Ivial

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AIVIAL (AIVIAL)

Composition:

Active substance: tibolone;

One tablet contains 2.5 mg of tibolone;

Excipients: lactose monohydrate, mannitol (E 421), potato starch, ascorbyl palmitate, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, uncoated tablets without markings.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the reproductive system. Estrogens. ATC code G03C X01.

Pharmacological properties.

Pharmacodynamics.

After oral administration, tibolone is rapidly metabolized into three components that influence the pharmacodynamic profile of the medicinal product IVIALE. Two of these metabolites (3α-OH-tibolone and 3β-OH-tibolone) exhibit estrogen-like activity, whereas the third metabolite (Δ4-isomer of tibolone) exhibits progestogenic- and androgenic-like activity.

Tibolone replaces the deficiency caused by reduced estrogen production in postmenopausal women and alleviates symptoms associated with menopause. Tibolone prevents bone loss associated with menopause or oophorectomy.

Information on clinical trials of tibolone

Alleviation of estrogen deficiency symptoms.

Relief of menopausal symptoms usually occurs within the first few weeks of treatment.

Effect on the endometrium and mechanism of bleeding.

Endometrial hyperplasia and endometrial cancer have been reported in patients receiving tibolone.

Amenorrhea was observed in 88% of women treated with tibolone 2.5 mg after 12 months of treatment. Breakthrough bleeding and/or spotting was recorded in 32.6% of women during the first 3 months of treatment and in 11.6% of women after 11–12 months of treatment.

Effect on the mammary glands

In clinical studies, mammographic density did not increase in women receiving tibolone compared to placebo.

Pharmacokinetics.

Absorption and biotransformation

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

Due to rapid metabolism, plasma levels of tibolone are very low. Plasma levels of the Δ4-isomer of tibolone are also very low. Therefore, some pharmacokinetic parameters cannot be determined. Peak plasma concentrations of the 3α-OH and 3β-OH metabolites are high, but no accumulation occurs.

Table 1

OD – single dose; BD – twice daily.

Elimination

Excretion of tibolone occurs mainly in the form of conjugated (predominantly sulfated) metabolites. Part 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.

Other specific populations

According to available data, the pharmacokinetic parameters of tibolone and its metabolites are not dependent on renal function.

Clinical characteristics.

Indications.

Treatment of estrogen deficiency symptoms in postmenopausal women when 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.

Contraindications.

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

Pregnancy and breastfeeding.

Suspicion of breast cancer, its current presence or history (tibolone 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.

History or current venous thromboembolism (deep vein thrombosis, pulmonary embolism).

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

Acute liver disease or history of liver disease until normalization of liver function tests.

Porphyria.

Existing thrombophilic disorders (e.g., protein C, protein S, or antithrombin deficiency).

Interaction with other medicinal products and other forms of interaction.

Since tibolone may increase blood fibrinolytic activity, this may enhance the effect of anticoagulants. This effect has been observed during concomitant use with warfarin. Therefore, careful monitoring of patients is required when tibolone is used concomitantly with anticoagulants, especially at the beginning of treatment and upon discontinuation. Warfarin dosage should be adjusted as necessary.

Information regarding pharmacokinetic interactions with tibolone is limited. In vivo studies have shown that concomitant use with tibolone may have a moderate effect on the pharmacokinetics of the CYP3A4 substrate midazolam. Based on these data, interactions with other CYP3A4 substrates may be expected.

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

Herbal preparations containing St. John's wort (Hypericum perforatum) may stimulate the metabolism of estrogens and progestogens via CYP3A4.

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

Special precautions for use.

Tibolone should be used for the treatment of postmenopausal symptoms only when these symptoms negatively affect quality of life. In all cases, a careful assessment of risks and benefits should be performed at least once a year. The medicinal product Ivial should be used only when the expected benefit outweighs the potential risk.

For each woman, the risk of stroke, breast cancer, and, in women with an intact uterus, endometrial cancer should be carefully evaluated, taking into account her individual risk factors, the incidence and characteristics of both cancers and stroke, treatment response, morbidity, and mortality.

Evidence regarding risks associated with hormone replacement therapy (HRT) or tibolone in the treatment of premature menopause is limited. However, due to the low level of absolute risk in younger women, the benefit-risk balance may be more favorable in younger women than in older women.

