Welledien - Instructions For Use, Reviews, Price, Drug Analogues

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Velledien

Welledien: instructions for use and reviews

1. 1. Release form and composition
2. 2. Pharmacological properties
3. 3. Indications for use
4. 4. Contraindications
5. 5. Method of application and dosage
6. 6. Side effects
7. 7. Overdose
8. 8. Special instructions
9. 9. Application during pregnancy and lactation
10. 10. In case of impaired renal function
11. 11. For violations of liver function
12. 12. Drug interactions
13. 13. Analogs
14. 14. Terms and conditions of storage
15. 15. Terms of dispensing from pharmacies
16. 16. Reviews
17. 17. Price in pharmacies

Latin name: Velledien

ATX code: G03CX01

Active ingredient: Tibolone (Tibolone)

Manufacturer: Laboratorios Leon Pharma S. A. (Laboratorios Leon Farma, SA) (Spain)

Description and photo update: 2019-11-07

Prices in pharmacies: from 790 rubles.

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Wellediene is an anti-climacteric estrogenic drug.

Release form and composition

Dosage form - tablets: white, flat-cylindrical, round (in a cardboard box 1 blister containing 28 tablets, and instructions for the use of Welledien).

Composition of 1 tablet:

• active substance: tibolone - 2.5 mg;
• auxiliary components: corn starch - 10 mg; lactose monohydrate - 69.44 mg; magnesium stearate - 0.5 mg; ascorbyl palmitate - 0.2 mg; microcrystalline cellulose - 17.36 mg.

Pharmacological properties

Pharmacodynamics

Wellediene is a tissue-selective regulator, since it selectively regulates estrogen-like activity in tissues. Pharmacodynamic properties of the drug are determined by the action of three pharmacologically active metabolites of tibolone - 3-alpha-hydroxytibolone, 3-beta-hydroxytibolone and delta-4-isomer. The first and second metabolites have estrogen-like activity, the third - progestogen-like and weak androgen-like activity.

Taking the drug in the postmenopausal period replenishes estrogen deficiency and relieves the associated symptoms - headache, depression, increased sweating and hot flashes.

Vellediene increases the concentration of peripheral and central opioids, which has a beneficial effect on libido and mood. Taking it after removal of the ovaries or the onset of menopause prevents bone loss. The drug, without causing endometrial proliferation, has a trophic effect on the vaginal mucosa. Reduces the concentration of calcium and phosphate in blood plasma.

Pharmacokinetics

After oral administration of Velledien, the absorption of tibolone occurs quickly and intensively, food intake does not have a noticeable effect on the process.

Due to its rapid metabolism, the concentration of tibolone in the blood plasma is very low, as well as the delta-4 isomer, which makes it impossible to determine a number of pharmacokinetic parameters. The maximum concentration of metabolites of 3-alpha-hydroxytibolone and 3-beta-hydroxytibolone in blood plasma is higher, but no cumulation occurs.

Pharmacokinetic parameters of a single dose of tibolone (dose 2.5 mg) / 3-alpha-hydroxytibolone / 3-beta-hydroxytibolone / delta-4-isomer and multiple dose of tibolone (dose 2.5 mg) / 3-alpha-hydroxytibolone / 3- beta-hydroxytibolone / delta-4-isomer are respectively:

• C _max - maximum concentration (ng per 1 ml): 1.37 / 14.23 / 3.43 / 0.47 and 1.72 / 14.15 / 3.75 / 0.43;
• C _s - average concentration: - / - / - / - and - / 1.88 / - / -;
• T _Cmax - time to reach the maximum concentration (h): 1.08 / 1.21 / 1.37 / 1.64 and 1.19 / 1.15 / 1.35 / 1.65;
• T _1/2 - half-life (h): - / 5.78 / 5.87 / - and - / 7.71 / - / -;
• C _min - the minimum concentration (ng per 1 ml): - / - / - / - and - / 0.23 / - / -;
• AUC - area under the curve (ng per 1 ml per hour): - / 53.23 / 16.23 / - and - / 44.73 / 9.2 / -.

