Ladybon^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Zentiva, k.s. (Czech Republic)

ATC Code

G03CX01 (Tibolone)

Active Substance

Tibolone (Rec.INN registered by WHO)

Dosage Form

Ladybon®

Tablets 2.5 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to almost white, round, flat, with an engraving “e” on one side.

Excipients: lactose monohydrate (micronized), lactose monohydrate (direct compression lactose), potato starch, ascorbyl palmitate, magnesium stearate.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric estrogenic drug

Pharmacotherapeutic Group

Other estrogens

Pharmacological Action

Anticlimacteric drug.

When taken orally, Tibolone is rapidly metabolized to form three compounds that determine the pharmacodynamic characteristics of Ladybon^®. Two metabolites of tibolone (3α-hydroxytibolone and 3β-hydroxytibolone) have estrogen-like activity, while the third metabolite, the Δ4-isomer of tibolone, has progestogen-like and androgen-like activity.

Ladybon^® replenishes estrogen deficiency in postmenopausal women, alleviating symptoms associated with their deficiency, such as vasomotor disorders (“hot flashes”, increased night sweating), irritability, vaginal dryness and discomfort, decreased mood and libido, and others.

Ladybon^® prevents bone loss after menopause or oophorectomy.

Pharmacokinetics

Absorption and Metabolism

Absorption is high.

Metabolized in the liver to form hydrophilic products, some of which are pharmacologically active.

Excretion

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 at high risk of fractures and with intolerance to other groups of drugs used for the prevention of osteoporosis.

ICD codes

Dosage Regimen

Ladybon^® should be taken after 12 months have passed since the last natural menstruation. If Ladybon^® is started earlier than this period, the likelihood of irregular bloody discharge/vaginal bleeding increases.

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

When treating with Ladybon^®, there is no need to add progestogen-containing drugs.

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

Rules for taking tablets

Blister packs with Ladybon^® are marked with days of the week. You should start using the drug by taking the tablet marked with the current day. For example, if the day of administration coincides with Monday, you need to take the tablet marked Monday from the top row of the blister. Then take the tablets according to the days of the week. From the next blister, the tablets are taken without omissions or breaks. Do not allow a gap in the use of the drug when changing the blister or package.

Missed tablet

If a scheduled tablet is missed, further tactics depend on the time of delay from the planned intake. If the delay is less than 12 hours, the missed tablet should be taken as soon as possible. If the delay in taking the tablets was more than 12 hours, the dose should be skipped, and the next tablet should be taken at the usual time. It is not recommended to take 2 tablets at the same time to make up for a missed dose.

Switching from cyclic or continuous regimen of HRT to Tibolone

When switching from a cyclic regimen of HRT, treatment with Ladybon^® should be started the day after the previous treatment regimen is completed. When switching from a continuous regimen of a combined HRT drug, treatment can be started at any time.

No dose adjustment is required for elderly patients.

Adverse Reactions

This section describes adverse effects that were registered during 21 placebo-controlled studies (including the study “Long Term Intervention on Fractures with Tibolone” (LIFT)) involving 4079 women receiving Tibolone in therapeutic doses (1.25 or 2.5 mg), and 3476 women receiving placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. Below are the adverse effects that occurred statistically significantly more often with tibolone treatment than with placebo.

From the digestive system often (>1% and <10%) - lower abdominal pain.

From the skin and subcutaneous tissues often (>1% and <10%) - increased hair growth, including on the face; infrequently (>0.1% and <1%) - acne.

From the reproductive system and breast often (>1% and <10%) - vaginal discharge, endometrial thickening, bloody discharge or bleeding from the vagina, breast pain, genital itching, candidal vulvovaginitis, pelvic pain, cervical dysplasia, vulvovaginitis; infrequently (>0.1% and <1%) - mycosis, breast engorgement, nipple tenderness.

Laboratory and instrumental data often (>1% and <10%) - weight gain, abnormal cervical smear results¹.

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

Most side effects were mild. The number of cases of cervical pathology (cervical cancer) did not increase with the use of Ladybon^® compared to placebo. Other possible side effects may be (frequency not established): dizziness, headache, migraine; depression; skin rash, itchy skin, seborrheic dermatitis; visual disturbances (including blurred vision); gastrointestinal disorders (diarrhea, flatulence); fluid retention in the body, peripheral edema; joint and muscle pain; liver function disorders (including increased transaminase activity).