Medical examination/monitoring

Before initiating or resuming HRT, particularly tibolone therapy, the physician must review the patient’s complete personal and family medical history and perform a physical examination (including pelvic organs and breasts). Periodic examinations should be performed during treatment according to individual patient characteristics. Women should be informed about changes in their breasts that should be reported to a physician or nurse. Investigations, including mammography, should be performed according to current recognized screening guidelines, taking into account the clinical needs of each patient.

Conditions requiring monitoring

If any of the following conditions are present or have been present in the past, or if they worsened during pregnancy or previous hormonal therapy, patients require careful monitoring. Consider that certain conditions may recur or worsen during tibolone treatment, particularly:

• leiomyoma (uterine fibroids) or endometriosis;
• risk factors for thromboembolic disorders;
• risk factors for estrogen-dependent tumors, e.g., first-degree family history of breast cancer;
• arterial hypertension;
• liver disease (e.g., hepatic adenoma);
• diabetes mellitus with or without vascular complications;
• 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 or in the following situations:

• jaundice or impaired liver function;
• significant increase in blood pressure;
• onset of new migraine-like headaches.

Endometrial cancer

Available data from randomized controlled trials are conflicting. However, observational studies have shown an increased risk of endometrial cancer in women treated with tibolone in routine clinical practice. According to these studies, the risk increased with longer duration of treatment. Transvaginal ultrasound findings indicate that tibolone increases endometrial wall thickness.

Breakthrough bleeding and spotting may occur during the first months of treatment. Patients should be advised to report any breakthrough bleeding or spotting to their physician, especially if such symptoms persist beyond 6 months of treatment, occur after this period, or continue after discontinuation of the medication. To determine the cause, the patient should undergo a gynecological examination, which may include endometrial biopsy to exclude malignant endometrial neoplasia.

Breast cancer

A meta-analysis of epidemiological studies, including the Million Women Study (MWS), showed a significant increase in the risk of breast cancer associated with tibolone at a dose of 2.5 mg. This risk becomes evident within 3 years of use and increases with duration of treatment. After discontinuation of treatment, the excess risk decreases over time, and the time required to return to baseline risk depends on the prior duration of HRT use. If HRT has been used for more than 5 years, the risk may persist for 10 years or longer.

There are no data on the persistence of risk after stopping tibolone, but a similar pattern cannot be excluded.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Large meta-analyses of epidemiological data suggest a slight increase in risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes evident within 5 years of use and decreases over time after discontinuation.

Some studies, such as the Women's Health Initiative (WHI), suggest that long-term use of combined HRT may result in a similar or slightly lower risk. The MWS study found that the relative risk of ovarian cancer associated with tibolone use is similar to that associated with other types of HRT.

Venous thromboembolism (VTE)

Estrogen-only or combined estrogen-progestogen HRT is associated with a 1.3- to 3.0-fold increased risk of venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. The occurrence of such events is more likely during the first year of HRT than later. In an epidemiological study using UK databases, the risk of VTE associated with tibolone was lower than that associated with conventional HRT, but only a few women used tibolone, so a small increase in risk compared to non-use cannot be excluded.

Patients with known thrombophilic conditions have an increased risk of VTE, and HRT or tibolone may further increase this risk. Therefore, HRT is contraindicated in these patients.

Established risk factors for VTE include estrogen therapy, older age, major surgery, prolonged immobilization, significant obesity (body mass index > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus, and cancer. There is no well-established evidence supporting a possible role of varicose veins in the development of VTE.

When patients are receiving HRT, prophylactic measures to prevent VTE should be considered after surgery. If prolonged immobilization is expected after elective surgery, temporary discontinuation of HRT 4 to 6 weeks before the procedure should be considered. Therapy may be restarted once the patient has fully resumed physical activity.

For women without a personal history of VTE but with a first-degree relative who experienced thrombosis at a young age, screening may be offered after careful counseling regarding its limitations (screening identifies only a subset of thrombophilic defects). If a thrombophilic defect associated with familial thrombosis is detected, or if the defect is "severe" (e.g., antithrombin, protein S or protein C deficiency, or a combination of defects), HRT or tibolone therapy is contraindicated.

For women already taking anticoagulants, the benefit-risk ratio of HRT or tibolone therapy should be carefully evaluated.

If VTE develops after starting HRT, the medication should be discontinued. Patients should be informed about the need to report potential thromboembolic symptoms (e.g., painful leg swelling, sudden chest pain, dyspnea).