Tibolone is excreted in the form of conjugated, mainly sulfated, metabolites. After oral administration, it is partially excreted by the kidneys, but most of it is excreted through the intestines. Renal function does not affect its pharmacokinetic parameters.

Indications for use

• therapy of manifestations of estrogen deficiency in postmenopausal women (immediately after surgical menopause or after at least 12 months after the last menstruation with the onset of natural menopause);
• prevention of postmenopausal osteoporosis in patients with a high risk of fractures who have intolerance or contraindications to the use of other drugs for the treatment of osteoporosis.

Contraindications

Absolute:

• liver failure, acute liver pathology or a history of liver disease, after which the indicators of liver function tests did not return to normal;
• cerebrovascular disorders, chronic heart failure (III-IV functional class);
• untreated endometrial hyperplasia;
• vaginal bleeding of unknown origin;
• otosclerosis that developed against the background of previous use of hormonal contraceptives or during pregnancy;
• porphyria;
• diagnosed or suspected (including a history of) estrogen-dependent malignant tumors and breast cancer;
• benign / malignant neoplasms currently or in history (including liver adenoma);
• conditions that precede thrombosis, including angina pectoris and transient ischemic attacks, present or in history;
• hemorrhagic and ischemic cerebrovascular disorders, myocardial infarction, ischemic heart disease, venous and arterial thrombosis and thromboembolism at present or in history, including pulmonary embolism, thrombosis and deep vein thrombophlebitis;
• identified predisposition to arterial or venous thrombosis, including the presence of antibodies to phospholipids (to cardiolipin - lupus anticoagulant), resistance to activated protein C, deficiency of protein C, antithrombin III or protein S;
• severe / multiple risk factors for arterial or venous thrombosis, including pathologies of the vessels of the coronary arteries and / or the brain, uncontrolled arterial hypertension, atrial fibrillation, complicated lesions of the valvular apparatus of the heart;
• extensive trauma, extended surgery with prolonged immobilization, obesity with a body mass index of more than 30 kg per 1 m ², smoking over the age of 35;
• glucose-galactose malabsorption, lactase deficiency or galactose intolerance;
• a period less than 12 months from the last menstrual period;
• pregnancy and lactation;
• individual intolerance to the components of the drug.

Relative (Velledien tablets are used under the close supervision of a physician if there are currently or have a history of certain conditions / diseases, their exacerbation against the background of previous hormone therapy or during pregnancy; it should be borne in mind that drug therapy can lead to relapse or exacerbation):

• renal failure;
• cardiovascular failure without signs of decompensation;
• a history of endometrial hyperplasia;
• endometriosis or uterine fibroma (leiomyoma);
• controlled arterial hypertension;
• cholelithiasis;
• hypercholesterolemia;
• disorders of carbohydrate metabolism, diabetes mellitus (in the presence / absence of complications);
• bronchial asthma;
• epilepsy;
• systemic lupus erythematosus;
• migraine or severe headache;
• otosclerosis that is not associated with previous use of hormonal contraceptives or pregnancy;
• the presence of risk factors for the formation of estrogen-dependent tumors (breast cancer in first-degree relatives).

Welledien, instructions for use: method and dosage

Welledien tablets are taken orally without chewing with water.

Recommended dosage: 1 pc. a day at the same time, continuously.

The first pill is taken from the top row cell, which is marked with the day of the week corresponding to the day of initiation of therapy. The rest of the tablets are taken sequentially from the cells in the direction of the arrow on the calendar package, to the last piece.

It is recommended to start taking Velledien for the treatment of postmenopausal manifestations only if symptoms appear that worsen the patient's quality of life.

