Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Pharma Dynamics (Pty) Ltd, 1<sup>st</sup> Floor, Grapevine House, Steenberg Office Park, Silverwood Close, Westlake, Cape Town, 7945, South Africa
TIBILIVE 2,5 MG is not intended for contraceptive use.
TIBILIVE 2,5 MG is prescribed for the treatment of postmenopausal symptoms and should only be initiated for symptoms that adversely affect quality of life.
The use of TIBILIVE 2,5 MG should be avoided until 12 months after the last natural menstrual bleed. If TIBILIVE 2,5 MG is taken sooner than this, the frequency of irregular bleeding may be increased.
In the event that signs of thromboembolic processes occur, results of liver function tests become abnormal or if cholestatic jaundice appears, treatment with TIBILIVE 2,5 MG should be discontinued.
As a result of an apparently stimulated endometrium due to some oestrogen production, vaginal bleeding may occur during TIBILIVE 2,5 MG therapy. Normally such bleeding is of short duration. Bleedings commencing after 3 months of treatment, or recurrent or of longer duration should be investigated.
When changing to TIBILIVE 2,5 MG from any other form of hormonal substitution therapy, it is always advisable to induce a withdrawal bleeding with a progestogen before starting TIBILIVE 2,5 MG.
Tibolone, as in TIBILIVE 2,5 MG has been shown to be teratogenic in experimental animals and should not be used in pre-menopausal women. The risks of stroke, breast cancer and endometrial cancer (women with an intact uterus) for each woman should be carefully assessed, in the light of her individual risk factors and bearing in mind the frequency and characteristics of both cancers and stroke, in terms of their response to treatment, morbidity and mortality.
Periodic examinations must be done for endometrial hyperplasia, as well as possible signs of virilisation.
Before initiating or reinstituting HRT or tibolone, as in TIBILIVE 2,5 MG, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use.
During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised that changes in their breasts should be reported to their doctor or nurse (see Breast cancer below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with TIBILIVE 2,5 MG, in particular:
TIBILIVE 2,5 MG therapy should be discontinued either in the case of a contraindication being discovered, or in any of the following situations:
The available data from randomised controlled trials are conflicting, however observational studies have consistently shown that women who are prescribed tibolone, as in TIBILIVE 2,5 MG, in normal clinical practice are at an increased risk of having endometrial cancer diagnosed. In these studies, risk increased with increasing duration of use. Tibolone, as in TIBILIVE 2,5 MG increases endometrial wall thickness, as measured by transvaginal ultrasound.
The endometrial cancer risk is about 5 in every 1 000 women with a uterus not using HRT or tibolone, as in TIBILIVE 2,5 MG.
Break-through bleeding and spotting may occur during the first months of treatment (see section 4.3). Women should be advised to report any break-through bleeding or spotting if it is still present after 6 months of treatment, if it starts beyond that time or if it continues after treatment has been discontinued. The woman should be referred for gynaecological investigation, which is likely to include endometrial biopsy to exclude endometrial malignancy.
TIBILIVE 2,5 MG contains tibolone which has combined estrogenic and progestogenic effects and therefore, on prolonged use, may increase the risk of developing breast cancer. A meta-analysis of prospective epidemiological studies from 1992 to 2018 reported a significant increase in the risk of developing breast cancer in 55,575 women 40 – 59 years of age who used menopausal hormone therapy (MHT). The risk increased steadily with duration of use and was slightly greater for oestrogen-progestogen than oestrogen only preparations, and the risk persisted for more than 10 years after stopping the treatment. The relative risk (RR) to develop breast cancer for oestrogen-progestogen preparations was 1.60 at 1-4 years and RR=2.08 at 5-14 years, while that for oestrogen only preparations was 1.17 at 1-4 years and 1.33 at 5-14 years. There was no risk of to develop breast cancer in women who started MHT at 60 years of age.
All women on TIBILIVE 2,5 MG should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. Mammography evaluations should be done based on patient age, risk factors, and prior mammogram results.
Ovarian cancer is much rarer than breast cancer.
Long-term (at least 5 to 10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8).
Some other studies suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk (see section 4.8). In one study it was shown that the relative risk for ovarian cancer with use of tibolone, as in TIBILIVE 2,5 MG was similar to the risk associated with use of other types of HRT.
Oestrogen or oestrogen-progestogen HRT is associated with a 1,3-3- fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8). In an epidemiological study using a UK database, the risk of VTE in association with tibolone was lower than the risk associated with conventional HRT, but only a small proportion of women were current users of tibolone and a small increase in risk compared with non-use cannot be excluded.
Patients with known thrombophilic states have an increased risk of VTE and HRT or tibolone, as in TIBILIVE 2,5 MG may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).
Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT or tibolone 4 to 6 weeks earlier is recommended, if possible. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT or TIBILIVE 2,5 MG is contraindicated.
Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT or TIBILIVE 2,5 MG.
If VTE develops after initiating therapy, TIBILIVE 2,5 MG should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
There is no evidence from randomised controlled trials of protection against myocardial infarction in woman with or without existing CAD who received combined oestrogenprogestogen or oestrogen-only HRT. In an epidemiological study using the GPRD no evidence was found of protection against myocardial infarction in post-menopausal women who received tibolone, as in TIBILIVE 2,5 MG.
TIBILIVE 2,5 MG increases the risk of stroke from the first year of treatment (see section 4.8). The baseline risk of stroke is strongly age-dependent and so the effect of TIBILIVE 2,5 MG is greater with older age.
Other adverse reactions have been reported in association with oestrogen and oestrogenprogestogen treatment:
Treatment with tibolone, as in TIBILIVE 2,5 MG results in a marked dose-dependent decrease in HDL cholesterol (from -16,7% with a 1,25 mg dose to –21,8% for the 2,5 mg dose after 2 years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known.
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
Treatment with TIBILIVE 2,5 MG results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. TIBILIVE 2,5 MG decreases the level of sex-hormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected.
HRT does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
TIBILIVE 2,5 MG contains lactose monohydrate. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, total lactose deficiency or glucosegalactose malabsorption should not take TIBILIVE 2,5 MG.
No examples of interaction between tibolone, as in TIBILIVE 2,5 MG and other medicines have been reported in clinical practice. However, the following potential interactions should be considered on a theoretical basis:
Since tibolone may increase blood fibrinolytic activity (lower fibrinogen levels; higher ATIII, plasminogen and fibrinolytic activity values), it may enhance the effect of anticoagulants. This effect has been demonstrated with warfarin.
Caution should therefore be exercised during the simultaneous use of TIBILIVE 2,5 MG and anticoagulants, especially when starting or stopping concurrent TIBILIVE 2,5 MG treatment. If necessary, the dose of warfarin should be adjusted.
There is limited information regarding pharmacokinetic interactions with tibolone. An in vivo study showed that simultaneous treatment of tibolone affects pharmacokinetics of the cytochrome P450 3A4 substrate midazolam to a moderate extent. Based on this, medicine interactions with other CYP3A4 substrates might be expected.
CYP3A4 enzyme-inducing medicines such as barbiturates, carbamazepine, hydantoins and rifampicin may enhance the metabolism of tibolone, as in TIBILIVE 2,5 MG, and thus decrease its therapeutic effect.
Herbal preparations containing St.John’s wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestogens via CYP3A4. Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
TIBILIVE 2,5 MG is contraindicated during pregnancy. If pregnancy occurs during medication with TIBILIVE 2,5 MG, treatment should be withdrawn immediately. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
TIBILIVE 2,5 MG is contraindicated during breastfeeding.
In animal studies, tibolone, as in TIBILIVE 2,5 MG, had anti-fertility activities by virtue of its hormonal properties.
TIBILIVE 2,5 MG is not known to have any effects on alertness and concentration.
This section describes undesirable effects, which were registered in 21 placebo-controlled studies and during post-marketing surveillance.
Tabulated summary of adverse reactions:
| System Organ Class | Frequency | Side effects |
|---|---|---|
| Metabolism and nutrition disorders | Less frequent | Oedema |
| Psychiatric disorders | Frequency unknown | Depression |
| Nervous system disorders | Frequency unknown | Dizziness, headache, migraine |
| Eye disorders | Frequency unknown | Visual disturbances, blurred vision |
| Gastrointestinal disorders | Frequent Less frequent | Lower abdominal pain Gastrointestinal upset*, abdominal discomfort* |
| Hepato-biliary disorders | Frequency unknown | Changes in liver function parameters |
| Skin and subcutaneous tissue disorders | Frequent Less frequent Frequency unknown | Abnormal hair growth Acne, pruritis Rash, seborrheic dermatosis |
| Musculoskeletal, connective tissue and bone disorders | Frequency unknown | Arthralgia, myalgia |
| Reproductive system and breast disorders | Frequent Less frequent | Vaginal discharge, endometrial wall thickening, postmenopausal haemorrhage, breast tenderness, genital pruritus, vaginal candidiasis, vaginal haemorrhage, pelvic pain, cervical dysplasia, genital discharge, vulvovaginitis Breast discomfort, fungal infection, vaginal mycosis, nipple pain |
| Investigations | Frequent Less frequent | Weight increase, abnormal cervical smear* Amnesia |
* The majority consisted of benign changes. Cervix pathology (cervical carcinoma) was not increased with tibolone compared to placebo.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8. An email can be sent directly to the company, pharmacovigilance@pharmadynamics.co.za to ensure safety of the product.
Not applicable.
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