Espa-Tibol tablets 2.5 mg blister No. 28

Instructions for Espa-Tibol tablets 2.5 mg blister No. 28

Composition

active ingredient: tibolone; 1 tablet contains tibolone 2.5 mg;

excipients: potato starch, magnesium stearate, ascorbyl palmitate, lactose monohydrate.

Dosage form

Pills.

Main physicochemical properties: white or almost white round tablets.

Pharmacotherapeutic group

Hormones of the sex glands and drugs used in the pathology of the genital area. Estrogens.

ATX code G03C X01.

Pharmacological properties

Pharmacodynamics

After oral administration, tibolone is rapidly metabolized into three components that influence the pharmacodynamic profile of ESPA-TIBOL®. Two of these metabolites (3α-OH-tibolone and 3β-OH-tibolone) exhibit estrogen-like activity, while the third metabolite (Δ4-isomer of tibolone) exhibits progestogen-like and androgen-like activity.

ESPA-TIBOL® replaces the loss of estrogen production in postmenopausal women and relieves symptoms caused by menopause.

Pharmacokinetics

After oral administration of tibolone, the drug is rapidly and extensively absorbed.

Due to rapid metabolism, tibolone plasma levels are very low. Plasma levels of the Δ4-isomer of tibolone are also very low. Therefore, some pharmacokinetic parameters cannot be determined. Peak plasma levels of the 3α-OH and 3β-OH metabolites are high, but accumulation does not occur.

SDU = single dose; MD = multiple dose

Tibolone is excreted mainly in the form of conjugated (mainly sulfated) metabolites. Some of the administered drug is excreted in the urine, but most is excreted in the feces.

Food intake does not have a significant effect on the absorption of the drug.

According to observations, the pharmacokinetic parameters of tibolone and its metabolites do not depend on renal function.

Indication

Treatment of symptoms of estrogen deficiency in postmenopausal women if menopause occurred more than 1 year ago.

The decision to prescribe tibolone should be based on an assessment of individual risk factors; when prescribing the drug to patients aged 60 years and older, the risk of stroke should be taken into account.

Contraindication

Hypersensitivity to the active substance or to any of the excipients.

Pregnancy and breastfeeding.

Suspected, current or past breast cancer (the drug increased the risk of breast cancer recurrence in a placebo-controlled study).

Suspected or existing estrogen-dependent tumors (e.g., endometrial cancer).

Vaginal bleeding of unknown etiology.

Untreated endometrial hyperplasia.

Venous thromboembolism in history or at present (deep vein thrombosis, pulmonary embolism).

History of arterial thromboembolic disease (e.g. angina pectoris, myocardial infarction, stroke or transient ischemic attack).

Acute liver disease or history of liver disease, until liver function tests return to normal.

Porphyria.

Interaction with other medicinal products and other types of interactions

Since tibolone may increase the fibrinolytic activity of the blood, this may enhance the effectiveness of anticoagulants. This effect has been observed with warfarin. Therefore, when tibolone is used concomitantly with anticoagulants, careful monitoring of the patient is necessary, especially at the beginning of treatment and when stopping treatment. If necessary, the dose of warfarin should be adjusted.

Information on pharmacokinetic interactions with tibolone is limited. An in vivo study showed that co-administration with tibolone may have a modest effect on the pharmacokinetics of the cytochrome P450 3A4 substrate midazolam. Based on these data, interactions with other CYP3A4 substrates can be expected.

Substances that induce CYP3A4, such as barbiturates, carbamazepine, hydantoins and rifampicin, may increase the metabolism of tibolone and thus affect its therapeutic efficacy.

Herbal preparations containing St. John's wort (Hypericum Perforatum) may stimulate the metabolism of estrogens and progestogens.

Clinically increased metabolism of estrogens and progestogens may lead to reduced efficacy and changes in the uterine bleeding profile.