Ischemic heart disease (IHD)

Randomized controlled trials have not demonstrated a protective effect of combined estrogen-progestogen HRT or estrogen-only therapy against myocardial infarction in women with or without IHD. Epidemiological data from the General Practice Research Database (GPRD) show no evidence of a protective effect against myocardial infarction in postmenopausal women taking tibolone.

Ischemic stroke

Tibolone increases the risk of ischemic stroke from the first year of treatment. The risk of stroke is significantly age-dependent; therefore, the effect of tibolone increases with advancing age.

Other conditions

The excipient mannitol (E 421) present in this medicinal product may have a mild laxative effect. The product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product. Therefore, if intolerance to certain sugars is diagnosed, consult a physician before taking this medicinal product.

Tibolone is not intended for use as a contraceptive.

Tibolone treatment leads to a pronounced, dose-dependent decrease in high-density lipoproteins (HDL) (−16.7% at 1.25 mg dose to −21.8% at 2.5 mg dose after 2 years). Total triglyceride and lipoprotein levels also decrease. Reduction in total cholesterol and very-low-density lipoprotein (VLDL) levels is dose-independent. Low-density lipoprotein (LDL) levels remain unchanged. The clinical significance of these findings is currently unknown.

Estrogens may cause fluid retention; therefore, careful monitoring is required in patients with cardiac or renal dysfunction.

Women with pre-existing hypertriglyceridemia should be closely monitored during estrogen replacement or HRT, as rare cases of marked increases in plasma triglyceride levels, potentially leading to pancreatitis, may occur.

Tibolone treatment 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 without affecting corticosteroid-binding globulin (CBG) or circulating cortisol levels.

HRT does not improve cognitive function. There is evidence of an increased risk of dementia in women who initiated combined or estrogen-only HRT after age 65.

Use during pregnancy or breastfeeding.

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

The medicinal product is contraindicated during breastfeeding.

Animal studies have shown that tibolone, due to its hormonal activity, has anti-fertility effects.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product does not affect reaction speed when driving or operating machinery.

Method of Administration and Dosage

The recommended dose is 1 tablet daily. The tablets should be taken with a small amount of water or other liquids, preferably at the same time each day. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest possible duration should be used. Progestogens should not be used separately during treatment with AIVIAL.

Initiation of AIVIAL treatment

Women with natural menopause are recommended to start treatment with AIVIAL no earlier than 12 months after the last natural menstrual bleeding. In cases of surgical menopause, treatment with AIVIAL can be initiated immediately. Women currently being treated with gonadotropin-releasing hormone (GnRH) analogues, for example for endometriosis, may immediately start using this medicinal product.

Before initiating treatment with AIVIAL, any irregular or unexpected vaginal bleeding, including bleeding occurring during hormone replacement therapy (HRT), should be investigated to exclude malignant neoplasia.

Switching from sequential or continuous combined HRT regimens

When switching from a sequential HRT regimen, AIVIAL should be started the day after completion of the previous regimen. When switching from a continuous combined HRT regimen, AIVIAL may be started at any time.

Missed dose

If a dose is missed, it should be taken as soon as remembered, provided the delay is less than 12 hours. If the delay exceeds 12 hours, the next dose should be taken at the usual time. Missing a dose increases the likelihood of breakthrough bleeding or spotting.

Method of administration

For oral use.

Elderly patients

Dosage adjustment in elderly patients is not required. Experience in women aged 65 years and older is limited.

Children

There are no indications for the use of this medicinal product in children.

Overdose

Acute toxicity of tibolone in animals is very low. Therefore, toxic symptoms are not expected, even after ingestion of several tablets simultaneously. In cases of acute overdose in women, nausea, vomiting, and vaginal bleeding may occur. There is no specific antidote. Symptomatic treatment should be administered if necessary.

Adverse reactions.

The adverse reactions listed below were recorded during 21 placebo-controlled studies (including the LIFT study) involving 4079 women who received therapeutic doses of tibolone (1.25 mg or 2.5 mg), as well as 3476 women who received placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years.

Table 2 shows adverse reactions that occurred significantly more frequently during tibolone treatment than with placebo.

Table 2

Tibolone adverse reactions

* Benign changes were observed in most cases. The incidence of cervical pathology (cervical carcinoma) did not increase during tibolone use compared to placebo.