With menopause due to surgery, Velledien can be used immediately. In natural menopause, at least 12 months should elapse from the last menstrual period to the first pill. In both cases, it is recommended to carefully assess the risks and benefits of therapy at least once every 6 months and to continue taking Wellediene in the time interval when the benefits of its use outweigh the potential risks.

Switching from another medication for hormone replacement therapy (HRT) to Welledien:

• preparations containing only estrogens: in order to eliminate the likely existing endometrial hyperplasia, patients with an intact uterus are advised to first cause menstrual bleeding with withdrawal by using a progestogen;
• combined funds with a continuous regimen of administration: drug therapy can be started at any time;
• cyclic drugs: Welledien can be used the day after the last dose.

If you skip taking Velliene or violate the drug intake regimen:

• less than 12 hours: the missed pill is drunk as early as possible on the same day, the next one - at the usual time of the day;
• more than 12 hours (the interval from the moment of taking the last pill is more than 36 hours): the missed dose is not taken, the next pill is drunk at the usual time.

Side effects

Possible adverse reactions [> 10% - very common; (> 1% and 0.1% and 0.01% and <0.1%) - rarely; <0.01%, including isolated messages - very rare]:

• gastrointestinal tract (GIT): often - pain in the lower abdomen;
• skin and subcutaneous tissue: often - increased hair growth, including on the face; infrequently - acne;
• reproductive system and mammary glands: often - vulvovaginitis, including candidiasis, pelvic pain, cervical dysplasia, genital itching, increased thickness of the endometrium, bleeding or vaginal discharge (including bloody), pain in the mammary glands; infrequently - soreness of the nipples, engorgement of the mammary glands, mycosis;
• laboratory and instrumental studies: infrequently - deviations in the results of a smear from the cervix, an increase in body weight;
• others: frequency not established - seborrheic dermatitis, skin rash or itching, migraine, headache, dizziness, gastrointestinal disorders (flatulence, diarrhea), visual impairment, including blurred vision, depression, muscle and joint pain, peripheral edema, delay body fluids, liver dysfunction, including increased transaminase activity.

In most cases, side effects were mild. Taking tibolone compared with placebo was not accompanied by an increase in the incidence of cervical diseases, including cancer.

The risk of developing breast cancer

In patients who received therapy with combined drugs (estrogen / gestagen) for more than 5 years, the frequency of diagnosing breast malignant neoplasms doubled.

While taking estrogen or tibolone, any increased risk is significantly lower than that with combination therapy (estrogen / progestogen). The duration of treatment affects the level of risk (upward).

According to the Million Women Study, the estimated additional risk of developing breast cancer after 5 years of using HRT only with estrogen / combined (estrogen / gestagen) drugs / tibolone in patients aged 50 to 65 years is:

• additional cases per 1000 women who have not previously received HRT, over a period of 5 years: 9-12 / 9-12 / 9-12;
• total hazard ratio (non-constant value, increasing with increasing duration of treatment), confidence interval (CI) 95%: 1.2 / 1.7 / 1.3;
• additional cases per 1000 patients previously treated with HRT over a period of more than 5 years, 95% CI: 1-2 (0-3) / 6 (5-7) / 3 (0-6).

Endometrial cancer risk

For 1000 women with an unremoved uterus who did not receive tibolone or HRT, the risk of developing endometrial cancer is about 5 cases.

The highest risk of endometrial malignant tumors was observed in a randomized, placebo-controlled study. It included patients who at the initial stage were not examined for the presence of endometrial diseases. Thus, its design was close to the conditions of clinical practice (LIFT study, the average age of women was 68 years).

In the course of this study, no cases of endometrial malignancy were detected in the placebo group (n = 1746) after follow-up for 2.9 years, while in the group receiving tibolone (n = 1746) there were 4 such cases. This corresponds to the diagnosis 0.8 additional cases of endometrial cancer per 1000 patients who received tibolone in this study for 12 months.

