Patient leaflets and SmPCs, drug interaction checker, official and paediatric dosages, pregnancy and breastfeeding guidance, and NHS pharmacy opening hours — all in one place.
Patient leaflets and SmPCs, drug interaction checker, official and paediatric dosages, pregnancy and breastfeeding guidance, and NHS pharmacy opening hours — all in one place.
This medicine is a Hormone Replacement Therapy (HRT). It contains tibolone, a substance that has favourable effects on different tissues in the body, such as brain, vagina and bone. This medicine is used in postmenopausal women with at least 12 months (1 year) since their last natural period.
Breast cancer Evidence shows that taking tibolone increases the risk of breast cancer. The extra risk depends on how long you use tibolone. In studies with HRT, after stopping HRT the extra risk decreased with time, but the risk may persist for 10 years or more when women have used HRT for more than 5 years. No data for persistence of risk after stopping are available for tibolone, but a similar pattern cannot be ruled out.
This medicine is used for: Relief of symptoms occurring after menopause During the menopause, the amount of the oestrogen produced by a woman's body drops. This can cause symptoms such as hot face, neck and chest ("hot flushes"). Tibolone alleviates these symptoms after menopause. You will only be prescribed this medicine if your symptoms seriously hinder your daily life.
Prevention of osteoporosis After the menopause some women may develop fragile bones (osteoporosis). You should discuss all available options with your doctor. If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use Tibolone to prevent osteoporosis after menopause.
Compare Women taking Tibolone have a lower risk than women using combined HRT and a comparable risk with oestrogen-only HRT.
• Regularly check your breasts. See your doctor if you notice any changes such as:
In section 6, 'Contents of the pack and other information' you can find more information about Tibolone and what it is used for.
o dimpling or sinking of the skin o changes in the nipple o any lumps you can see or feel
Ovarian cancer Ovarian cancer is rare – much rarer than breast cancer. The use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer varies with age. For example, 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. For women who have been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case).
Before you start taking or restart HRT or Tibolone Your doctor will ask about your own and your family's medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and /or an internal examination, if necessary.
With use of Tibolone, the increased risk of ovarian cancer is similar to other types of HRT.
Regular check-ups Once you have started on Tibolone you should see your doctor for regular check-ups (at least once a year). At these check-ups, discuss with your doctor the benefits and risks of continuing with Tibolone.
Effect of HRT on heart and circulation Blood clots in a vein (thrombosis) The risk of blood clots in the veins is about 1.3 to 3-times higher in HRT users than in non-users, especially during the first year of taking it.
Go for regular breast screening, as recommended by your doctor.
Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death.
Some women should not take Tibolone Do not take Tibolone If any of the following applies to you. If you are not sure about any of the points below, talk to your doctor before taking Tibolone • If you have or have ever had breast cancer, or if you are suspected of having it • If you have cancer which is sensitive to oestrogens, such as cancer of the womb lining (endometrium), or if you are suspected of having it • If you have any unexplained vaginal bleeding • If you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated. • If you have or have ever had a blood clot in a vein (thrombosis), such as in the legs (deep venous thrombosis) or the lungs (pulmonary embolism) • If you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency) • If you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina • If you have or have ever had a liver disease and your liver function tests have not returned to normal • If you have a rare blood problem called "porphyria" which is passed down in families (inherited) • If you are allergic to tibolone or any of the other ingredients of this medicine (listed in section 6) • If you are pregnant or think you might be pregnant. • If you are breastfeeding.
You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations apply to you: • you are pregnant or recently had a baby • you use oestrogens • you are unable to walk for a long time because of major surgery, injury or illness (see also section 3, If you need to have surgery) • you are seriously overweight (BMI >30 kg/m2) • you have any blood clotting problem that needs longterm treatment with a medicine used to prevent blood clots • if any of your close relatives has ever had a blood clot in the leg, lung or another organ • you have systemic lupus erythematosus (SLE) • you have cancer.
For signs of a blood clot, see "Stop taking Tibolone and see a doctor immediately".
Compare Looking at women in their 50s who are not taking HRT, on average, over a 5 year period, 4 to 7 in 1000 would be expected to get a blood clot in a vein.
For women in their 50s who have been taking oestrogenprogestogen HRT for over 5 years, there will be 9 to 12 cases in 1000 users (i.e. an extra 5 cases).
With use of Tibolone the increased risk of getting a blood clot in a vein is lower than with other types of HRT.
Heart disease (heart attack) There is no evidence that HRT or Tibolone will prevent a heart attack.
