oestrogen-progestogen combinations. The level of risk is symptoms. Tibolone prevents bone loss following Ischaemic stroke oestrogens and progestogens via CYP3A4. Clinically, an dependent on the duration of use. menopause or ovariectomy. continuous-combined HRT preparation, treatment can taken. Physical (including pelvic and breast) examination stopping treatment • Tibolone increases the risk of ischaemic stroke from the increased metabolism of oestrogens and progestogens Endometrial cancer risk Pharmacokinetic properties start at any time. should be guided by this and by the contraindications and Ovarian cancer rst year of treatment. The baseline risk of stroke is may lead to decreased eect and changes in the uterine Postmenopausal women with a uterus Absorption and biotransformation Missed dose warnings for use. During treatment, periodic check-ups • Ovarian cancer is much rarer than breast cancer. strongly age-dependent and so the eect of Tibolone is bleeding prole. The endometrial cancer risk is about 5 in every 1000 Following oral administration, Tibolone is rapidly and A missed dose should be taken as soon as remembered, are recommended of a frequency and nature adapted to Long-term (at least 5-10 years) use of estrogen-only HRT greater with older age. Pregnancy and Breastfeeding women with a uterus not using HRT or Tibolone. extensively absorbed. Due to rapid metabolism, the unless it is more than 12 hours overdue. In the latter case, the individual woman. Women should be advised what products may be associated with a slightly increased risk Other conditions Tibolone is contraindicated during pregnancy. If Ovarian cancer plasma levels of Tibolone are very low. The plasma levels the missed dose should be skipped and the next dose changes in their breasts should be reported to their doctor of ovarian cancer. Data suggest that the long-term use of • Patients with rare hereditary problems of galactose pregnancy occurs during medication with Tibolone, Use of estrogen-only or combined estrogen-progestogen of the ∆4-isomer of Tibolone are also very low. Therefore ( ) should be taken at the normal time. Missing a dose may or nurse. Investigations, including appropriate imaging combined HRTs may confer a similar or slightly smaller intolerance, the Lapp lactase deciency or treatment should be withdrawn immediately. For HRT may be associated with a slightly increased risk of some of the pharmacokinetic parameters could not be increase the likelihood of breakthrough bleeding and tools, e.g. mammography, should be carried out in risk. Data suggests that the relative risk for ovarian cancer glucose-galactose malabsorption should not take this Tibolone no clinical data on exposed pregnancies are having ovarian cancer diagnosed. determined. Peak plasma levels of the 3α-OH and the 3 spotting. accordance with currently accepted screening practices, with use of Tibolone is similar to the risk associated with QUALITATIVE AND QUANTITATIVE COMPOSITION medicine. available. The potential risk for humans is unknown. Tibol Risk of venous thromboembolism β-OH metabolites are higher but accumulation does not Dosage Adjustment modied to the clinical needs of the individual. use of other types of HRT. Each tablet contains: • Tibolone is not intended for contraceptive use. is contraindicated during breastfeeding. HRT is associated with a 1.3-3-fold increased relative risk of occur. Pediatrics Conditions which need supervision Venous thromboembolism Tibolone (BP)…………………… 2.5 mg • Treatment with Tibolone results in a marked developing venous thromboembolism (VTE), i.e. deep Elimination There is no relevant use of Tibol (Tibolone) in the • If any of the following conditions are present, have • Estrogen or estrogen-progestogen HRT is associated dose-dependent decrease in HDL cholesterol (from E ects on ability to drive and use machines vein thrombosis or pulmonary embolism. The occurrence Excretion of Tibolone is mainly in the form of conjugated paediatric population. occurred previously, and / or have been aggravated with a 1.3-3 fold risk of developing venous DESCRIPTION -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose Tibolone is not known to have any eects on alertness and of such an event is more likely in the rst year of using HRT. (mostly sulfated) metabolites. Part of the administered Elderly during pregnancy or previous hormone treatment, the thromboembolism (VTE), i.e. deep vein thrombosis or Tibol (Tibolone) is a synthetic anabolic steroid with after 2 years). Total triglycerides and lipoprotein(a) levels concentration. Risk of coronary artery disease compound is excreted in the urine, but most is eliminated No dose adjustment is necessary for the elderly. patient should be closely supervised. It should be taken pulmonary embolism. The occurrence of such an event is estrogenic, androgenic and progestogenic activities. are also known to be reduced. The decrease in total The risk of coronary artery disease is