The risk of ischemic stroke

Age or duration of drug intake does not affect the relative risk of ischemic stroke, however, the absolute risk indicator strongly depends on age. In patients receiving tibolone, the overall risk of pathology will increase with age.

In a 2.9-year randomized controlled trial, it was found that taking tibolone at a dose of 1.25 mg in patients of 68 years (mean age) compared with the group receiving placebo led to an increased risk of stroke by 2.2 times. In 80% of cases, strokes were ischemic.

The absolute risk of the onset of the disease in 5 years per 1000 women, depending on age, is: 50–59 years - 3 cases; 60–69 years - 11 cases.

For every 1000 patients receiving tibolone for 5 years, between the ages of 50 and 59, about 4 additional cases can be expected, and 13 additional cases between the ages of 60 and 69.

Other risks

Other adverse events associated with the use of drugs for HRT, which contain only estrogen, and combined (estrogen / gestagen) drugs are:

• cholecystitis, gallstone disease (pathology of the gallbladder);
• increased blood pressure (BP);
• vascular purpura, erythema multiforme and nodosum, chloasma, pancreatitis;
• dementia (in patients who were 65 years old at the beginning of therapy);
• venous thromboembolism (VTE);
• ovarian cancer;
• ischemic heart disease (CHD).

Long-term therapy with drugs for HRT (combined or containing only estrogen) was associated with a slight increase in the risk of ovarian malignant tumors. According to the Million Women Study, for every 2500 patients who received HRT for 5 years, there is 1 additional case of oncology. This study revealed that the relative risk of developing ovarian cancer while taking tibolone is similar to that when using other drugs for HRT.

The risk of coronary artery disease is slightly increased in women over 60 years of age who receive combined HRT. There is no reason to believe that this risk is different when taking tibolone.

Treatment with tibolone, often in the first year of admission, is accompanied by an increase in the relative risk of VTE (pulmonary thromboembolism, deep vein thrombosis) by 1.3–3 times.

According to the study "Women's Health Initiative", the additional risk of VTE in patients 50–59 years old who have been taking only estrogen orally for more than 5 years (women with a removed uterus) / estrogen + progestogen combination is:

• the incidence of disease per 1000 patients, in the placebo group over 5 years: 7/4;
• risk ratio (CI 95%): 1.2 (0.6–2.4) / 2.3 (1.2–4.3);
• additional cases per 1000 patients previously receiving HRT: 1 (3-10) / 5 (1-13).

Overdose

• symptoms of tibolone overdose: since the acute toxicity of the substance is very low, even when several tablets are taken simultaneously, toxic symptoms are not observed. In acute overdose, vaginal bleeding, nausea and vomiting may occur;
• therapy: no antidote, symptomatic treatment is indicated.

special instructions

It should be borne in mind that Velledien does not protect against unwanted pregnancy and is not intended to be used as a contraceptive.

The decision to start taking pills should be based on the ratio of the possible benefits to the potential risks, taking into account all individual risk factors, and in patients aged 60 years and older, taking into account the increased risk of stroke.

The drug for the treatment of postmenopausal symptoms is required to be used only in relation to manifestations that worsen the woman's quality of life. At least once every 12 months in all cases, a thorough assessment of the risk and benefit of treatment should be carried out, and continue taking the pills only if the benefit outweighs the risk.

In each patient with an intact uterus, a thorough assessment of the likelihood of developing a stroke, the formation of endometrial and breast malignant tumors is recommended, as well as taking into account all individual risk factors, the incidence and characteristics of stroke / both types of cancer in terms of curability, morbidity and mortality.

The evidence for the relative risk associated with tibolone or HRT in premature menopause is limited. Since the level of absolute risk increases with age, the ratio of potential risks / benefits in patients with premature menopause may be more favorable than in older women.