If any of the above conditions appear for the first time while taking Tibolone stop taking it at once and consult your doctor immediately.
Women over the age of 60 who use oestrogen-progestogen HRT are slightly more likely to develop heart disease than those not taking any HRT. As the risk of heart disease strongly depends on age, the number of extra cases of heart disease due to use of oestrogen-progestogen HRT is very low in healthy women close to menopause, but will rise with more advanced age. There is no evidence to suggest that the risk of myocardial infarction with Tibolone is different to the risk of other HRT.
Warnings and precautions Talk to your doctor, pharmacist or nurse before taking Tibolone
If you have ever had any of the following problems, tell your doctor before you start the treatment, as these may return or become worse during treatment with Tibolone. If so, you should see your doctor more often for check-ups: • fibroids inside your womb • growth of the womb lining outside your womb (endometriosis) or a history of excessive growth of the womb lining (endometrial hyperplasia) • increased risk of developing blood clots (see "Blood clots in a vein (thrombosis)") • increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer) • high blood pressure • a liver disorder, such as a benign liver tumour • diabetes • gallstones • migraine or severe headaches • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE) • epilepsy • asthma • a disease affecting the eardrum and hearing (otosclerosis) • a very high level of fat in your blood (triglycerides) • fluid retention due to cardiac or kidney problems
Stroke Recent research suggests that HRT and Tibolone slightly increases the risk of having a stroke. The increased risk is seen mainly in women over 60 years old.
Compare Looking at women in their 50s who are not taking Tibolone – on average, over a 5-year period, 3 in 1000 would be expected to have a stroke.
For women in their 50s who are taking Tibolone , the figure would be 7 in 1000 (i.e. an extra 4 cases).
Looking at women in their 60s who are not taking Tibolone – on average, over a 5-year period, 11 in 1000 would be expected to have a stroke.
For women in their 60s who are taking Tibolone , the figure would be 24 in 1000 (i.e. an extra 13 cases).
Other conditions HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Speak to your doctor for advice.
Stop taking Tibolone and see a doctor immediately If you notice any of the following when taking Tibolone • any of the conditions mentioned in the "Do not take Tibolone " section • yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease • a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness)
Other medicines and Tibolone Some medicines may interfere with the effect of Tibolone This might lead to irregular bleeding. This applies to the following medicines: • Medicines against blood clotting (such as warfarin) • Medicines for epilepsy (such as phenobarbital, phenytoin and carbamazepin)
180 x 600 mm Front Side 180 x 600 mm Back Side
Tibolone 2.5 mg tablets
180 x 600 mm
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The Marketing Authorisation Holder and Manufacturer: Strides Pharma UK Ltd. Unit 4, The Metro Centre, Dwight Road, Watford WD18 9SS, United Kingdom
The recommended dose is one tablet every day. Take this dose unless your doctor or pharmacist told you to do something different.
Press the tablet so that it comes through the foil. Swallow the tablet with some water or other drink, without chewing.
This leaflet was revised in 11/2022
Take Tibolone at the same time each day. The strips of tablets are marked with the days of the week. Start by taking a tablet marked with the current day. For example, if it is Monday, take a tablet marked Monday on the top row of the strip. Follow the arrows until the strip is empty. Start the next strip the next day. Do not leave a break between strips or packs.
More about Tibolone In women, the most important sex hormones are estrogens and progestagens. These hormones are necessary for the normal sexual development of women and have an important role in regulating the menstrual cycle. Estrogens play an important role in the formation of bones. The bones are formed during youth and the peak of bone mass is reached between the 20-30 years of age. After this age, the bone mass decreases, first slowly, but in later ages the loss of bone mass is accelerated, especially after menopause. The period in which this happens (usually around the age of 50) is called climacteric or menopause. If the ovaries are removed surgically (ovariectomy) before menopause, the decrease in hormone production will occur very abruptly.
You should not take Tibolone until 12 months after your last natural menstruation. If Tibolone is taken before this period of time, the likelihood of irregular vaginal hemorrhaging may be increased.
Your doctor will aim to prescribe the lowest dose to treat your symptoms for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough.
In many cases, this decrease in hormone production leads to well-known menopausal complaints, such as hot flashes and night sweats. Lack of sex hormones can also cause the vaginal wall to become thinner and drier. For this reason, intercourse can become painful and vaginal infections may be more frequent. In many women, these physical problems are accompanied by mood swings, nervousness, depression, irritability, and loss of sexual desire.
