Livifem 2,5 mg TABLET

u2022 Symptomatic treatment of hot flushes and associated sweating resulting from natural or surgical menopause.

u2022 Prevention of post-menopausal osteoporosis.

u2022 Improvement of bone-mineral density in patients with established post-menopausal osteoporosis.

The dosage is 1 tablet per day. 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.

Improvement of symptoms generally occurs within a few weeks, but optimal results are obtained when therapy is continued for at least 3 months.

Administration: LIVIFEM tablets should be swallowed whole with some water or other drink, preferably at the same time each day.

Starting LIVIFEM: Women experiencing a natural menopause should commence treatment with LIVIFEM at least 12 months after their last natural bleed. In case of a surgical menopause, treatment with LIVIFEM may commence immediately. Any irregular/unscheduled vaginal bleeding, either on or off HRT, for which there is no obvious cause, should be investigated before starting LIVIFEM.

u2022 Pregnancy and lactation.

u2022 Known or suspected hormone-dependent tumours.

u2022 Known, past or suspected breast cancer - LIVIFEM increased the risk of breast cancer recurrence in a placebo-controlled trial.

u2022 Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer).

u2022 Vaginal bleeding of unknown etiology.

u2022 Untreated endometrial hyperplasia.

u2022 Cardiovascular or cerebrovascular disorders e.g. thrombophlebitis, thromboembolic processes or a history of these conditions.

u2022 Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).

u2022 Known thrombophilic disorders e.g. protein C, protein S or antithrombin deficiency (see u201cWARNINGS AND SPECIAL PRECAUTIONSu201d ).

u2022 Any history of thromboembolic disease [e.g. angina, myocardial infarction, stroke or transient ischaemic attack (TIA)].

u2022 Severe liver disease.

u2022 Known hypersensitivity to the active substance or to any of the excipients.

u2022 Porphyria.

LIVIFEM is not intended for contraceptive use. The use of LIVIFEM should be avoided until 12 months after the last natural menstrual bleed. If LIVIFEM is taken sooner than this, the frequency of irregular bleeding may be increased. Treatment should be discontinued if signs of thromboembolic processes occur, if results of liver function tests become abnormal or if cholestatic jaundice appears. Vaginal bleeding may occur during LIVIFEM therapy, because of an apparently stimulated endometrium due to some estrogen production. Normally such bleeding is of short duration. Bleedings commencing after 3 months of treatment, or recurrent or of longer duration should be investigated. In women changing from another form of hormonal substitution therapy to LIVIFEM therapy, it is always advisable to induce a withdrawal bleeding with a progestogen before starting LIVIFEM.

Tibolone has been shown to be teratogenic in experimental animals, and should not be used in pre-menopausal women. Periodic examinations must be done for endometrial hyperplasia, as well as possible signs of virilisation. 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.

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 LIVIFEM, in particular:
• leiomyoma (uterine fibroids) or endometriosis
• a history of, or risk factors for, thromboembolic disorders (see below)
• risk factors for oestrogen dependent 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 contra-indication 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 LIVIFEM in normal clinical practice are at an increased risk of having endometrial cancer diagnosed. In these studies risk increased with increasing duration of use. LIVIFEM 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 LIVIFEM. 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 cases of endometrial cancer in every 1 000 women who used LIVIFEM for one year in this study.

No examples of interaction between LIVIFEM and other medicines have been reported in clinical practice. 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 decrease its therapeutic effect.
• Since tibolone may increase blood fibrinolytic activity (lower fibrinogen levels; higher ATIII, plasminogen and fibrinolytic activity values), it may enhance the effect of anticoagulants. Therefore the simultaneous use of LIVIFEM and warfarin should be monitored, especially when starting or stopping concurrent LIVIFEM treatment, and the warfarin dose should be appropriately adjusted.
• 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.

LIVIFEM is contra-indicated during pregnancy. If pregnancy occurs during medication with LIVIFEM, treatment should be withdrawn immediately.

LIVIFEM is contra-indicated during breastfeeding.

LIVIFEM 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 4 079 women receiving therapeutic doses (1,25 or 2,5 mg) of LIVIFEM and 3 476 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 LIVIFEM than with placebo.

Table 1 Undesirable effects of LIVIFEM

System organ class Common > 1 %, 0,1 %, < 1 %

Gastrointestinal disorders Lower abdominal pain

Skin and subcutaneous disorders Abnormal hair growth Acne

Reproductive system and breast disorders Vaginal discharge Endometrial wall thickening Post-menopausal haemorrhage Breast tenderness Genital pruritus Vaginitis candidiasis Vaginal haemorrhage Pelvic pain Cervical dysplasia Genital discharge Vulvovaginitis Breast discomfort Fungal infection Vaginal mycosis Nipple pain

Investigations Weight increase Abnormal Cervical smear* Amnesia * 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.

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.