** These adverse reactions were observed during post-marketing surveillance. Frequencies were estimated based on relevant clinical studies.

Additional adverse reactions reported after marketing authorization include dizziness, rash, seborrheic dermatitis, headache, migraine, visual disturbances (including blurred vision), depression, musculoskeletal system disorders such as arthralgia or myalgia, and changes in liver function tests.

Breast cancer risk

A doubling of the risk of developing breast cancer has been reported in women receiving combined estrogen-progestogen therapy for more than 5 years.

The increased risk associated with estrogen-only therapy or tibolone is lower than that associated with estrogen-progestogen combinations.

The level of risk depends on the duration of treatment.

The results of the MWS study are presented in Table 3.

Table 3

Predicted additional risk of breast cancer after 5 years of tibolone treatment in the MWS study

Risk of endometrial cancer

The risk of developing endometrial cancer is approximately 5 per 1,000 women with a uterus who do not use HRT or tibolone.

A randomized, placebo-controlled study that included women who did not undergo screening for endometrial abnormalities at baseline, thus reflecting clinical practice, identified the highest risk of endometrial cancer (the LIFT study, mean age 68 years). In this study, no cases of endometrial cancer were diagnosed in the placebo group (n = 1773) over 2.9 years, compared with 4 cases in the tibolone group (n = 1746). This corresponds to an additional 0.8 cases of endometrial cancer per 1,000 women taking tibolone for one year in this study.

Ovarian cancer

The use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slight increase in the risk of ovarian cancer diagnosis.

A meta-analysis of 52 epidemiological studies concluded that there is an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (relative risk 1.43; 95% CI 1.31–1.56). In women aged 50 to 54 years who used HRT for 5 years, approximately one additional case per 2,000 users was observed. Approximately 2 out of 2,000 women aged 50 to 54 years who do not use HRT will be diagnosed with ovarian cancer over a 5-year period.

In the MWS study, 5 years of tibolone use resulted in one additional case per 2,500 users.

VTE risk

HRT is associated with a 1.3- to 3-fold increase in the relative risk of developing venous thromboembolism (VTE), specifically deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely during the first year of HRT use.

Table 4 presents the results from the WHI study.

Table 4

Additional VTE risk with HRT over 5 years (WHI study)

* Studies in women without a uterus.

Risk of ischaemic heart disease

It has been established that the risk of developing IHD tends to increase slightly in women aged 60 years and older receiving combined oestrogen-progestogen HRT. There is no evidence that the risk of myocardial infarction with tibolone differs from that with other HRT.

Risk of ischaemic stroke

• The relative risk of ischaemic stroke is independent of age and duration of use; however, since the baseline risk increases strongly with age, the overall risk of ischaemic stroke in women on HRT or tibolone will rise with age.
• In a randomised controlled trial lasting 2.9 years, a 2.2-fold increased risk of stroke was observed in women (mean age 68 years) taking tibolone 1.25 mg compared to those on placebo (28/2249 vs 13/2257). In most cases (80%), the stroke was ischaemic.
• The likelihood of stroke occurrence increases substantially with age. Thus, the expected incidence over 5 years would be 3 cases per 1000 women aged 50–59 years and 11 cases per 1000 women aged 60–69 years (see Table 5).
• For women using tibolone for 5 years, the expected number of additional cases would be approximately 4 per 1000 women aged 50–59 years and 13 per 1000 women aged 60–69 years.

Table 5

Additional risk of ischaemic stroke with HRT for more than 5 years

* No distinction was made between ischemic and hemorrhagic stroke.

Other adverse reactions known to be associated with estrogen-progestogen therapy include:

• gallbladder disease;
• skin and subcutaneous tissue disorders (chloasma, erythema multiforme, erythema nodosum, vasculitic purpura);
• dementia in women aged 65 years and older.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

This medicinal product requires no special storage temperature conditions. Store in the original packaging to protect from light and moisture.

Keep out of the reach of children.

Packaging.

28 tablets per blister pack, 1 or 3 blister packs per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Cenexi, France.

Manufacturer's address and place of business.

17 Rue de Pontoise, Osny, 95520, France.

Marketing Authorization Holder.

Aicur Life Sciences B.V., Netherlands.

Address of the Marketing Authorization Holder.

Boxbergerweg 119, 7431 PM Diepenveen, Netherlands.