Tibolone

Registered South African indications:

• Symptomatic treatment of hot flushes and associated sweating resulting from natural or surgical menopause
• Prevention of post-menopausal osteoporosis
• Improvement of bone-mineral density in patients with established post-menopausal osteoporosis

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Known or suspected hormone-dependent tumours
• Personal and family history of breast cancer
• Known, past or suspected breast cancer - tibolone increased the risk of breast cancer recurrence in placebo-controlled trial
• Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)
• Vaginal bleeding of unknown etiology
• Untreated endometrial hyperplasia
• Cardiovascular or cerebrovascular disorders, e.g. thrombophlebitis, thromboembolic processes, or a history of these conditions
• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
• Inherited thrombophilia
• Known thrombophilic disorders, e.g. protein C, protein S, or antithrombin deficiency
• Any history of thromboembolic disease, e.g. angina, myocardial infarction, stroke, or transient ischaemic attack (TIA)
• Severe liver disease, or a history of liver disease as long as liver function tests have failed to return to normal
• Porphyria
• Patients known with inherited genetic mutations: BRCA1 and BRCA2 genes
• Early menstrual periods (before the age of 12 years)
• History of non-cancerous breast diseases (atypical hyperplasia or lobular carcinoma in situ)
• Previous treatment using radiation therapy to the chest or breast
• Previous exposure to diethylstilbestrol (DES)

South African recommendations

Caution in the following patient groups

• Renal impairment
• Elderly

Considerations for use

• Tibolone is not intended for contraceptive use
• It is prescribed for the treatment of postmenopausal symptoms and should only be initiated for symptoms that adversely affect quality of life
• The use of tibolone should be avoided until 12 months after the last natural menstrual bleed
• If tibolone is taken sooner than this, the frequency of irregular bleeding may be increased

Considerations in bleeding

• Vaginal bleeding may occur during tibolone therapy, which is normally of short duration
• Bleeding commencing after 3 months of treatment, or recurrent or of longer duration should be investigated
• When changing to tibolone from any other form of hormonal substitution therapy, it is always advisable to induce a withdrawal bleeding with a progestogen before starting tibolone

Pre-menopausal considerations

• Tibolone has been shown to be teratogenic in experimental animals and should not be used in pre-menopausal women

Risk of stroke, breast cancer and endometrial cancer

• The risks of stroke, breast cancer and endometrial cancer 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, these conditions may recur or be aggravated during treatment with tibolone
  • Leiomyoma (uterine fibroids) or endometriosis
  • History of, or risk factors for, thromboembolic disorders
  • Risk factors for oestrogen dependant 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
  • History of endometrial hyperplasia
  • Epilepsy
  • Asthma
  • Otosclerosis

Reasons for immediate withdrawal therapy

• Tibolone therapy should be discontinued either in the case of a contraindication being discovered, or in any of the following situations
  • Jaundice or deterioration in liver function
  • Significant increase in blood pressure
  • New onset of migraine-type headache
  • Pregnancy
  • In the event that signs of thromboembolic processes occur, results of liver function tests become abnormal or if cholestatic jaundice appears

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 are at an increased risk of having endometrial cancer diagnosed
• 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
• 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
• 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
• In this study, a diagnosis of 0,8 additional cases of endometrial cancer in every 1 000 women who used tibolone for one year in this study were made

Breast Cancer

• Tibolone has combined estrogenic and progestogenic effects and therefore, on prolonged use, may increase the risk of developing breast cancer
• All women on tibolone should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations
• Women should be advised on what changes in their breasts should be reported to their doctor or nurse
• Mammography evaluations should be done based on patient age, risk factors, and prior mammogram results
• No data for persistence of risk after stopping are available for tibolone, but a similar pattern cannot be ruled out
• Hormone Replacement Therapy (HRT), especially oestrogen-progestogen 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
• Long-term (at least 5 to 10 years) use of oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer
• Some other studies suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk
• In one 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
• 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
• Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilisation, 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, tibolone 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, dyspnoea)

Coronary artery disease (CAD)

• There is no evidence from randomised controlled trials of protection against myocardial infarction in woman with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT
• In an epidemiological study using the General Practice Research Database (GPRD) no evidence was found of protection against myocardial infarction in post-menopausal women who received tibolone