Application features

In the treatment of postmenopausal symptoms, tibolone should only be used to treat symptoms that have a negative impact on quality of life. In all cases, a careful risk-benefit assessment should be performed at least annually. Tibolone should only be used if the benefits outweigh the risks.

Every woman should be carefully assessed for the risks of stroke, breast cancer, and in women with an intact uterus, the risk of endometrial cancer.

Before initiating or reinstituting hormone replacement therapy, including tibolone therapy, the physician should take a complete personal and family medical history and perform a physical examination (including pelvic and breast examination). Periodic examinations are recommended during treatment, as appropriate for the individual woman. Women should be advised to report any changes in their breasts to their physician. Screening, including mammography, should be performed according to current accepted screening guidelines, taking into account the clinical needs of each patient.

Conditions that require observation

If any of the following conditions or diseases are present or have been present and/or have deteriorated during pregnancy or previous hormone therapy, patients should be closely monitored. It should be noted that certain conditions may recur or worsen during treatment with tibolone, including:

Leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders; risk factors for estrogen-dependent tumors, such as 1st degree heredity for breast cancer; hypertension; impaired liver function (e.g., hepatic adenoma); diabetes mellitus with or without vascular pathology; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; history of endometrial hyperplasia; epilepsy; asthma; otosclerosis.

Reasons for immediate discontinuation of therapy

Therapy should be discontinued if contraindications are identified and in the following situations:

jaundice or worsening of liver function; significant increase in blood pressure; new attacks of migraine-like headaches.

Endometrial cancer

The available data from randomized, controlled trials are conflicting. However, observational studies have shown that women who were treated with tibolone in routine clinical practice had an increased risk of endometrial cancer. According to these studies, the risk increased with increasing duration of use. Tibolone increased the thickness of the endometrial wall as measured by transvaginal ultrasound.

During the first months of treatment, breakthrough bleeding and spotting may occur. Patients should be advised to report any breakthrough bleeding or spotting to their doctor if such symptoms persist after 6 months of treatment or after discontinuation of treatment. To determine the cause, the patient should undergo a gynecological examination, which may include endometrial biopsy to exclude endometrial malignancy.

Ovarian cancer

Ovarian cancer is much less common than breast cancer. Long-term (at least 5-10 years) use of monoestrogenic HRT has been shown to be associated with a small increased risk of ovarian cancer. Some studies, such as the Women's Health Initiative (WHI), have suggested that long-term use of combined HRT may have a similar or slightly lower risk. The Million Women Study found that the relative risk of ovarian cancer associated with tibolone was similar to that associated with other types of HRT.

Breast cancer

A meta-analysis of epidemiological studies, including the Million Women Study, has shown a significantly increased risk of breast cancer associated with the 2.5 mg dose. The risk was apparent within 3 years of use and increased with duration of use. After discontinuation of treatment, the additional risk decreases over time, and the time taken to return to baseline risk will depend on the duration of HRT use. When HRT is continued for more than 5 years, the increased risk may persist for 10 years or more.
There is no evidence for tibolone that the increased risk persists after discontinuation, but such dependence cannot be ruled out.

Estrogen or combined estrogen-progestogen hormone replacement therapy is associated with an increased relative risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. In randomized, controlled clinical trials and epidemiological studies, a 2- to 3-fold increased risk was found in women who underwent treatment. In 1000 women who had not used the drug for 5 years, about 3 cases of VTE occurred in the age group 50-59 years and 8 cases in the age group 60-69 years. In 1000 healthy women who had used the drug during hormone replacement therapy for 5 years, an additional 2 to 6 cases of VTE occurred in the age group 50-59 years and 5 to 15 cases in the age group 60-69 years. The incidence of VTE was higher in the first year of HRT than later. The risk associated with tibolone is unknown.

Generally recognized risk factors for VTE include a personal or family history of VTE, significant obesity (body mass index > 30 kg/m2), and systemic lupus erythematosus. There is no evidence to support the possible role of varicose veins in the development of VTE.

