4.1. Therapeutic indications

Treatment of oestrogen deficiency symptoms in women more than one year after the menopause.

For all women the decision to prescribe tibolone should be based on an assessment of the individual patient´s overall risks and, particularly in the over 60s, should include consideration of the risk of stroke (see sections 4.4 and 4.8).

4.2. Posology and method of administration

Posology

The dosage is one tablet per day.

Method of administration

The tablets should be swallowed, with some water or other drink, preferably at the same time every day.

Elderly

No dose adjustment is necessary for the elderly.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

A separate progestogen should not be added with Tibolone 2.5 mg tablets treatment.

Starting Tibolone 2.5 mg tablets

Women experiencing a natural menopause should commence treatment with Tibolone 2.5 mg tablets at least 12 months after their last natural bleed. Women experiencing a surgical menopause may commence treatment with Tibolone 2.5 mg tablets immediately.

Any irregular/unscheduled vaginal bleeding, either on or off HRT, for which there is no obvious cause, should be investigated to exclude malignancy before starting Tibolone 2.5 mg tablets (see section 4.3).

Switching from a sequential or continuous combined HRT preparation

If changing from a sequential HRT preparation, treatment with Tibolone 2.5 mg tablets should start the day following completion of the prior regimen. If changing from a continuous- combined HRT preparation, treatment can start at any time.

Missed dose

A missed dose should be taken as soon as remembered, unless it is more than 12 hours overdue. In the latter case, the missed dose should be skipped and the next dose should be taken at the normal time. Missing a dose may increase the likelihood of breakthrough bleeding and spotting.

4.3. Contraindications

- Pregnancy and lactation

- Known, past or suspected breast cancer –Tibolone 2.5 mg tablets increased the risk of breast cancer recurrence in a placebo controlled trial

- Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)

- Undiagnosed genital bleeding

- Untreated endometrial hyperplasia

- Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

- Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4)

- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke, transitory ischemic attack)

- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

- Porphyria

- Known hypersensitivity to the active substance, or to any of the excipients listed in section 6.1

4.4. Special warnings and precautions for use

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.

Medical examination and follow-up

Before initiating or reinstituting HRT or therapy with 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 (see ´Breast cancer´ below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

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 2.5 mg tablets, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- Risk factors for, thromboembolic disorders (see below)

- Risk factors for oestrogendependent tumours, e.g. 1st-degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contraindication is discovered and in the following situations:

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

Endometrial hyperplasia and cancer

- 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 also section 5.1). Women should be advised to report any breakthrough bleeding or spotting if it is still present after 6 months of treatment, if it starts beyond that time or continues after treatment has been discontinued, the reason should be gynaecologically investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

A meta-analysis of epidemiological studies including the Million Women Study (MWS) showed a significant increase in the risk of breast cancer in association with use of the 2.5 mg dose. This risk became apparent within 3 years of use and increased with duration of intake, see section 4.8. These results could not be confirmed in a study using the General Practitioners Research Database. After stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more. No data for persistence of risk after stopping are available for tibolone, but a similar pattern cannot be ruled out.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian 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.

Risk of venous thromboembolism

- 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 chronic 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 doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).

Risk of coronary artery disease

- 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.

Ischaemic stroke

- Tibolone increases the risk of ischemic 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.

Other conditions

- Tibolone 2.5 mg tablets is not intended for contraceptive use.

- Treatment with Tibolone 2.5 mg tablets 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- cholesterol levels was not dose-dependent. Levels of LDL- cholesterol 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 2.5 mg tablets results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Tibolone 2.5 mg tablets 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

As tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants. This effect has been observed with warfarin. Consequently, women simultaneously treated with Tibolone 2.5 mg tablets and anticoagulants should be closely monitored, especially when commencing or discontinuing treatment with Tibolone 2.5 mg tablets. If necessary, the dose of warfarin should be adjusted.

There is limited information regarding pharmacokinetic interactions with tibolone. One in vivo study showed that simultaneous treatment with tibolone can affect the pharmacokinetics of midazolam, a cytochrome P450 3A4 substrate, to a moderate extent. Based on this, interactions can also be expected with other CYP3A4 substrates.

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 progestagens.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

4.6. Fertility, pregnancy and lactation

Pregnancy

Tibolone is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during medication with Tibolone 2.5 mg tablets, treatment should be withdrawn immediately. For Tibolone 2.5 mg tablets no clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity. Tibolone was teratogenic in rabbits (see section 5.3.). The potential risk to humans is unknown.

Breast-feeding

Tibolone 2.5 mg tablets is contraindicated during lactation (see section 4.3).

4.7. Effects on ability to drive and use machines

Tibolone 2.5 mg tablets is not known to have any effects on alertness and concentration.

4.8. Undesirable effects

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 2.5 mg tablets

System organ class

Common >1%,<10%

Uncommon >0.1%,<1%

Rare >0,01%,<0,1%

Metabolism and nutrition disorders

Edema**

Gastrointestinal disorders

Lower abdominal pain

Abdominal pain**

Skin and subcutaneous tissue disorders

Abnormal hair growth

Acne

Pruritus**

Reproductive system and breast disorders

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

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.

Breast cancer risk

- 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.

- The increased risk in users of oestrogen-only and tibolone therapy 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.

In Table 2: Million women study (MWS) – 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#

Additional cases per 1000 HRT users over 5 years (95%CI)

Oestrogen only HRT

50-65

9-12

1.2

1-2 (0-3)

Combined oestrogen-progestagen

50-65

9-12

1.7

6 (5-7)

Tibolone

50-65

9-12

1.3

3 (0-6)

*With reference to baseline incidence in industrial countries

#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of use

Endometrial cancer risk

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)."

Ovarian cancer

Use of oestrogen-only or combined oestrogen-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 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).

Risk of ischaemic stroke

- 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.

- 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 ischemic.

- 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.

Other adverse reactions have been reported in association with oestrogen-progestogen treatment:

- Long term use of oestrogen-only and combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users. This study showed that the relative risk for ovarian cancer with tibolone was similar to the risk with other types of HRT.

- 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 oestrogen-only*

50-59

7

1.2 (0.6-2.4)

1 (-3-10)

Oral combined oestrogen-progestogen

50-59

4

2.3 (1.2–4.3)

5 (1-13)

*Study in women with no uterus

- The risk of coronary artery disease is slightly increased in users of combined oestrogen-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.

- Gall bladder disease

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

- Probable dementia over the age of 65 (see section 4.4)

Reporting of suspected adverse reactions

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The acute toxicity of tibolone in animals is very low. Therefore toxic symptoms are not expected to occur even when several tablets are taken simultaneously. In cases of acute overdose, nausea, vomiting and vaginal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.