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SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

<TRADENAME> 2.5 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains: 2.5 mg tibolone.

Excipient:

One tablet contains approximately 75 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White to whitish, flat round tablets of approximately 6 mm diameter.

4    CLINICAL PARTICULARS

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

For oral use Posology

Adults and the elderly

The dosage is one tablet per day without interruption. 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 <TRADENAME> treatment.

Starting <TRADENAME>

• Women experiencing a natural menopause should commence treatment with <TRADENAME> at least 12 months after their last natural bleed.

• Women experiencing a surgical menopause may commence treatment with <TRADENAME> 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 <TRADENAME> (see section 4.3).

Method of administration

The tablets should be swallowed without chewing, with some water or other drink, preferably at the same time every day.

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Switching from a sequential or continuous combinedHRT preparation If changing from a sequential HRT preparation, treatment with <TRADENAME> 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.

Paediatric population Not applicable.

4.3    Contraindications

•    Pregnancy and lactation

•    Known, past or suspected breast cancer -<TRADENAME> 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 or TIA)

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

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

•    Porphyria

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.

Medical examination and follow-up

•    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.

•    Before initiating or reinstituting HRT, a complete personal and family medical history

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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 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 <TRADENAME>, in particular:

Leiomyoma (uterine fibroids) or endometriosis Risk factors for, thromboembolic disorders (see below)

Risk factors for oestrogendependent tumours, e.g. 1^st-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

•    Pregnancy

Venous thromboembolism

•    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).

•    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/m ), 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

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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).

•    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.

Endometrial hyperplasia and cancer

•    In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

•    The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

•    Break-through bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

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 2.5 mg 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 Practitioners Research Database.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies including the Women's Health Initiative (WHI) trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller risk (see section 4.8).

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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.

Coronary artery disease (CAD)

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

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

o <TRADENAME> 2.5 mg tablets is not intended for contraceptive use.

o Treatment with <TRADENAME> 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-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known.

o Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

o Women with pre-existing hypertriglyceridaemia should be followed closely during estrogen replacement or HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

o Treatment with <TRADENAME> 2.5 mg tablets results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. <TRADENAME> 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.

o 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.

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 <TRADENAME> 2.5 mg tablets and warfarin should be closely monitored, especially when commencing or discontinuing treatment with <TRADENAME>

2.5    mg tablets. If necessary, the dose of warfarin should be adjusted.

There is limited information regarding pharmacokinetic interactions with tibolone. One in

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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.

In vitro metabolism data suggest that tibolone and its metabolites may inhibit CYP2C9, a P450 enzyme. Great caution should be observed if combining tibolone with other drugs metabolised by CYP2C9. This especially applies to drugs with narrow therapeutic intervals such as warfarin, phenytoin and tolbutamide.

The effects of inhibition or induction of tibolone metabolism have not been studied. Because of the substance’s complex profile, including several metabolites with different effects, the effect of inhibition or induction of tibolone metabolism cannot be predicted. However, the following potential interactions should be considered on a theoretical basis:

Enzyme 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.Johns 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

Fertility

In animal studies, tibolone demonstrated anti-fertility effects (see section 5.3)

Pregnancy

Tibolone is contraindicated during pregnancy (see section 4.3).. If pregnancy occurs during medication with <TRADENAME> 2.5 mg tablets, treatment should be withdrawn immediately. For <TRADENAME> 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

<TRADENAME> 2.5 mg tablets is contraindicated during lactation (see section 4.3).

4.7    Effects on ability to drive and use machines

<TRADENAME> 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 <TRADENAME> 2.5 mg tablets

System organ class	Common >1%,<10%	Uncommon >0.1%,<1%
Gastrointestinal disorders	Lower abdominal pain
Skin and subcutaneous tissue disorders	Abnormal hair growth	Acne
Reproductive system and	Vaginal discharge	Breast discomfort

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breast disorders	Endometrial wall thickening Postmenopausal haemorrhage Breast tenderness Genital pruritus Vaginal candidiasis Vaginal haemorrhage Pelvic pain Cervical dysplasia Genital discharge Vulvovaginitis	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.

In market use, other undesirable effects that have been observed include: dizziness, rash, pruritus, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), gastrointestinal upset, depression, edema, 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.

•    Any 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 (MWS) are presented.

