Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Limited, Capital House, 85 King William Street, London, EC4N 7BL
For the treatment of postmenopausal symptoms, Tibolone should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and Tibolone should only be continued as long as the benefit outweighs the risk.
The risks of stroke, breast cancer and, in women with an intact uterus, endometrial cancer (see below and section 4.8) 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.
Evidence regarding the risks associated with HRT or tibolone in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Before initiating or reinstituting HRT or tibolone, 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 what 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 Tibolone, in particular:
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
The available data from randomised controlled trials are conflicting, however, observational studies have consistently shown that women who are prescribed Tibolone in normal clinical practice are at an increased risk of having endometrial cancer diagnosed (see also Section 4.8). In these studies risk increased with increasing duration of use. Tibolone increases endometrial wall thickness, as measured by transvaginal ultrasound.
Break-through bleeding and spotting may occur during the first months of treatment (see section 5.1). 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.
Evidence with respect to breast cancer risk in association with tibolone is inconclusive. The Million Women Study (MWS) has identified a significant increase in the risk of breast cancer in association with use of the 2.5mg dose. This risk became apparent within a few years of use and increased with duration of intake, returning to baseline within a few (at most five) years after stopping treatment (see section 4.8). These results could not be confirmed in a study using the General Practice Research Database (GPRD).
HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the Women’s Health Initiative (WHI) trial, suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk (see section 4.8).
In the Million Women Study it was shown that the relative risk for ovarian cancer with use of tibolone 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 may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3).
Generally recognized risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilization, 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 tibolone is contraindicated.
Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT or tibolone.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctor immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT. In an epidemiological study using the GPRD no evidence was found of protection against myocardial infarction in postmenopausal women who received tibolone.
Tibolone increases the risk of ischaemic 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 tibolone is greater with older age.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Tibolone is not intended for contraceptive use.
Treatment with Tibolone 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 HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
Treatment with Tibolone results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Tibolone decreases the level of sexhormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected.
HRT use 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.
Since Tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants. This effect has been demonstrated with warfarin. Caution should therefore be exercised during the simultaneous use of Tibolone and anticoagulants, especially when starting or stopping concurrent Tibolone 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, drug interactions with other CYP3A4 substrates might be expected.
CYP3A4 inducing compounds such as barbiturates, carbamazepine, hydantoins and rifampicin may enhance the metabolism of tibolone and thus affect 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.
Tibolone is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during medication with Tibolone, treatment should be withdrawn immediately. For Tibolone no clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Tibolone is contraindicated during lactation (see section 4.3).
In animal studies, Tibolone had anti-fertility activities by virtue of its hormonal properties.
Tibolone is not known to have any effects on alertness and concentration.
This section describes undesirable effects, which were registered in 21 placebo-controlled studies (including the LIFT study), with 4079 women receiving therapeutic doses (1.25 or 2.5 mg) of Tibolone and 3476 women receiving placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. Table 1 shows the undesirable effects that occurred statistically significantly more frequently during treatment with Tibolone than with placebo.
Table 1. Undesirable effects of Tibolone:
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Uncommon: Oedema**
Common: Lower abdominal pain
Uncommon: Abdominal discomfort**
Common: Abnormal hair growth
Uncommon: Acne
Rare: Pruritus**
Common: Vaginal discharge, Endometrial was thickening, Postmenopausal haemorrhage, Breast tenderness, Genital pruritus, Vaginal candidiasis, Vaginal haemorrhage, Pelvic pain, Cervical dysplasia, Genital discharge, Vulvovaginitis
Uncommon: Breast discomfort, Fungal infection, Vaginal mycosis, Nipple pain
Common: Weight increase, Abnormal cervical smear*
* The majority consisted of benign changes. Cervix pathology (cervical carcinoma) was not increased with Tibolone compared to placebo.
** These adverse reactions were identified through post-marketing surveillance. The frequency category was estimated based on relevant clinical trials.
In market use, other undesirable effects that have been observed include: dizziness, rash, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), depression, effects on the musculoskeletal system such as arthralgia or myalgia and changes in liver function parameters.
An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.
Any increased risk in users of oestrogen-only and tibolone therapies is substantially lower than seen in users of oestrogen-progestogen combinations.
The level of risk is dependent on the duration of use (see section 4.4).
Results of the largest epidemiological study (Million Women Study) are presented.
Table 2. Million Women study – Estimated additional risk of breast cancer after 5 years' use:
| Age range (Years) | Additional cases per 1000 never-users of HRT over a 5 year period (*2) | Risk ratio (95% CI) (*3) | Additional cases per 1000 HRT users over 5 years (95% CI) |
|---|---|---|---|
| Estrogen-only HRT | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined estrogen-progestagen | |||
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
| Tibolone | |||
| 50-65 | 9-12 | 1.3 | 3 (0-6) |
*2 Taken from baseline incidence rates in developed countries
*3 Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of use
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT or tibolone.
The randomised placebo controlled trial that included women who had not been screened for endometrial abnormalities at baseline, and therefore reflected clinical practice, identified the highest risk of endometrial cancer (LIFT study, mean age 68 years). In this study, 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 corresponds to a diagnosis of 0.8 additional case of endometrial cancer in every 1000 women who used Tibolone for one year in this study (see section 4.4).
Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4).
A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.
In the Million Women Study, taking 5 years of tibolone resulted in 1 extra case per 2500 users (see section 4.4).
HRT is associated with a 1.3-3-fold increased relative 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 using HRT (see section 4.4).
Results of the WHI studies are presented.
Table 3. WHI Studies – Additional risk of VTE over 5 years' use:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio (95% CI) | Additional cases per 1000 HRT users |
|---|---|---|---|
| Oral estrogen-only (*4) | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3-10) |
| Oral combined estrogen-progesteron | |||
| 50-59 | 4 | 2.3 (1.2–4.3) | 5 (1-13) |
*4 Study in women with no uterus
The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see section 4.4). There is no evidence to suggest that the risk of myocardial infarction with tibolone is different to the risk with other HRT.
The relative risk of ischaemic stroke is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of ischaemic stroke in women who use HRT or tibolone will increase with age, see section 4.4.
The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
A 2.9 year randomised controlled study has estimated a 2.2-fold increase in the risk of stroke in women (mean age 68 years) who used 1.25 mg Tibolone (28/2249) compared with placebo (13/2257). The majority (80%) of strokes were ischaemic.
The baseline risk of stroke is strongly age-dependent. Thus, the baseline incidence over a 5 year period is estimated to be 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years.
For women who use Tibolone for 5 years, the number of additional cases would be expected to be about 4 per 1000 users aged 50-59 years and 13 per 1000 users aged 60-69 years.
Table 4. WHI Studies combined – Additional risk of ischaemic stroke over 5 years' use:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio (95% CI) | Additional cases per 1000 HRT users over 5 years |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1-1.6) | 3 (1-5) |
Other adverse reactions have been reported in association with oestrogen/progestagen treatment:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via theYellow Card Scheme: Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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