slightly increased in via the feces. Administration Requirements into account that these conditions may recur or be more likely in the rst year of HRT than later. Data suggests Tibolone is a 19-nortestosterone derivative and is related cholesterol and VLDL-C levels is not dose-dependent. Adverse Reactions users of combined estrogen-progestogen HRT over the The consumption of food has no signicant eects on the The tablets should be swallowed with some water or other aggravated during treatment with Tibolone, in particular: that the risk of VTE in association with Tibolone is lower structurally to other 19-nortestosterone progestins.It is Levels of LDL-C are unchanged. The clinical implication of age of 60. There is no evidence to suggest that the risk of extent of absorption. drink, preferably at the same time every day. • Leiomyoma (uterine broids) or endometriosis than the risk associated with conventional HRT, but only a the 7α-methyl derivative of noretynodrel. these ndings is not yet known. myocardial infarction with Tibolone is dierent to the risk The pharmacokinetic parameters for Tibolone and its • Risk factors for thromboembolic disorders small proportion of women are current users of Tibolone • Estrogens may cause uid retention, and therefore with other HRT. metabolites are found to be independent of renal H H O C Contraindications • Risk factors for estrogen dependent tumors, e.g. and a small increase in risk compared with non-use cannot C patients with cardiac or renal dysfunction should be Risk of ischaemic stroke function. • Pregnancy and lactation rst degree heredity for breast cancer be excluded. H carefully observed. • The relative risk of ischaemic stroke is not dependent on • Known, past or suspected breast cancer known or • Hypertension • Patients with known thrombophilic states have an HH • Women with pre-existing hypertriglyceridemia should age or on duration of use, but as the baseline risk is PHARMACEUTICAL INFORMATION suspected estrogen dependent malignant tumors (e.g. • Liver disorders (e.g. liver adenoma) increased risk of VTE and HRT or Tibolone may add to this O be followed closely during estrogen replacement or HRT, strongly age-dependent, the overall risk of ischaemic Shelf life endometrial cancer) • Diabetes mellitus with or without vascular involvement risk. HRT is therefore contraindicated in these patients. since rare cases of large increases of plasma triglycerides stroke in women who use HRT or Tibolone will increase 2 years • Undiagnosed genital bleeding • Cholelithiasis • Generally recognized risk factors for VTE include use of CLINICAL INFORMATION leading to pancreatitis are known to occur with estrogen with age. • Untreated endometrial hyperplasia • Migraine or (severe) headache estrogens, older age, major surgery, prolonged Indications therapy in this condition. • The use of estrogen-only and estrogen + progestogen Special Precautions for Storage • Previous or current venous thromboembolism (deep • Systemic lupus erythematosis immobilization, obesity (BMI > 30 kg/m2), • Treatment of estrogen deciency symptoms in • Treatment with Tibolone results in a very minor decrease therapy is associated with an up to 1.5 fold increased • Store below 25°C. venous thrombosis, pulmonary embolism) • A history of endometrial hyperplasia pregnancy/postpartum period, systemic lupus postmenopausal women, more than one year after of thyroid binding globulin (TBG) and total T4. Levels of relative risk of ischaemic stroke. The risk of haemorrhagic • Protect from light and moisture. • Known thrombophilic disorders (e.g. protein C, protein S, • Epilepsy erythematosus (SLE), and cancer. There is no consensus menopause. total T3 are unaltered. Tibolone decreases the level of stroke is not increased during use of HRT. • Keep out of the reach of children. or antithrombin deciency) • Asthma about the possible role of varicose veins in VTE. As in all • Prevention of osteoporosis in postmenopausal women at sex-hormone-binding globulin (SHBG), whereas the levels Other adverse reactions that may be associated with • Any history of arterial thromboembolic disease (e.g. • Otosclerosis postoperative patients, prophylactic measures need be high risk of future fractures who are intolerant of, or of corticoid binding globulin (CBG) and circulating cortisol estrogen/progestogen treatment: To be sold on the prescription of a angina, myocardial infarction, stroke or TIA) Reasons for immediate withdrawal of therapy considered to prevent VTE following surgery. If prolonged contraindicated for, other medicinal products approved are unaected. • Gall bladder disease registered medical practitioner only. • Acute liver disease or a history of liver disease as long as Therapy should be discontinued in case a contraindication immobilisation is to follow elective surgery temporarily for the prevention of osteoporosis. • HRT use does not improve cognitive function. There is • Skin and subcutaneous disorders: chloasma, erythema liver function tests have failed to return to normal is discovered and in the following situations: stopping HRT or Tibolone 4 to 6 weeks earlier is For all women the decision to prescribe Tibol (Tibolone) some evidence of increased risk of probable dementia in multiforme, erythema nodosum, vascular purpura Nature and contents of container • Known hypersensitivity to the active substance • Jaundice or deterioration in liver function recommended. Treatment should not be restarted until should be based on an assessment of the individual women who start using continuous combined or • Probable dementia over the age of 65 Tibol (Tibolone) 2.5 mg tablets are available in a blister • Porphyria • Signicant increase in blood pressure the woman is completely mobilised. patient’s overall risks and, particularly in the over 60s, estrogen-only HRT after the age of 65. pack of 28‘s (1 x 28’s). • New onset of migraine-type headache • In women with no personal history of VTE but with a rst should include consideration of the risk of stroke. Overdose Warnings and Precautions Endometrial hyperplasia and carcinoma degree relative with a history of thrombosis at young age, Interactions The acute toxicity of Tibolone is very low. Therefore, toxic For the treatment of postmenopausal symptoms, • Data suggests that women who are prescribed Tibolone screening may be oered after careful counselling Dosage and Administration • Since Tibolone may increase blood brinolytic activity, it symptoms are not expected to occur, even when several Tibolone should only be initiated for symptoms that in normal clinical practice are at an increased risk of having regarding its limitations (only a proportion of The dosage is one tablet per day. For initiation and may enhance the eect of anticoagulants. This eect may tablets are taken simultaneously. In cases of acute adversely aect quality of life. In all cases, a careful endometrial cancer diagnosed. Risk may be increased thrombophilic defects are identied by screening). If a continuation of treatment of postmenopausal symptoms, be seen with warfarin. Caution should therefore be overdose, nausea, vomiting and vaginal bleeding in appraisal of the risks and benets should be undertaken at with increasing duration of use. Tibolone increases thrombophilic defect is identied which segregates with the lowest eective dose for the shortest duration should exercised during the simultaneous use of Tibolone and females may occur. No specic antidote is known. least annually and Tibolone should only be continued as endometrial wall thickness, as measured by transvaginal thrombosis in family members or if the defect is ‘severe’ be used. A separate progestogen should not be added anticoagulants, especially when starting or stopping Symptomatic treatment can be given if necessary. long as the benet outweighs the risk. ultrasound. (e.g, antithrombin, protein S, or protein C deciencies or a with Tibol (Tibolone) treatment. concurrent Tibolone treatment. If necessary, the dose of The risks of stroke, breast cancer and, in women with an • Break-through bleeding and spotting may occur during combination of defects) HRT or Tibolone is Starting Tibol (Tibolone) warfarin should be adjusted. PHARMACOLOGICAL PROPERTIES intact uterus, endometrial cancer (below) for each woman the rst months of treatment. Women should be advised contraindicated. Women experiencing a natural menopause should • There is limited information regarding pharmacokinetic Pharmacotherapeutic group: ATC code: G03CX01, other should be carefully assessed, in the light of her individual to report any break-through bleeding or spotting if it is • Women already on anticoagulant treatment require commence treatment with Tibol (Tibolone) at least 12 interactions with Tibolone. Data indicates that estrogens risk factors and bearing in mind the frequency and still present after 6 months of treatment, if it starts beyond careful consideration of the benet-risk of use of HRT or months after their last natural bleed. In case of a surgical simultaneous treatment of Tibolone aects Other adverse reactions that may be observed include: Pharmacodynamic properties characteristics of both cancers and stroke, in terms of their that time or if it continues after treatment has been Tibolone. menopause, treatment with Tibol (Tibolone) may pharmacokinetics of the cytochrome P450 3A4 substrate dizziness, rash, seborrheic dermatosis, headache, Following oral administration, Tibolone is rapidly response to treatment, morbidity and mortality. discontinued. The woman should be referred for • If VTE develops after initiating therapy, the drug should commence immediately. midazolam to a moderate extent. Based on this, drug migraine, visual disturbances (including blurred vision), metabolized into three compounds, which all contribute Evidence regarding the risks associated with HRT or gynecological investigation, which is likely to include be discontinued. Patients