In Table 2: Million women study - estimated additional risk of breast cancer after 5 years’ use Additional cases per 1000

Age ränge (years) never-users of HRT over a Risk ratio Additional cases per

5 year period*2    &95%CI#    1000 HRT users over 5

years (95%CI)

Estrogen only HRT

50-6    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)

#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

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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

Long term use of estrogen-only and combined estrogen-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.

Risk of coronary artery disease

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

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 estrogen-progestogen treatment:

•    HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deepvein 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 and 95%CI	Additional cases per 1000 HRT users
Oral estrogen-only1
50-59	7	1.2 (0.6-2.4)	1 (-3-10)
Oral combined estrogen-progestogen
50-59	4	2.3 (1.2-4.3)	5 (1-13)

*Study in women with no uterus

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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 [to be completed nationally].

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 or capsules 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Other oestrogens ATC code: G03CX01

Following oral administration tibolone is rapidly metabolised into three compounds, which all contribute to the pharmacodynamic profile of <TRADENAME> 2.5 mg tablets. Two of these metabolites (3a-OH-tibolone and 3ß-OH-tibolone) have oestrogenic-like activities, whereas the third metabolite (delta4-isomer of tibolone) has progestonic and androgenic-like activities.

<TRADENAME> 2.5 mg tablets substitutes for the loss of oestrogen production in postmenopausal women and alleviates menopausal symptoms <TRADENAME> 2.5 mg tablets prevents bone loss following menopause or ovariectomy.

Clinical trial information of <TRADENAME> 2.5 mg tablets:

Relief of estrogen-deficiency symptoms

• Relief of menopausal symptoms generally occurs during the first few weeks of treatment.

Effects on the endometrium and bleeding patterns

•    There have been reports of endometrial hyperplasia and endometrial cancer in patients treated with tibolone (see section 4.4 and 4.8).

•    Amenorrhea has been reported in 88% of women using tibolone 2.5 mg after 12 months of treatment. Breakthrough bleeding and/or spotting has been reported in 32.6% of women during the first 3 months of treatment, and in 11.6% of women after 11-12 months of use.

Effects on the breast

•    In clinical studies mammographic density is not increased in women treated with <TRADENAME> 2.5 mg tablets compared to placebo.

5.2 Pharmacokinetic properties

Absorption

Tibolone is extensively absorbed within 1-4 hours after oral administration. Simultaneous consumption of food reduces C_max and delays Tmax, but does not affect AUC values for oestrogenic metabolites.

Distribution

The protein binding level of tibolone is approximately 96%. The protein binding level of the

three active metabolites has not been studied

Biotransformation

Tibolone is metabolised into three active metabolites, one with progestogenic/androgenic effects (delta4 metabolite) and two with oestrogenic effects (3a-OH- and 3ß-OH metabolites). The pharmacokinetic documentation is primarily based on the oestrogenic metabolites at peak plasma levels.

There is no information on the metabolising enzyme.

Elimination

The metabolites are excreted into the bile and eliminated in the faeces. A small proportion is excreted in the urine.

Pharmacokinetic parameters of <TRADENAME> 2.5 mg tablets (2.5 mg)

5.3 Preclinical safety data

In animal studies, tibolone had anti-fertility and embryotoxic activities by virtue of its hormonal properties. Tibolone was not teratogenic in mice and rats. It displayed teratogenic potential in the rabbit at near-abortive dosages (see section 4.6). Tibolone is not genotoxic under in vivo conditions. Although a carcinogenic effect was seen in certain strains of rat (hepatic tumors) and mouse (bladder tumors), the clinical relevance of this is uncertain.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Potato starch

Magnesium stearate (vegetable)

Ascorbyl palmitate Lactose monohydrate

6.2    Incompatibilities

Not applicable.

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6.3    Shelf life

30 months

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of Container

PVC/PVDC/Al calendar blister in packs of 1x 28, 3x28 and 6x28 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7 MARKETING AUTHORISATION HOLDER

[To be competed nationally]

8.    MARKETING AUTHORISATION NUMBER(S)

[To be competed nationally]

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

{DD/MM/YYY}

[To be competed nationally]

10.    DATE OF REVISION OF THE TEXT

{DD/MM/YYY}

[To be competed nationally]

1

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