Velledien (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

Contact Information

EXELTIS HEALTHCARE S.L. (Spain)

ATC Code

G03CX01 (Tibolone)

Active Substance

Tibolone (Rec.INN registered by WHO)

Dosage Form

Velledien

Tablets 2.5 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, round, flat-cylindrical.

Excipients: lactose monohydrate – 69.44 mg, microcrystalline cellulose – 17.36 mg, ascorbyl palmitate – 0.2 mg, corn starch – 10 mg, magnesium stearate – 0.5 mg.

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

Clinical-Pharmacological Group

Anticlimacteric estrogenic drug

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system, estrogens, other estrogens

Pharmacological Action

The drug selectively regulates estrogen-like activity in tissues and is a tissue-selective regulator. Its pharmacodynamic properties are determined by the action of three pharmacologically active metabolites of tibolone: 3-alpha-hydroxytibolone and 3-beta-hydroxytibolone have estrogen-like activity, while the delta-4-isomer has progestogen-like and weak androgen-like activity.

The drug replenishes estrogen deficiency in the postmenopausal period, alleviating symptoms associated with their deficiency – hot flashes, depression, night sweats, headache. It has a positive effect on libido and mood (increases the concentration of central and peripheral opioids). It has a trophic effect on the vaginal mucosa without causing endometrial proliferation. It prevents bone loss after menopause or oophorectomy. It reduces the concentration of phosphates and calcium in blood plasma.

Pharmacokinetics

After oral administration, Tibolone is rapidly and intensively absorbed. Food intake does not have a noticeable effect on the absorption of the drug.

Due to the rapid metabolism of tibolone, its concentration in blood plasma is very low. The concentration of the delta-4-isomer in blood plasma is also very low, so a number of pharmacokinetic parameters cannot be determined. The C_max in blood plasma of the metabolites 3-alpha-hydroxytibolone (3-α-OH) and 3-beta-hydroxytibolone (3-β-OH) is higher, but no accumulation occurs.

Table 1. Pharmacokinetic parameters of tibolone (dose 2.5 mg )

SD – single dose; MD – multiple dose.

Elimination of tibolone occurs mainly in the form of conjugated metabolites (mainly sulfated). Part of the administered tibolone is excreted by the kidneys, most of it – through the intestines.

The pharmacokinetic parameters of tibolone do not depend on kidney function.

Indications

• Treatment of symptoms of estrogen deficiency in women in the postmenopausal period (not earlier than 1 year after the last menstruation in case of natural menopause or immediately after surgical menopause);
• Prevention of postmenopausal osteoporosis in women at high risk of fractures in case of intolerance or contraindications to the use of other drugs intended for the treatment of osteoporosis.

ICD codes

Dosage Regimen

The drug is taken orally, 1 tablet/day, without chewing, with water, preferably at the same time, continuously.

The first tablet is taken from the cell of the upper row, marked with the day of the week corresponding to the day of starting the intake. All other tablets are taken sequentially from the cells in the direction of the arrow on the calendar packaging, until all tablets have been taken.

Starting Velledien

For the treatment of postmenopausal symptoms, Velledien should be used only for symptoms that adversely affect the woman’s quality of life. Velledien should be started no earlier than 12 months after the last menstruation in case of natural menopause. Patients with surgically induced menopause can start taking the drug immediately. In all cases, a thorough risk-benefit assessment should be performed at least once every 6 months, and the drug should be continued for the period when the benefit of therapy outweighs the risk.

Switching to Velledien after another hormone replacement therapy (HRT) drug

For women with an intact uterus when switching to Velledien after using another HRT drug containing only estrogens, it is recommended to first induce a withdrawal bleeding by using a progestogen to eliminate probable existing endometrial hyperplasia.

When switching from an HRT drug with a cyclic regimen, Velledien should be started the day after completing the progestogen intake.

If switching from a combined HRT drug with a continuous regimen, Velledien can be started at any time.

Missed dose

If a tablet is missed and less than 12 hours have passed since the missed time, the woman should take it as soon as possible on the same day. The next tablet is taken at the usual time of day.

If the delay in taking the tablet is more than 12 hours (the interval since the last tablet was taken is more than 36 hours), the missed tablet should not be taken, and the next tablet should be taken at the usual time.