Patients with a history of VTE or thrombophilia are at increased risk of VTE. Hormone replacement therapy increases this risk. Personal and family history of VTE or recurrent spontaneous abortion should be considered to exclude a predisposition to thrombophilia. Hormone replacement therapy or tibolone is contraindicated until a thorough evaluation for thrombophilic factors has been performed or anticoagulant therapy has been initiated. In women already taking anticoagulants, the benefit-risk ratio of hormone replacement therapy should be carefully weighed.

The risk of VTE increases with prolonged immobilisation, severe trauma or major surgery. If the patient is taking HRT, prophylactic measures should be taken to prevent VTE after surgery. If prolonged immobilisation is expected after elective surgery, particularly of the abdomen or lower extremities, temporary discontinuation of HRT should be considered for 4 to 6 weeks prior to surgery. Therapy should only be restarted when the patient has fully returned to normal physical activity.

If VTE develops after starting HRT, the drug should be discontinued. Patients should be advised to report any potential thromboembolic symptoms (e.g., painful swelling of a leg, sudden chest pain, shortness of breath) to their physician.

Coronary heart disease (CHD)

There is no evidence from randomised controlled trials of a protective effect against myocardial infarction in women with or without coronary heart disease who have received combined oestrogen-progestogen HRT or oestrogen alone. There is no evidence from an epidemiological study using the GPRD that tibolone is protective against myocardial infarction in postmenopausal women.

Ischemic stroke

Tibolone increases the risk of ischemic stroke during the first year of treatment. The risk of stroke is significantly age-dependent, so the effect of tibolone increases with increasing age.

Other conditions

Tibolone is not intended for use as a contraceptive.

Tibolone treatment results in a marked, dose-dependent reduction in high-density lipoprotein (HDL) (from -16.7% at 1.25 mg to -21.8% at 2.5 mg after 2 years). Total triglyceride and lipoprotein levels are also reduced. The reduction in total cholesterol and low-density lipoprotein (LDL) levels is not dose-dependent. LDL cholesterol levels remain unchanged. The clinical significance of these findings is still unknown.

Estrogens can cause fluid retention, so patients with impaired cardiac and renal function require careful monitoring.

Women with hypertriglyceridemia should be monitored during estrogen replacement or hormone replacement therapy, as rare cases of significant increases in plasma triglyceride levels leading to pancreatitis have occurred in these circumstances.

Treatment with tibolone leads to a slight decrease in thyroxine-binding globulin (TBG) and total T4. Total T3 levels remain unchanged. Tibolone reduces sex hormone binding globulin (SHBG) levels, but has no effect on corticosteroid binding globulin (CBG) and circulating cortisol levels.

HRT does not improve cognitive function. There is evidence of an increased risk of dementia in women who start continuous combined or monoestrogenic HRT after the age of 65. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug does not affect the reaction speed when driving or working with other mechanisms.

Use during pregnancy or breastfeeding

Tibolone is contraindicated for use during pregnancy. If pregnancy occurs during treatment with tibolone, treatment should be discontinued immediately. There are no clinical data on use during pregnancy. Animal studies have shown reproductive toxicity. Animal studies have shown teratogenicity of tibolone. The potential risk to humans is unknown.

Tibolone is contraindicated during breastfeeding.

Method of administration and doses

The recommended dose is 1 tablet per day. There is no need to adjust the dose for elderly patients. The tablets should be taken with a small amount of water or other drinks, preferably at the same time of day. To start and continue treatment for postmenopausal symptoms, the lowest effective dose should be used for the shortest period of time. When treating with ESPA-TIBOL®, progestogens should not be used separately. Starting ESPA-TIBOL®.

Women with natural menopause are recommended to start treatment with ESPA-TIBOL® no earlier than 12 months after the last natural bleeding. In the case of menopause that occurred after surgical intervention, treatment with ESPA-TIBOL® can be started immediately.