If you take more Tibolone than you should It is unlikely that taking more than one tablet will do you any harm, but you may feel sick, be sick or have some vaginal bleeding. If you take more Tibolone than you should, you should see a doctor or pharmacist immediately. If you have taken too much Tibolone , immediately contact your doctor, pharmacist or Poison control center.
If you forget to take Tibolone If you forget to take a tablet, take it as soon as you remember, unless you are more than 12 hours late. If you are more than 12 hours late, just skip it, and take your next tablet at the usual time. Don't take a double dose.
One problem that often goes unnoticed is the rapid bone loss that occurs in many women after menopause. For this reason, the bones become brittle and can break easily (osteoporosis), especially the spine, hip and wrists. Osteoporosis can also cause back pain, weight loss and back curvature.
If you need to have surgery If you are going to have surgery, tell the surgeon that you are taking Tibolone. You may need to stop taking Tibolone about 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, 'Blood clots in a vein'). Ask your doctor when you can start taking Tibolone again.
Tibolone contains tibolone, a substance that has beneficial effects of sex hormones on different tissues of the body such as brain, vagina and bone. This results in Tibolone relieving menopausal complaints, such as hot flashes and night sweats. This medicine also has a stimulating effect on the inner lining of the vagina, and a favourable effect on mood and sexual desire. Tibolone stops and also treats the osteoporosis process, i.e. the bone loss that occurs after menopause, in the spine, hip and wrists. Unlike other medications used in hormone replacement therapy, Tibolone does not stimulate the lining of the uterus (endometrium). Therefore, treatment with Tibolone does not cause monthly vaginal bleeding.
The following diseases are reported more often in women using HRT compared to women not using HRT: • breast cancer • abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer) • ovarian cancer • blood clots in the veins of the legs or lungs (venous thromboembolism) • heart disease • stroke • probable memory loss if HRT is started over the age of 65 For more information about these side effects, see section 2.
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are mild.
Other side effects Common (may affect up to 1 in 10 women): • breast pain • stomach or pelvic pain • unusual hair growth • vaginal bleeding or spotting. • vaginal problems such as more secretions, itching, irritation and thrush • weight gain.
Uncommon (may affect up to 1 in 100 women): • swollen hands, ankles or feet – a sign of fluid retention • stomach upset • acne • painful nipples or breasts feeling uncomfortable • vaginal infections
Rare (may affect up to 1 in 1000 women): • itchy skin
Some women taking Tibolone have also reported: • depression, dizziness, migraine, headache • joint pain or muscle pain • skin problems such as rash or itching • loss of vision or blurred vision • Gastrointestinal disorders • changes in liver tests • Water retention
There have been reports of breast cancer and of an increased cell growth or cancer of the lining of the womb in women using Tibolone.
→Tell your doctor if any of the above mentioned side effects continues or becomes troublesome.
The following side effects have been reported with other HRTs: • gall bladder disease • various skin disorders:
− discolouration of the skin especially of the face or neck known as "pregnancy patches" (chloasma) − painful reddish skin nodules (erythema nodosum) − rash with target-shaped reddening or sores (erythema multiforme) − ''Purpura vascular "- small haemorrhagic points on the skin
Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side affects you can help provide more information on the safety of this medicine.
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• Medicines for tuberculosis (such as rifampicin) • Herbal remedies containing St John's Wort (Hypericum perforatum).
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after 'EXP'. The expiry date refers to the last day of that month.
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription, herbal medicines or other natural products.
This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
Tibolone with food and drink You can eat or drink normally while you are taking Tibolone
Pregnancy and breast-feeding Tibolone is for use in postmenopausal women only. If you become pregnant, stop taking Tibolone and contact your doctor.
What Tibolone contains The active substance is tibolone. The other ingredients are potato starch, lactose monohydrate, ascorbyl palmitate, anhydrous lactose and magnesium stearate.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines Tibolone has no known effect on the ability to drive or use machines.
What Tibolone looks like and the contents of the pack Tibolone tablets are White to off white, circular with flat face beveled edge, uncoated tablet debossed with 'TO above 2' on one side and plain on other side. Approximate Diameter 6.00±0.20 mm.
Tibolone contains Lactose If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before using Tibolone.
Tibolone tablets are packaged in blisters consisting of a transparent polyvinyl chloride film and an aluminium blister foil. The following packages are available: Carton packs containing 1, 3 blisters of 28 tablets and Carton packs containing 2,3 blisters of 10 tablets.
Tibolone 2.5 mg Tablets comes as tablet containing 2.5mg. Always follow the dose your doctor or pharmacist has given you, and read the leaflet that comes with the medicine.