Adverse Reactions

The following classification is used to determine the frequency of adverse drug effects: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000).

Gastrointestinal disorders: common – lower abdominal pain.

Skin and subcutaneous tissue disorders: common – increased hair growth, incl. on the face; uncommon – acne.

Reproductive system and breast disorders: common – vaginal discharge, increased endometrial thickness, vaginal spotting or bleeding, breast pain, genital itching, candidal vulvovaginitis, pelvic pain, cervical dysplasia, vulvovaginitis; uncommon – mycosis, breast engorgement, nipple soreness.

Laboratory and instrumental data: uncommon – weight increase; abnormal cervical smear results (deviation from normal cytological characteristics of cervical epithelium).

Most adverse effects were mild. The number of cases of cervical pathology (cervical cancer) did not increase with tibolone compared to placebo.

Other possible adverse effects may be (frequency not established): dizziness, headache, migraine; depression; skin rash, skin itching, seborrheic dermatitis; visual disturbances (including blurred vision); gastrointestinal disorders (diarrhea, flatulence); fluid retention, peripheral edema; joint and muscle pain; liver function disorders (including increased transaminase activity).

Risk of 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-only 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 (see section “Special Instructions”).

Table 2. Estimated additional risk of 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 endometrial cancer

The risk of endometrial cancer is about 5 cases per 1000 women with an intact uterus not receiving HRT or Tibolone.

The highest risk of endometrial cancer was observed in a randomized placebo-controlled study that included women who were not initially screened for endometrial pathology, thus the study design was close to clinical practice conditions (LIFT study, average age 68 years). In this study, no cases of endometrial cancer were diagnosed in the placebo group (n=1746) after 2.9 years of observation, 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 (see section “Special Instructions”).

Risk of ischemic stroke

The relative risk of ischemic stroke does not depend on age or duration of drug use, but the absolute risk is highly dependent on age. The overall risk of ischemic stroke in women taking Tibolone will increase with age (see section “Special Instructions”).

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%) strokes were ischemic.

The absolute risk of stroke is highly dependent on age. Thus, the absolute risk over 5 years 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 estrogen-only HRT drugs and combined (estrogen/progestogen) drugs have been noted

• Long-term use of estrogen-only HRT drugs 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 when taking tibolone is similar to the risk when using other HRT drugs;
• Taking 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 (see section “Special Instructions”).

Table 3. Additional risk of VTE with use for more than 5 years according to the Women’s Health Initiative study

* In women with a removed uterus.

CI – confidence interval.

• A slight increase in the risk of coronary heart disease (CHD) 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 of using other types of HRT.
• Gallbladder diseases (cholelithiasis, cholecystitis).
• Skin diseases: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
• Dementia when starting therapy over the age of 65 (see section “Special Instructions”).
• Pancreatitis.
• Increased blood pressure.

Contraindications

• Diagnosed (including in history) breast cancer or suspicion of it and diagnosed (including in history) estrogen-dependent malignant tumors (e.g., endometrial cancer) or suspicion of them;
• Vaginal bleeding of unknown etiology;
• Current or history of thrombosis (venous and arterial) and thromboembolism (including deep vein thrombosis and thrombophlebitis, pulmonary embolism), CHD, myocardial infarction, ischemic and hemorrhagic cerebrovascular disorders;
• Conditions preceding thrombosis (including transient ischemic attacks, current or history of angina pectoris);
• Identified predisposition to venous or arterial thrombosis, including activated protein C resistance, protein C deficiency, protein S deficiency or antithrombin III deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Multiple or pronounced risk factors for venous or arterial thrombosis, incl.:
  • Complicated heart valve lesions;
  • Atrial fibrillation;
  • Cerebrovascular or coronary artery diseases;
  • Uncontrolled arterial hypertension;
  • Major surgery with prolonged immobilization, extensive trauma;
  • Smoking over the age of 35;
  • Obesity with BMI>30 kg/m²;
• Current or history of malignant or benign tumors (incl. liver adenoma);
• Liver failure, acute liver disease or history of liver disease, after which liver function tests have not normalized;
• Porphyria;
• Otosclerosis that occurred during a previous pregnancy or with the use of hormonal contraceptive drugs in history;
• Chronic heart failure (III-IV FC);
• Cerebrovascular disorders;
• Period less than 1 year after the last menstruation;
• Untreated endometrial hyperplasia;
• Pregnancy;
• Breastfeeding period;
• Rare hereditary diseases (galactose intolerance, lactase deficiency or glucose-galactose malabsorption);
• Hypersensitivity to the drug or any of its components.