Before starting ESPA-TIBOL®, the cause of any irregular/unscheduled vaginal bleeding, including when using hormone replacement therapy (HRT), should be determined to exclude malignancy.

Switching from sequential or continuous use of a combined HRT drug.

When switching from a sequential HRT regimen, ESPA-TIBOL® should be started the day after the previous regimen is completed. If switching from a continuous combined HRT regimen, ESPA-TIBOL® treatment can be started at any time.

Missed dose.

The missed dose should be taken as soon as the patient remembers, if the delay is no more than 12 hours. If the delay in taking is more than 12 hours, the next dose is taken at the usual time. Skipping a dose increases the likelihood of breakthrough bleeding or spotting.

Children

There is no information on the use of the drug in children.

Overdose

The acute toxicity of tibolone in animals is very low. Therefore, no symptoms of toxicity are expected, even when several tablets are taken at the same time. In case of acute overdose, nausea, vomiting and vaginal bleeding may occur in women. There is no specific antidote. If necessary, symptomatic therapy should be carried out.

Adverse reactions

The following adverse reactions were reported in 21 placebo-controlled studies (including the LIFT study) involving 4079 women receiving therapeutic doses of tibolone (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.

The table shows adverse reactions that occurred significantly more frequently during treatment with tibolone than during treatment with placebo.

Adverse effects of tibolone

* In most cases, benign changes were observed. The incidence of cervical pathology (cervical carcinoma) did not increase with tibolone compared to placebo.

Other adverse reactions have been observed since the drug was marketed, such as dizziness, rash, seborrheic dermatitis, pruritus, gastrointestinal disorders, edema, headache, migraine, visual disturbances (including blurred vision), depression, musculoskeletal effects such as arthralgia or myalgia, and changes in liver function tests.

Breast cancer risk

A 2-fold increase in the risk of developing breast cancer has been reported in women receiving combined estrogen-progestagen therapy for more than 5 years.

The increased risk in those receiving monoestrogen therapy or tibolone is significantly lower than the risk in those taking estrogen-progestogen combinations.

The level of risk depends on the duration of use.

The Million Women Study (MWS) reported that the number of additional cases of breast cancer in those taking tibolone was comparable to those using estrogen monotherapy.

The risk of developing endometrial cancer exists in about 5 out of 1000 women with a uterus who are not using HRT or tibolone.

In the LIFT trial, no cases of endometrial cancer were diagnosed in the placebo group (n = 1,773) after 2.9 years compared with 4 cases of endometrial cancer in the tibolone group (n = 1,746). This is consistent with a rate of 0.8 additional cases of endometrial cancer per 1000 women taking tibolone for one year in this study.

Risk of ischemic stroke

A randomized controlled trial found a 2.2-fold increased risk of stroke in women (mean age 68 years) taking tibolone 1.25 mg compared with those taking placebo (28/2249 vs 13/2257) after 2.9 years. The majority of strokes (80%) were ischemic.

The probability of having a stroke is highly dependent on age. Thus, the expected probability of having a stroke in 5 years would be 3 cases per 1000 women aged 50-59 years and 11 cases per 1000 women aged 60-69 years.

Among women taking tibolone for 5 years, the number of additional cases of stroke is expected to be about 4 per 1000 women aged 50 to 59 years and 13 per 1000 women aged 60 to 69 years.

Other adverse reactions associated with estrogen-gestagen therapy are also known:

estrogen-dependent benign and malignant neoplasias, such as endometrial cancer; venous thromboembolism (deep vein thrombosis of the legs or pelvic veins) and pulmonary embolism; myocardial infarction; gallbladder disease; skin and subcutaneous tissue diseases (chloasma, erythema multiforme, erythema nodosum, vascular purpura); dementia.

Expiration date

30 months.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

28 tablets in a blister, 1 blister in a cardboard box.

Vacation category

According to the recipe.

Producer

Lindopharm GmbH.

Location of the manufacturer and its business address

Neustrasse 82, 40721 Gilden, Germany.