The active substance in Tibolone 2.5 mg Tablets is tibolone.
Medicines with the same active substance, strength and form include: Livial 2.5mg tablets, Tibolone 2.5 mg tablets, Tibolone 2.5 mg tablets. They are interchangeable only if your prescriber or pharmacist says so.
This leaflet reproduces the patient information leaflet approved for Tibolone 2.5 mg Tablets, as published on the electronic medicines compendium (emc). The version printed inside your medicine’s packaging is the one that applies to you.
Whether a medicine is available over the counter or on prescription only depends on its licence. Check the leaflet, or ask your pharmacist — they can tell you straight away.
The text above reproduces the patient information leaflet approved for this medicine, restructured for easier reading.
• Treatment of oestrogen deficiency symptoms in postmenopausal women, more than one year after menopause.
• Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis. (See also section 5.1.)
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).
Posology
The dosage is one tablet per 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 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 HRT, should be investigated to exclude malignancy before starting Tibolone (see section 4.3).
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.
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.
Elderly
No dose adjustment is necessary for the elderly. Paediatric population
There is no relevant use of Tibolone in the paediatric population.
Method of administration
Oral use. The tablets should be swallowed with some water or other drink, preferably at the same time every day.
• Pregnancy and lactation
• Known, past or suspected breast cancer – Tibolone 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)
• Any history of 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
• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
• Porphyria
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 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 (see also below and section 4.8).
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. 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.
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. 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
• Pregnancy
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.
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.
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 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, 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)
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 total 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 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.
Since Tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants. This effect has been demonstrated with warfarin. Caution should therefore be exercised during the simultaneous use of Tibolone and anticoagulants, especially when starting or stopping concurrent Tibolone treatment. If necessary, the dose of warfarin should be adjusted.
There is limited information regarding pharmacokinetic interactions with tibolone. An in vivo study showed that simultaneous treatment of tibolone affects pharmacokinetics of the cytochrome P450 3A4 substrate midazolam to a moderate extent. Based on this, drug interactions with other CYP3A4 substrates might be expected.
Compounds that induce CYP3A4 activity 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 progestogens via CYP3A4. Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
Pregnancy
Tibolone is contraindicated during pregnancy (see section 4.3). 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.
Breast-feeding
Tibolone is contraindicated during breast-feeding (see section 4.3).
Fertility
In animal studies, Tibolone had anti-fertility activities by virtue of its hormonal properties.
Tibolone 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 Tibolone 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 Tibolone than with placebo.
Table 1 Undesirable effects of Tibolone
System organ class
Common >1%, <10%
Uncommon >0.1%, <1%
Rare >0.01%, <0.1%
Metabolism and nutrition disorders
Oedema**
Gastrointestinal disorders
Lower abdominal pain
Abdominal discomfort**
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
• 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 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.
Table 2 Million Women study – Estimated additional risk of breast cancer after 5 years' use
Age range (years)
Additional cases per 1,000 never-users of HRT over a 5 year period*
Risk ratio & 95%CI# ratio
Additional cases per 1,000 HRT users over 5 years (95%CI)
Oestrogen only HRT
50-65
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)
*With reference to the baseline incidence in developed countries
#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of use.
Endometrial cancer risk Postmenopausal women with a uterus
The endometrial cancer risk is about 5 in every 1,000 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 1,000 women who used Tibolone for one year in this study (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 (28/2,249) compared with placebo (13/2,257). 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 1,000 women aged 50-59 years and 11 per 1,000 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 1,000 users aged 60-69 years.
Other adverse reactions have been reported in association with oestrogen and oestrogen-progestogen treatment:
- Ovarian cancer
Long-term use of estrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4). 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
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 years taking 5 years of HRT, this results in about 1 extra case per 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 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 2,500 users (see section 4.4).
Risk of venous thromboembolism
- 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:
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-only*4
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)
Risk of coronary artery disease
- 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.
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.
- The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
- 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 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 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.
Table 4 WHI Studies combined - Additional risk of ischaemic stroke 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 over 5 years
50-59
8
1.3 (1.1-1.6)
3 (1-5)
Other adverse reactions have been reported in association with oestrogen/progestogen treatment:
-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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
Ask anything about Tibolone 2.5 mg Tablets. The assistant answers only from this leaflet — if the leaflet does not cover it, it will say so. It does not give medical advice.
Answers come from the patient leaflet published on the electronic medicines compendium (emc). They are not medical advice. Ask a pharmacist or your GP if you are unsure. For urgent help call NHS 111, or 999 in an emergency.
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