Before starting treatment or before resuming therapy, the doctor must collect a medical history (individual and family). Taking into account absolute / relative contraindications and history data, a physical examination should be performed, including the mammary glands and pelvic organs. During the period of taking Velledien, it is recommended to carry out preventive repeated examinations. Their nature and frequency are determined taking into account the individual characteristics of the patient, but they are carried out at least once every six months. A woman should be warned that if changes in the mammary glands are detected, she should inform her doctor about it.

Mammography and other imaging methods are required to be performed in accordance with the currently accepted examination scheme, which is adapted to the clinical characteristics of each patient, but at least once every six months.

Immediate cancellation of Welledien is necessary if contraindications are found and / or the development of conditions / pathologies such as:

• migraine-type headache;
• worsening liver function or jaundice;
• a sudden increase in blood pressure, which differs from the usual, characteristic of the patient, blood pressure indicators.

According to observational studies, taking Welledien increases the risk of endometrial hyperplasia and cancer. An increase in the duration of treatment increases the risk of developing endometrial malignant neoplasms.

With tibolone therapy, the thickness of the endometrium may increase, which is measured by transvaginal ultrasound.

During the first months of using the drug, spotting and breakthrough bleeding may occur. The patient should seek medical help if these symptoms are observed for more than six months from the start of therapy, or occur after six months after its start and continue even after the discontinuation of Velledien, since they may indicate endometrial hyperplasia.

From the point of view of evidence-based medicine, the available data from various clinical studies regarding the risk of the formation of malignant breast tumors while taking the drug are contradictory, which requires further research.

According to the Million Women Study, a significant increase in the risk of breast cancer was noted with 2.5 mg tibolone. This risk became apparent after several years of therapy and increased with an increase in its duration, returning to the initial level several years after its cancellation (most often after 5 years). The reported results were not validated in a general practice database (GPRD) study.

Significantly less often breast cancer is diagnosed with ovarian oncology. With prolonged (at least 5–10 years) estrogen replacement monotherapy, the risk of ovarian cancer increased insignificantly.

The Women's Health Initiative and other studies suggest that long-term use of combination HRT can be associated with a similar or slightly lower risk. The "Million Women Study" showed that the relative risk of ovarian cancer with tibolone is similar to that of other types of HRT.

Combined or containing only estrogens for HRT can increase the possibility of developing VTE by 1.3–3 times, especially during the first year of treatment.

There are insufficient data indicating an increase in the likelihood of developing VTE when taking Velledien, but it is impossible to exclude a slight increase in risk in comparison with patients who did not take the drug.

Women with known thrombophilic conditions have an increased chance of developing VTE. Taking the drug can increase this risk, and therefore its use in such cases is contraindicated.

Risk factors for VTE include:

• prolonged immobilization;
• extensive surgical intervention;
• obesity (body mass index exceeds 30 kg per 1 m ²);
• systemic lupus erythematosus;
• crayfish;
• the use of estrogens;
• pregnancy, postpartum period;
• elderly age.

Preventive measures aimed at preventing the development of thrombosis and VTE in the postoperative period are of great importance. If in the future long-term adherence to bed rest is expected, the drug Velledien is canceled 28-42 days before the operation. Until the woman's motor activity is restored, therapy cannot be resumed.

Patients who do not have a history of VTE but are first-degree related to those with a history of thrombosis at a young age may be offered screening. Reception of Welledien is contraindicated in cases of detection of a thrombophilic condition, isolated from thrombosis in relatives, or a serious disorder (for example, a deficiency of protein C, protein S, antithrombin III, or a combination of disorders).

For patients taking anticoagulants, Velledien can be prescribed only after assessing the balance of benefits with risks from taking HRT or tibolone.

With the development of VTE against the background of initiation of therapy with Velledien, the course is stopped. Women should take into account that if shortness of breath, sudden chest pain, unilateral edema or pain in the lower limb (signs of potential thromboembolism) occurs, they should immediately consult a doctor.

