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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Tibolone 2.5mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains as active substance 2.5mg of tibolone. Excipient: Lactose monohydrate and Lactose spray dried.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet

White to off-white, round, flat bevelled edge tablets, coded “TIB” on one side and “2.5” on the reverse.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of estrogen deficiency symptoms in postmenopausal women, more than one year after menopause.

There is limited experience in treating women over age 65 years

4.2    Posology and method of administration

Adults and the elderly

The dosage is one tablet per day without interruption. No dose adjustment is necessary for the elderly. Tibolone tablets should be swallowed without chewing, with some water or other drink, preferably at the same time of day. 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 treatment.

Starting Tibolone

-    Women experiencing a natural menopause should commence treatment with Tibolone at least 12 months after their last natural bleed.

-    Women experiencing a surgical menopause may commence treatment with Tibolone immediately

Switching from a sequential or continuous-combined HRT Preparation

If changing from a Sequential HRT preparation, treatment with Tibolone should start the day following completion of the prior regimen.

If changing from a Continuous-combined HRT preparation, treatment can start at any time.

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

Missed pills

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.

Children Not applicable.

4.3 Contraindications

Known hypersensitivity to the active substance or any of the excipients.

Pregnancy and lactation.

Known, past or suspected breast cancer.

Known or suspected estrogen - dependent malignant tumours (e.g. endometrial cancer). Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism).

Any history of arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke or TIA);

Undiagnosed vaginal bleeding.

Untreated endometrial hyperplasia.

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

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.

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/follow-up

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.

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, in particular:

-    Leiomyoma (uterine fibroids) or endometriosis

-    Risk factors for thromboembolic disorders (see below)

-    Risk factors for oestrogen dependent 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 erythematosis

-    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 carcinoma

•    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.

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 2.5mg 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).

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). 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.

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 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).

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 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.

Other conditions

•    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 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.

4.5 Interactions with other medicinal products and other forms of interaction

The information regarding interactions between tibolone and other medicinal products is limited. The effect of inhibition or induction of the metabolism of tibolone has not

been studied. Due to the complex profile with different metabolites contributing to different pharmacological effects, the effects of an interaction are difficult to predict. 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.John's wort (Hyperuricum 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.

Since tibolone may increase blood fibrinolytic activity (lower fibrinogen levels, higher antithrombin III, plasminogen and fibrinolytic activity values) it may enhance the effect of anticoagulants, such as warfarin. Therefore, the simultaneous use of tibolone and warfarin should be monitored, especially when starting or stopping concurrent tibolone treatment, and the warfarin dose should be appropriately adjusted.

An in vivo study showed that tibolone moderately affected the pharmacokinetics of the CYP3A4 substrate midazolam and based on this, interactions with other CYP3A4 substrates may also be expected.

In vitro data indicate that tibolone and its metabolites can inhibit the cytochrome P450 isoenzyme 2C9. Caution is therefore advised if tibolone is combined with medicinal products metabolised via CYP2C9, especially those with a narrow therapeutic range, e.g. warfarin, phenytoin and tolbutamide.

4.6 Pregnancy and lactation

Tibolone is contraindicated during pregnancy. 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 not indicated during lactation.

4.7 Effects on Ability to Drive and Use Machines

Tibolone 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 Livial 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 Livial than with placebo.

Table 1    Undesirable effects of Livial

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

• 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 therapyis substantially lower than seen in users of oestrogen-progestogen combinations

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 Livial group (n=1,746). This corresponds to a diagnosis of 0.8 additional case of endometrial cancer in every 1000 women who used Livial 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 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 Livial (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 Livial 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 and oestrogen-progestogen treatment:

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

Tab

e (y ea rs)		CI
Ora	estrogen-only*4
50		1.2
-	7	(0.6-	1 (-3-10)
59		2.4)
Ora	combined estrogen-progestogen
50		2.3
-	4	(1.2-	5 (1-13)
59		4.3)

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.