With caution

If any of the following conditions/diseases is currently present, was observed previously and/or worsened during pregnancy or previous hormone therapy, the patient should be under close medical supervision. It should be taken into account that these conditions/diseases may recur or worsen during treatment with Velledien, in particular

• Leiomyoma (uterine fibroids) or endometriosis;
• Cardiovascular insufficiency without signs of decompensation;
• Presence of risk factors for estrogen-dependent tumors (e.g., breast cancer in first-degree relatives);
• Controlled arterial hypertension;
• Hypercholesterolemia;
• Carbohydrate metabolism disorders, diabetes mellitus, both with and without complications;
• Cholelithiasis;
• Migraine or severe headache;
• Systemic lupus erythematosus;
• History of endometrial hyperplasia;
• Epilepsy;
• Bronchial asthma;
• renal failure;
• otosclerosis not associated with pregnancy or previous use of hormonal contraceptive drugs.

Use in Pregnancy and Lactation

Use of the drug is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic insufficiency, acute liver disease, or a history of liver disease after which liver function test indicators have not returned to normal.

Use in Renal Impairment

Use with caution in renal failure.

Geriatric Use

There is evidence of an increased risk of possible development of dementia in women when starting continuous therapy with estrogen-only HRT drugs at the age of 65 years or older.

Special Precautions

The drug Velledien is not intended for use as a contraceptive and does not protect against unwanted pregnancy.

The decision to start taking Velledien should be based on a benefit/risk assessment taking into account all individual risk factors, and in women over 60 years of age, the increased risk of stroke development should also be taken into account.

For the treatment of postmenopausal symptoms, Velledien 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 performed at least once a year, and Velledien should be continued only if 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 (see the “Adverse Reactions” section), taking into account all individual risk factors, the incidence and characteristics of both types of cancer and stroke in terms of curability, morbidity and mortality.

Evidence on 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 level of absolute risk in younger women.

Medical examination/monitoring

Before starting or resuming Velledien, a personal and family medical history should be collected.

A physical examination (including pelvic and breast examination) should be performed taking into account the history, absolute and relative contraindications. During treatment with the drug, preventive follow-up examinations are recommended, the frequency and nature of which are determined by the individual characteristics of the patient, but not less than once every 6 months. In particular, the woman should be informed of the need to report any breast changes to the doctor.

Examinations, including appropriate imaging methods, such as mammography, should be performed in accordance with the currently accepted examination scheme, adapted to the clinical needs of each patient, but not less than once every 6 months.

Reasons for immediate discontinuation of the drug and urgent medical consultation

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

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

Endometrial hyperplasia and cancer

Observational study data have shown an increased risk of developing endometrial hyperplasia or cancer in women taking Tibolone. 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 taking tibolone, “breakthrough” bleeding and spotting may occur.

If spotting/bleeding occurs while taking Velledien, which

– continues for more than 6 months from the start of taking the drug,

– starts 6 months after starting the drug and continues even after its discontinuation,

The woman should consult a doctor – this may be a sign of endometrial hyperplasia.

Breast cancer

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

According to the “Million Women Study”, a significant increase in the risk of developing breast cancer was found when using tibolone at a dose of 2.5 mg (see the “Adverse Reactions” section). This risk became apparent after several years of drug use and increased with the duration of use, returning to the baseline level several years (usually after 5 years) after discontinuation of the drug.

These results were not confirmed in a study using the General Practice Research Database (GPRD).

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Long-term (at least 5-10 years) estrogen-only replacement therapy has been associated with a slight increase in the risk of 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 when using tibolone was similar to the risk associated with the use of other types of HRT.

Venous thromboembolism

Estrogen-only HRT drugs or combined HRT drugs containing estrogen and progestogen may increase the risk of VTE (deep vein thrombosis or pulmonary embolism) by 1.3-3 times, especially during the first year of using HRT drugs (see the “Adverse Reactions” section).