Risk of developing breast cancer

In women receiving therapy with combined (estrogen/progestogen) drugs for more than 5 years, a twofold increase in the frequency of diagnosed breast cancer was noted. Any increased risk in patients receiving estrogen alone or Tibolone is significantly lower than the risk observed in patients receiving therapy with combined (estrogen/progestogen) 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 “Million Women Study”)

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

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, thus the study design was close to clinical practice conditions (LIFT study, average 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 receiving Tibolone for 1 year in this study.

Risk of developing ischemic stroke

The relative risk of developing ischemic stroke does not depend on age or duration of drug use, but the absolute risk strongly depends on age. The overall risk of developing ischemic stroke in women taking Tibolone will increase with age.

A randomized controlled study over 2.9 years established a 2.2-fold increase in the risk of stroke in women (average age 68 years) taking Tibolone at a dose of 1.25 mg (28/2249) compared to placebo (13/2257). Most (80%) of the strokes were ischemic.

The absolute risk of stroke depends on age. Thus, the absolute risk over a 5-year period is 3 cases per 1000 women aged 50-59 years and 11 cases per 1000 women aged 60-69 years.

For women taking Tibolone for 5 years, about 4 additional cases per 1000 patients aged 50-59 years and 13 additional cases per 1000 patients aged 60-69 years can be expected.

Other adverse events associated with the use of HRT drugs (estrogen-containing drugs, combined (estrogen/progestogen) drugs, Tibolone) have been noted. Long-term use of estrogen-only HRT and combined (estrogen/progestogen) drugs was associated with a slight increase in the risk of ovarian cancer. According to the “Million Women Study”, HRT for 5 years led to 1 additional case of cancer per 2500 patients. This study showed that the relative risk of ovarian cancer with the use of tibolone is similar to the risk with the use of other HRT drugs.

The use of tibolone is associated with an increase in the relative risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis and pulmonary embolism, by 1.3-3 times. This phenomenon occurs more often during the first year of drug use.

Table 2. Additional risk of developing venous thromboembolism (VTE) with use for more than 5 years based on the results of the “Women’s Health Initiative” study

* In women with removed uterus

A slight increase in the risk of developing coronary artery disease is noted in patients over 60 years of age receiving HRT with combined (estrogen/progestogen) drugs (there is no reason to believe that the risk of myocardial infarction when taking tibolone differs from the risk when using other types of HRT); increased blood pressure; pancreatitis; gallbladder diseases (cholelithiasis, cholecystitis); skin diseases: chloasma, erythema multiforme, erythema nodosum, vascular purpura; dementia when starting therapy at the age of over 65 years.

Contraindications

• 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 (e.g., endometrial cancer) or suspicion of them;
• Vaginal bleeding of unknown etiology;
• Untreated endometrial hyperplasia;
• Thrombosis (venous or arterial) and thromboembolism currently or in history (including deep vein thrombosis and thrombophlebitis, pulmonary embolism, myocardial infarction, ischemic or hemorrhagic cerebrovascular disorders);
• Diagnosed thrombophilic conditions (e.g., protein C, protein S or antithrombin III deficiency);
• Conditions preceding thrombosis (including transient ischemic attacks, angina), currently or in history;
• Severe or multiple risk factors for the development of venous or arterial thrombosis (including atrial fibrillation, complicated lesions of the heart valve apparatus and subacute bacterial endocarditis, uncontrolled arterial hypertension, extensive surgical intervention accompanied by prolonged immobilization, extensive trauma, obesity (BMI >30 kg/m²), smoking at the age of over 35 years;
• Decompensated heart failure;
• Acute liver disease or a history of liver disease after which liver function tests have not returned to normal;
• Hepatic insufficiency;
• Malignant or benign liver tumors (including liver adenoma) currently or in history;
• Porphyria;
• Otosclerosis that occurred during a previous pregnancy or with the use of hormonal contraceptive drugs in history;
• Rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption;
• Pregnancy;
• Lactation (breastfeeding) period;
• Hypersensitivity to the active substance or any excipient of the drug.

