

Attitude

risks

(95% CI)

Additional cases for 1000 patients receiving HRT over 5 years (95% CI)

Only estrogen orally*

50-59

7

1,2 (0,6­ - 2,4)

1 (-3-10)

Oral estrogen / progestin combination

50-59

4

2,3 (1,2- 4.3)

5 (1-13)

*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 / gestagen) drugs. There is no reason to believe that the risk of myocardial infarction when taking tibolone is different from the risk of using other types of HRT.

  • Increased blood pressure.

  • Pancreatitis.

  • Gallbladder diseases (cholelithiasis, cholecystitis).

  • Skin diseases: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

  • Dementia at the start of treatment at the age of 65 years (see section "Special Instructions").

  • Pregnancy and breastfeeding period.

  • Period less than a year after the last menstruation.

  • Diagnosed (including a history of) 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 currently or in history (including thrombosis and deep vein thrombophlebitis, pulmonary embolism, myocardial infarction, ischemic or hemorrhagic cerebrovascular disorders).

  • Diagnosed thrombophilic conditions (for example, deficiency of protein C, protein S or antithrombin III) (see the section "Special Instructions").

  • Conditions preceding thrombosis (including transient ischemic attacks, angina), currently or in history.

  • Significant 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 accompanied by prolonged immobilization; extensive trauma; obesity (body mass index, body mass index), a body mass of the body, a hiv, an index of body surgery, accompanied by prolonged immobilization, extensive trauma; / m2), smoking over the age of 35).

  • Cardiovascular failure in the stage of decompensation.

  • A history of acute liver disease or liver disease, after which liver function indicators did not return to normal.

  • Liver failure.

  • Malignant or benign liver tumors (including liver adenoma) now or in history.

  • Porphyria.

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

  • Established hypersensitivity to the active substance or to any excipient of the drug.

  • Rare hereditary diseases: galactose intolerance, Lapp's lactase deficiency, or glucose-galactose malabsorption.

Carefully

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

  • leiomyoma (uterine fibroma) and / or endometriosis;
  • 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;

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

  • cholelithiasis;

  • migraine or severe headache;

  • systemic lupus erythematosus;

  • 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.

Drug interactions

Tibolone increases blood fibrinolytic activity, which can lead to increased anticoagulant action of anticoagulants, in particular warfarin, therefore, the dose of warfarin should be adjusted accordingly for INR (international normalized ratio). The simultaneous use of tibolone and anticoagulants must be controlled, especially at the beginning and at the end of treatment with Tibolone. There is only limited information regarding pharmacokinetic interactions in the treatment of tibolone. An in vivo study demonstrated that co-administration with tibolone to a small extent affects the pharmacokinetics of the cytochrome P450 3A4 substrate midazolam.

Based on this, drug interactions with other CYP3A4 substrates are possible. CYP3A4 inductive drugs, 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 progestins through induction of the CYP3A4 isoenzyme. Increased metabolism of estrogens and progestins can lead to a decrease in their clinical effect and a change in the profile of uterine bleeding.

Pregnancy and Lactation

Use of the Tibolone during pregnancy and breastfeeding is contraindicated. In case of pregnancy, treatment with Tibolone must stop immediately.

Special instructions

Tibolone not intended for use as a contraceptive and does not protect against unwanted pregnancy. The decision to start taking the Tibolone 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 Tibolone it is necessary to appoint only concerning symptoms which adversely influence quality of life. In all cases, it is necessary to conduct a thorough assessment of the risks 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 evaluate the risk of developing stroke, the risk of developing breast cancer and endometrial cancer in every woman with an intact uterus (see section “Side Effects”), 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.

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 lower absolute risk level in younger women.

Medical examination / observation

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

Physical examination (including examination of the pelvic organs and the 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 of the need to inform the doctor about changes in the mammary glands.

Examinations, including appropriate imaging techniques, such as 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 the immediate cancellation 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;

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

  • the occurrence of migraine headaches.

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 (see also the “Adverse Effects” section). 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.

During the first months of treatment, "breakthrough" bleeding and bloody discharge may occur.

With the appearance of bleeding / bleeding on the background of the use of the Tibolonewhich

  • last more than 6 months from the start of taking the drug,

  • begin 6 months after the start of the Tibolone and continue even after the patient has discontinued the use of the Tibolone,

you need to see a doctor - this may be a sign of endometrial hyperplasia.

Mammary cancer

Evidence-based clinical evidence from clinical trials for the risk of developing breast cancer when taking Tibolone is inconsistent, 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 therapy was associated with a slight increase in the risk of ovarian cancer.

Some studies, including the Women's Health Health Initiative (WHI) study, suggest that long-term therapy with combination drugs for HRT 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

HRT preparations containing only estrogen, or combination drugs containing estrogen and progestogen, can increase the risk of venous thromboembolism (VTE) (ie, deep vein thrombosis or pulmonary embolism) during the first year of use (see section "Side Effects").

According to an epidemiological study using the UK database, the risk of developing VTE associated with taking tibolone was lower than the risk associated with traditional drugs for hormone therapy, 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 (see section "Contraindications").

Risk factors for VTE are estrogen use, advanced age, extensive surgery, prolonged immobilization, obesity (body mass index (BMI)> 30 kg / m2), pregnancy and the postpartum period, systemic lupus erythematosus 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 temporary discontinuation of the Tibolone 4-6 weeks before surgery. Treatment should not be resumed until the woman has restored physical activity. Women who have a history of VTE are absent, but who have first-degree relatives with a history of thrombosis at a young age, may be offered screening (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, a deficiency of antithrombin III, protein S, protein C, or a combination of disorders), take Tibolone contraindicated.

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

If after the start of treatment develops VTE, the drug should be stopped. Patients 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 was 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 (see the “Side Effects” section). The absolute risk of stroke is strictly dependent on age, and, consequently, this effect of tibolone is greater, the greater 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 can 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 the available data, taking tibolone led to a significant dose-dependent decrease in HDL cholesterol (high density lipoproteins) (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 (very low density lipoprotein) cholesterol was not dose-dependent. The concentration of LDL cholesterol (low density lipoprotein) 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 doctor while taking the Tibolone, as rare cases of a significant increase in the concentration of triglycerides in the blood plasma, contributing to the development of pancreatitis, were observed during estrogen therapy in this state.

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

  • Against the background of the drug Ledibon® there is a chance of fluid retention. In this regard, careful monitoring of patients with heart or kidney failure.

INFLUENCE ON THE ABILITY OF MANAGEMENT OF VEHICLES AND MECHANISMS

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

Overdosage

While taking a large number of tablets Ledibon® need to see a doctor.

Main symptoms: malaise, nausea, or vaginal bleeding.

Treatment: symptomatic.

  • Brand name: Livial
  • Active ingredient: Tibolon
  • Dosage form: Pills
  • Manufacturer: Schering-Plough
  • Country of Origin: USA

Studies and clinical trials of Tibolon (Click to expand)

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