Data on the increased risk of VTE when using tibolone are insufficient, but 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 VTE and taking Velledien may increase this risk, so the use of the drug in this patient population is contraindicated (see the “Contraindications” section).

Risk factors for VTE include the use of estrogens, old age, major surgery, prolonged immobilization, obesity (BMI>30 kg/m²), pregnancy and the postpartum period, systemic lupus erythematosus and cancer.

Particular attention should be paid to preventive measures to prevent the development of thrombosis and VTE in the postoperative period. It is recommended to discontinue therapy with Velledien 4-6 weeks before surgery if prolonged bed rest is expected thereafter. 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 that is separate from thrombosis in relatives, or a serious disorder (e.g., antithrombin III deficiency, protein S, protein C deficiency, or a combination of disorders) is detected, taking Velledien is contraindicated.

Before prescribing tibolone to women receiving anticoagulants, the physician should carefully assess the benefit/risk ratio of using HRT or tibolone.

If VTE develops after starting treatment, the drug must be discontinued. The woman should be informed of the need to immediately consult a doctor if symptoms of potential thromboembolism appear (pain and unilateral swelling of the lower limb, sudden chest pain, shortness of breath).

Coronary artery disease

Randomized controlled trials have not provided evidence of protection against myocardial infarction in women with or without CAD who received combined HRT (estrogen/progestogen) or estrogen-only HRT drugs. Epidemiological studies using the GPRD database did not provide evidence of protection against myocardial infarction in postmenopausal women receiving Tibolone.

Velledien or any other HRT drugs should not be used for the prevention of cardiovascular diseases.

Ischemic stroke

Taking tibolone increases the risk of ischemic stroke, starting from the first year of use (see the “Adverse Reactions” section). The absolute risk of stroke is strictly age-dependent, and therefore this effect of tibolone is greater the older the 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

According to available data, the use of tibolone led to a significant dose-dependent decrease in HDL (high-density lipoprotein) cholesterol (from 16.7% at a dose of 1.25 mg to 21.8% at a dose of 2.5 mg after 2 years of use).

The total concentration of triglycerides and lipoproteins decreased. The decrease in the concentration of total cholesterol and VLDL (very low-density lipoprotein) cholesterol was not dose-dependent. The concentration of LDL (low-density lipoprotein) cholesterol did not change. The clinical significance of these data is not yet known.

Estrogens can cause fluid retention, so patients with heart or kidney failure should be under close medical supervision.

Women with pre-existing hypertriglyceridemia should be under close medical supervision during therapy with tibolone, as rare cases of a significant increase in plasma triglyceride concentrations, contributing to the development of pancreatitis, have been noted during estrogen therapy in this condition.

Taking tibolone may cause a slight decrease in the plasma concentration of thyroxine-binding globulin (TBG) and total T₄. The concentration of total T₃ does not change. Tibolone reduces the concentration of sex hormone-binding globulin (SHBG) but does not affect the concentration of corticosteroid-binding globulin (CBG) and free cortisol.

The use of HRT drugs does not improve cognitive function. There is evidence of an increased risk of possible development of dementia in women when starting continuous therapy with estrogen-only HRT drugs at the age of 65 years or older (see the “Adverse Reactions” section).

Effect on ability to drive vehicles and operate machinery

No effect of tibolone on concentration and the ability to drive vehicles and other machinery has been noted.

Overdose

The acute toxicity of tibolone in animals is very low, so toxic symptoms are not to be expected, even if the patient has taken several tablets at the same time.

Symptoms in cases of acute overdose may include nausea, vomiting and vaginal bleeding.

Treatment no antidote is known. Symptomatic therapy is recommended.

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 dose of warfarin should be adjusted appropriately according to the INR (international normalized ratio).

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

There is only limited information regarding pharmacokinetic interactions during treatment with tibolone. An in vivo study demonstrated that co-administration with tibolone slightly affects the pharmacokinetics of the cytochrome P4503A4 substrate midazolam. Based on this, a drug interaction with other CYP3A4 substrates is possible. CYP3A4-inducing drugs (barbiturates, carbamazepine, hydantoin derivatives, rifampicin) when used concomitantly may increase the metabolism of tibolone and thus affect its therapeutic effect.

Drugs 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 – 3 years. Do not use the drug after the expiration date.

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.