With caution

If any of the following conditions/diseases is currently present, has been observed previously and/or worsened during pregnancy or previous hormone therapy, the patient should be under close medical supervision. Such conditions/diseases include

• Heart failure without signs of decompensation;
• Presence of risk factors for estrogen-dependent tumors (e.g., presence of breast cancer in close relatives (mother, sisters));
• Controlled arterial hypertension;
• Increased blood cholesterol concentration;
• Carbohydrate metabolism disorders, diabetes mellitus both with and without complications;
• Cholelithiasis;
• Migraine or severe headache;
• SLE;
• History of endometrial hyperplasia;
• Epilepsy;
• Bronchial asthma;
• Renal failure;
• Otosclerosis not associated with pregnancy or previous use of hormonal contraceptive drugs.

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

Use in Pregnancy and Lactation

The use of Ladybon^® during pregnancy and breastfeeding is contraindicated. In case of pregnancy, treatment with Ladybon^® must be stopped immediately.

Use in Hepatic Impairment

Contraindicated for use in acute liver disease or a history of liver disease after which liver function tests have not returned to normal; hepatic insufficiency; malignant or benign liver tumors (including liver adenoma) currently or in history.

Use in Renal Impairment

Should be prescribed with caution in renal failure.

Geriatric Use

No dose adjustment is required for elderly patients.

The increased risk of developing dementia should be taken into account when starting therapy with tibolone in women over 65 years of age.

Special Precautions

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

The decision to start using Ladybon^® should be based on an assessment of the “benefit/risk” ratio, taking into account all individual risk factors, and in women over 60 years of age, the increased risk of strokes should also be taken into account.

For the treatment of postmenopausal symptoms, Ladybon^® should be prescribed only for symptoms that adversely affect the quality of life. In all cases, a thorough assessment of the risk and benefit of therapy should be carried out at least once a year, and therapy with Ladybon^® should be continued only for the period when the benefit of therapy outweighs the risk. It is necessary to carefully assess the risk of stroke, the risk of breast cancer and endometrial cancer in each woman with an intact uterus, taking into account all individual risk factors, the frequency of occurrence and features of both types of cancer and stroke in terms of curability, morbidity and mortality.

Evidence of 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 level of risk in younger women.

Medical Examination/Monitoring

Before starting or resuming therapy with Ladybon^®, a personal and family medical history should be collected.

A physical examination (including pelvic and breast examination) should be performed taking into account the anamnesis data, absolute and relative contraindications.

During therapy, preventive follow-up 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, the woman should be informed about the need to report any changes in the breasts to the doctor.

Examinations, including appropriate imaging methods, for example, mammography, should be performed in accordance with the currently accepted examination scheme, adapted to the clinical needs of each patient, but at least once every 6 months.

Reasons for immediate therapy discontinuation and prompt medical consultation

Therapy should be discontinued if a contraindication is identified and/or in the following conditions/diseases

• Jaundice or worsening liver function;
• Sudden increase in blood pressure, differing from the patient’s usual blood pressure readings;
• Onset of migraine-type headache.

Endometrial hyperplasia and cancer

Data from randomized controlled clinical trials are conflicting, but observational study data have shown an increased risk of developing endometrial hyperplasia or cancer in women taking Tibolone.

These studies showed that the risk of developing endometrial cancer increases with the duration of drug use.

Tibolone may increase endometrial thickness, as measured by transvaginal ultrasound.

During the first months of treatment, breakthrough bleeding and spotting may occur.

If spotting/bleeding occurs during the use of Ladybon^®, which persists for more than 6 months from the start of use or begins 6 months after starting the drug and continues even after the patient has discontinued Ladybon^®, a doctor should be consulted – this may be a sign of endometrial hyperplasia.

Breast cancer

Data from various clinical studies from the perspective of evidence-based medicine regarding the risk of developing breast cancer when taking tibolone are conflicting, and further research is required.

Ovarian cancer

Ovarian cancer is much less common than breast cancer.

Long-term (at least 5-10 years) estrogen-only replacement monotherapy has been associated with a slight increase in the risk of developing ovarian cancer.

Some studies, including the Women’s Health Initiative (WHI), suggest that long-term therapy with combined HRT drugs may have a similar or slightly lower risk.

The Million Women Study showed that the relative risk of developing ovarian cancer with tibolone use was similar to the risk associated with other types of HRT.

Venous thromboembolism

HRT drugs containing only estrogens or combined drugs containing estrogen and progestogen may increase the risk of venous thromboembolism (VTE) (i.e., deep vein thrombosis or pulmonary embolism) by 1.3-3 times, especially during the first year of use.

According to an epidemiological study using UK databases, the risk of VTE associated with tibolone use was lower than the risk associated with conventional HRT drugs, but since only a small proportion of women were taking Tibolone at that time, a slight increase in risk compared to women not taking Tibolone cannot be ruled out.