In the course of randomized controlled trials, there was no evidence of protection against myocardial infarction in women with or without coronary artery disease who received HRT (combined or containing only estrogen drugs). Epidemiological studies using the GPRD database did not provide evidence of protection against myocardial infarction in patients taking tibolone in postmenopausal women.

Like any other medicine for HRT, Velledien cannot be used to prevent diseases of the cardiovascular system.

From the first year of taking tibolone, the risk of ischemic stroke increases. The absolute risk of developing pathology strictly depends on the age of the patient, therefore, this effect is the greater, the older the woman is.

The appearance of unexplained migraine-like headaches with or without visual impairment is a reason for an emergency visit to a doctor. Such headaches can be an early symptom of a possible stroke; therefore, tablets are not taken until the doctor confirms the safety of continuing HRT.

The use of tibolone led to a significant dose-dependent decrease in high-density lipoprotein cholesterol, reduced the total concentration of triglycerides and lipoproteins. There was no dose-dependent decrease in the concentration of very low density lipoprotein cholesterol and total cholesterol. There were no changes in the concentration of low-density lipoprotein cholesterol.

Careful medical supervision during treatment is required in the presence of the following diseases / conditions:

• heart or kidney failure: estrogens can lead to fluid retention in the body;
• hypertriglyceridemia: in rare cases, estrogens can significantly increase the concentration of triglycerides in the blood plasma, which contributes to the occurrence of pancreatitis.

Wellediene does not affect the concentration of total T3, free cortisol and CGS (corticosteroid-binding globulin), however, it can reduce the concentration of globulin that binds sex hormones, slightly lower the concentration of total T4 and thyroxine-binding globulin in blood plasma.

There is no improvement in cognitive function while taking HRT drugs. In women over the age of 65, at the beginning of continuous use of estrogen-only HRT drugs, the risk of possible dementia is increased.

Application during pregnancy and lactation

Vellediene is not prescribed during pregnancy / lactation.

With impaired renal function

Velledien is prescribed with caution to patients with renal failure.

For violations of liver function

Wellediene is not used for liver adenoma (currently or in history), liver failure, acute disease or liver pathology in history, after which the indicators of organ function tests did not normalize.

Drug interactions

Since tibolone enhances the fibrinolytic activity of the blood, it is possible to enhance the anticoagulant effect of warfarin (anticoagulants) when used simultaneously. In this regard, the dose of the second is appropriately adjusted according to the international normalized ratio. The combined intake of Velledien with anticoagulants should be monitored, especially at the beginning and at the end of treatment first.

There is limited information on the pharmacokinetic interaction with tibolone therapy.

According to in vivo studies, tibolone has a small effect on the pharmacokinetics of the cytochrome P4503A4 substrate midazolam. Based on this, drug interactions may occur with other CYP3A4 substrates. Rifampicin, hydantoin derivatives, carbamazepine, barbiturates (drugs-inductors of CYP3A4), when used together, can increase the metabolism of tibolone and, therefore, influence its therapeutic effect.

Medicines containing St. John's wort can increase the metabolism of estrogens and progestogens through the induction of the isoenzyme CYP3A4.

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

Analogs

Equivalents of Welledien are Livial, Ladybon.

Terms and conditions of storage

Store in a place protected from light and moisture at temperatures up to 25 ° C. Keep out of the reach of children.

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Wellediene

According to a few reviews, Velledien is a safe and effective drug used for the manifestation of estrogen deficiency in the postmenopausal period. Among the shortcomings, women note the appearance of spotting vaginal discharge.

Price for Welledien in pharmacies

The approximate price for Velledien, 2.5 mg tablets, per pack containing 28 pcs. Is 1,014 rubles.

Welledien: prices in online pharmacies

Drug name Price Pharmacy

Velledien 2.5 mg tablets 28 pcs. RUB 790 Buy

Velledien tablets 2.5mg 28 pcs. 795 RUB Buy

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!