Ischaemic stroke

• Tibolone increases the risk of stroke from the first year of treatment. The baseline risk of stroke is strongly age-dependent and so the effect of tibolone is greater with older age

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

• Long term use of oestrogen-only or combined oestrogen-progestogen HRT has been associated with an increased risk of ovarian cancer
• In one study, 5 years of HRT resulted in 1 extra case per 2 500 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
• The risk of coronary artery disease is increased in users of combined oestrogen-progestogen HRT over the age of 60
• 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

Other conditions

• 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 hormone replacement therapy, 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

Excipient cautions

• Tibolone contains lactose monohydrate
• Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, total lactose deficiency or glucose-galactose malabsorption should not take tibolone

Effects on ability to drive and use machines

• Tibolone is not known to have any effects on alertness and concentration. However, dizziness and visual disturbances may occur resulting in a minor influence on the ability to drive and use machines. Patients should be advised to exercise caution until they know how tibolone affects them

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Symptomatic treatment of hot flushes and associated sweating resulting from natural or surgical menopause
Prevention of post-menopausal osteoporosis
Improvement of bone-mineral density in patients with established post-menopausal osteoporosis

• Oral (tab): 2.5mg, dly

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Women experiencing a natural menopause should commence treatment with tibolone at least 12 months after their last natural bleed. In case of a surgical menopause, treatment with tibolone may commence immediately
Any irregular/unscheduled vaginal bleeding, either on or off hormone replacement therapy (HRT), should be fully investigated to exclude malignancy before starting tibolone

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Tibolone tablets should be swallowed whole with some water or other drink, preferably at the same time each day

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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

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

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Not intended for contraceptive use
Prescribed for the treatment of postmenopausal symptoms and should only be initiated for symptoms that adversely affect quality of life
The use of tibolone should be avoided until 12 months after the last natural menstrual bleed. If tibolone is taken sooner than this, the frequency of irregular bleeding may be increased

Not indicated for use in children

Pregnancy

South African recommendations

• Contraindicated
• Tibolone is contraindicated during pregnancy. If pregnancy occurs during medication with tibolone, treatment should be withdrawn immediately

Breastfeeding

South African recommendations

• Contraindicated

Fertility

South African recommendations

• In animal studies, tibolone, had anti-fertility activities by virtue of its hormonal properties

South African recommendations

• Caution; no dose adjustment recommended
  Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed

South African recommendations 

• Active liver disease, severe liver disease, or a history of liver disease as long as liver function tests have failed to return to normal: Contraindicated

South African recommendations

• Caution; no dose adjustment recommended

Metabolism and Nutrition Disorders

Frequent

• Weight increase

Gastrointestinal Disorders

Frequent

• Lower abdominal pain

Skin and Subcutaneous Tissue Disorders

Frequent

• Abnormal hair growth

Less frequent

• Acne

Reproductive System and Breast Disorders

Frequent

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

Less frequent

• Breast discomfort
• Fungal infection
• Vaginal mycosis
• Nipple pain

Investigations

Frequent

• Abnormal cervical smear

Less frequent

• Amnesia

• Anticoagulants
• Warfarin
• CYP3A4 substrates
• Midazolam
• CYP3A4 inducers
• Barbiturates
• Carbamazepine
• Hydantoins
• Rifampicin

Other interactions

• St. John's wort (Hypericum Perforatum)

• Breast examination
• Pelvic examination
• Periodic examinations must be done for endometrial hyperplasia, as well as possible signs of virilisation

Specific cases may require

• Mammography

Additional observations

• Complete personal and family medical history

Tibolone stabilises the hypothalamic-pituitary system after failure of ovarian function in the climacteric, which leads to the occurrence of vasomotor complaints as a result of the involvement of the thermoregulatory centre in the hypothalamus. The therapeutic central effect of tibolone is due to the combined estrogenic, progestogenic and weak androgenic activities of the medicine. Tibolone has a moderate gonadotrophin suppressing effect in post-menopausal woman. The peripheral effect of tibolone is the combination of hormonal activities which exerts a balanced effect and does not stimulate the endometrium in post-menopausal woman.

Tablet 2.5mg

• Livifem (MSD) originator