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

Risk factors for VTE include estrogen use, advanced age, major surgery, prolonged immobilization, obesity (BMI >30 kg/m²), pregnancy and the postpartum period, SLE and cancer.

In patients after surgical interventions, special attention should be paid to preventive measures to prevent VTE in the postoperative period.

If prolonged immobilization after surgery is necessary, temporary discontinuation of Ladybon^® is recommended 4-6 weeks before surgery.

Treatment should not be resumed until the woman has regained mobility.

Women with no history of VTE but who have first-degree relatives with a history of thrombosis at a young age may be offered screening (the woman should be informed that screening detects only a portion of thrombophilic conditions).

If a thrombophilic condition is identified that is separate from thrombosis in relatives, or a serious disorder (e.g., antithrombin, protein S, protein C deficiency, or a combination of disorders), the use of Ladybon^® is contraindicated.

For women already receiving anticoagulant treatment, a careful benefit/risk assessment of HRT or tibolone use is required.

If VTE develops after starting treatment, the drug should be discontinued.

The patient should be informed of the need to immediately consult a doctor if symptoms of potential thromboembolism occur (e.g., pain and unilateral swelling of the lower limb, sudden chest pain, shortness of breath).

Coronary heart disease (CHD)

Randomized controlled trials have not provided evidence of protection against myocardial infarction in women with or without CHD who received combined HRT (estrogen/progestogen) or estrogen-only drugs.

Epidemiological studies using the GPRD database did not provide evidence of protection against myocardial infarction in postmenopausal women receiving 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 age-dependent, and therefore this effect of tibolone is greater with increasing age.

If unexplained migraine-like headaches with or without visual disturbances occur, a doctor should be consulted as soon as possible.

In this case, the drug should not be taken until the doctor confirms the safety of continuing HRT, as such headaches may be an early diagnostic sign of a possible stroke.

Other conditions

Available data indicate that tibolone use 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).

Total triglyceride and VLDL concentrations were also reduced.

The decrease in total cholesterol and VLDL cholesterol concentrations was not dose-dependent.

LDL cholesterol concentrations did not change.

The clinical significance of these data is not yet known.

Women with pre-existing hypertriglyceridemia should be under close medical supervision during the use of Ladybon^®, as rare cases of significant increases in plasma triglyceride concentrations, contributing to the development of pancreatitis, have been observed during estrogen therapy in this condition.

Tibolone treatment leads to a very small decrease in thyroxine-binding globulin (TBG) and total T₄.

Total T₃ concentration does not change.

Ladybon^® reduces the concentration of sex hormone-binding globulin (SHBG), whereas concentrations of corticosteroid-binding globulin (CBG) and circulating cortisol do not change.

The increased risk of developing dementia should be considered when initiating tibolone therapy in women over 65 years of age.

During the use of Ladybon^®, fluid retention may occur.

In this regard, careful monitoring of patients with cardiac or renal failure is necessary.

Effect on ability to drive vehicles and machinery

No negative effects of the drug on concentration and reaction, ability to drive vehicles and other machinery have been noted.

Overdose

If a large number of Ladybon^® tablets are taken simultaneously, the patient should consult a doctor.

Symptoms malaise, nausea or vaginal bleeding.

Treatment symptomatic.

Drug Interactions

Tibolone enhances the fibrinolytic activity of the blood, which may lead to an enhancement of the anticoagulant effect of anticoagulants, in particular warfarin, so the warfarin dose should be adjusted accordingly by INR.

Concomitant use of tibolone and anticoagulants should be monitored, especially at the beginning and end of treatment with Ladybon^®.

There is only limited information regarding pharmacokinetic interaction during tibolone treatment.

An in vivo study demonstrated that concomitant use with tibolone slightly affects the pharmacokinetics of the CYP3A4 substrate midazolam.

Based on this, a drug interaction with other CYP3A4 substrates is possible.

Drugs that are CYP3A4 inducers, such as barbiturates, carbamazepine, hydantoins and rifampicin, may increase the metabolism of tibolone and thus affect its therapeutic effect.

Preparations containing St. John’s wort (Hypericum perforatum) may enhance the metabolism of estrogens and progestogens by inducing the CYP3A4 isoenzyme.

Increased metabolism of estrogens and progestogens may lead to a decrease in their clinical effect and a change in the uterine bleeding profile.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.