-    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)

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 withdrawal bleeding in females may develop. No specific antidote is known. Symptomatic treatment can be given if necessary.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Other estrogens, ATC code: G03CX01

After oral administration tibolone is rapidly metabolised into three compounds which all contribute to the pharmacological effects of tibolone. Two of these metabolites (3a-OH-tibolone and 3^-OH-tibolone) have predominantly estrogenic activity, whereas the third metabolite (A4-isomer of tibolone) and the parent compound have predominantly progestogenic and androgenic activities.

Tibolone substitutes for the loss of estrogen production in postmenopausal women, and alleviates menopausal symptoms. Tibolone prevents bone loss following menopause or ovariectomy.

In vitro studies suggest that tibolone is subject to tissue-selective local metabolism, with the A4-isomer mainly formed in endometrial tissue. In the breast, tibolone inhibits the sulfatase enzyme thereby reducing the levels of the 3-OH -tibolone metabolites produced in this tissue. The clinical relevance of these studies is not known (see section 4.8).

Clinical trial information on tibolone:

•    Relief of estrogen-deficiency symptoms

- Improvement of symptoms generally occurs within a few weeks

•    Effects on the endometrium and bleeding patterns

- There have been reports of endometrial hyperplasia and endometrial cancer in patients treated with tibolone.

- Amenorrhea (no bleeding or spotting) was seen in 88.4% of the women during months 10-12 of tibolone treatment. Break through bleeding and/or spotting appeared in 32.6% of the women during the first three months of treatment and in 11.6% during months 10-12 of treatment.

• Effects on the breast

Data from clinical studies suggest that mammographic density is not increased in women treated with tibolone compared to placebo.

5.2 Pharmacokinetic properties

Following oral administration tibolone is rapidly and extensively absorbed.

The consumption of food has no significant effects on the extent of absorption.

Due to rapid metabolism the plasma levels of tibolone are very low. The plasma levels of the A4-isomer of tibolone are also very low. Therefore some of the pharmacokinetic parameters could not be determined. Peak plasma levels of the 3a-OH and the 3^-0H metabolites are higher but accumulation does not occur.

Table 2: Pharmacokinetic parameters of Tibolone

	tibolone SD MD		3a-OH metabolite SD MD		3p-0H metabolite SD MD	A4-isomer SD MD
Cmax (ng/ml)	1.37	1.72	14.23 14.15		3.43 3.75	0.47 0.43
C v-/ Averaae	----	----	—	1.88	---- ----	.........
Tmax(h)	1.08	1.19	1.21	1.15	1.37 1.35	1.64 1.65
D/2(h)	----	----	5.78	7.71	5.87 ----	.........
Cmin (ng/ml)	----	----	—	0.23	---- ----	.........
Auc 0-24 (ng/ml.h)	----	----	53.23	44.73	16.23 9.20	..........

SD = Single Dose; MD = Multi Dose

Excretion of tibolone is mainly in the form of conjugated (mostly sulfated) metabolites. Part of the administered compound is excreted in the urine, but most is eliminated via the faeces.

The pharmacokinetic parameters for tibolone and its metabolites were found to be independent of renal function.

5.3 Preclinical safety data

Tibolone is not genotoxic. The results of animal studies of repeated-dose toxicity and carcinogenesis were in agreement with the expected effects of high-dose sex steroids, especially estrogens. Furthermore, a carcinogenic effect on non-hormone-dependent tissues was seen in certain strains of rat (hepatic tumours) and mouse (bladder tumours), the relevance of this evidence to man is uncertain.

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)

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Monohydrate Maize starch pregelatinized Ascorbyl Palmitate (E304)

Sodium citrate Sodium laurilsulfate Croscarmellose Sodium Magnesium Stearate

6.2. Incompatibilities

Not applicable

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

PVC-PVDC /Aluminium foil blisters in pack sizes of 28, 30, 60, 84 and100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Norton Healthcare Ltd (trading as IVAX Pharmaceuticals UK)

Albert Basin, Royal Docks London, E16 2QJ United Kingdom

8    MARKETING AUTHORISATION NUMBER

PL 00530/0771

9    DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORIZATION

10-04-2006

10    DATE OF REVISION OF THE TEXT

24/07/2012

1

   The level of risk is dependent on the duration of use (see section 4.4).

•    Results of the largest epidemiological study (MWS) are presented.

Table 2 Million Women study - Estimated additional risk of breast cancer after