should be told to contact their Any irregular/unscheduled vaginal bleeding, either on or interactions with other CYP3A4 substrates might be depression, eects on the musculoskeletal system such as to the pharmacodynamic prole of Tibolone. Two of the Tibolone in the treatment of premature menopause is endometrial biopsy to exclude endometrial malignancy. doctors immediately when they are aware of a potential o HRT, should be investigated to exclude malignancy expected. arthralgia or myalgia and changes in liver function metabolites (3α-OH-Tibolone and 3β-OH-Tibolone) have limited. Due to the low level of absolute risk in younger Breast cancer thromboembolic symptom (e.g. painful swelling of a leg, before starting Tibol (Tibolone). • CYP3A4 inducing compounds such as barbiturates, parameters. estrogenic-like activities, whereas the third metabolite ( ∆ women, however, the balance of benets and risks for • Evidence with respect to breast cancer risk in association sudden pain in the chest, dyspnea). Switching from a sequential or continuous combined carbamazepine, hydantoins and rifampicin may enhance Breast cancer 4-isomer of Tibolone) has progestogenic and these women may be more favourable than in older with Tibolone is inconclusive. Data suggests a signicant Coronary artery disease (CAD) HRT preparation the metabolism of Tibolone and thus aect its therapeutic An up to 2-fold increased risk of having breast cancer androgenic-like activities. women. increase in the risk of breast cancer in association with use There is no evidence of protection against myocardial If changing from a sequential HRT preparation, treatment eect. diagnosed may be observed in women taking combined Tibolone substitutes for the loss of estrogen production in Medical examination/follow-up of the 2.5mg dose. This risk may become apparent within infarction in women with or without existing CAD who with Tibol (Tibolone) should start the day following • Herbal preparations containing St. John`s wort oestrogen-progestogen therapy for more than 5 years. postmenopausal women and alleviates menopausal • Before initiating or reinstituting HRT or Tibolone, a a few years of use and increased with duration of intake, received combined estrogen-progestogen or completion of the prior regimen. If changing from a (Hypericum Perforatum) may induce the metabolism of Any increased risk in users of oestrogen-only and Tibolone complete personal and family medical history should be returning to baseline within a few (at most ve) years after estrogen-only HRT. therapies is substantially lower than in users of 1 oestrogen-progestogen combinations. The level of risk is symptoms. Tibolone prevents bone loss following Ischaemic stroke oestrogens and progestogens via CYP3A4. Clinically, an dependent on the duration of use. menopause or ovariectomy. continuous-combined HRT preparation, treatment can taken. Physical (including pelvic and breast) examination stopping treatment • Tibolone increases the risk of ischaemic stroke from the increased metabolism of oestrogens and progestogens Endometrial cancer risk Pharmacokinetic properties start at any time. should be guided by this and by the contraindications and Ovarian cancer rst year of treatment. The baseline risk of stroke is may lead to decreased eect and changes in the uterine Postmenopausal women with a uterus Absorption and biotransformation Missed dose warnings for use. During treatment, periodic check-ups • Ovarian cancer is much rarer than breast cancer. strongly age-dependent and so the eect of Tibolone is bleeding prole. The endometrial cancer risk is about 5 in every 1000 Following oral administration, Tibolone is rapidly and A missed dose should be taken as soon as remembered, are recommended of a frequency and nature adapted to Long-term (at least 5-10 years) use of estrogen-only HRT greater with older age. Pregnancy and Breastfeeding women with a uterus not using HRT or Tibolone. extensively absorbed. Due to rapid metabolism, the unless it is more than 12 hours overdue. In the latter case, the individual woman. Women should be advised what products may be associated with a slightly increased risk Other conditions Tibolone is contraindicated during pregnancy. If Ovarian cancer plasma levels of Tibolone are very low. The plasma levels the missed dose should be skipped and the next dose changes in their breasts should be reported to their doctor of ovarian cancer. Data suggest that the long-term use of • Patients with rare hereditary problems of galactose pregnancy occurs during medication with Tibolone, Use of estrogen-only or combined estrogen-progestogen of the ∆4-isomer of Tibolone are also very low. Therefore should be taken at the normal time. Missing a dose may or nurse. Investigations, including appropriate imaging combined HRTs may confer a similar or slightly smaller intolerance, the Lapp lactase deciency or treatment should be withdrawn immediately. For HRT may be associated with a slightly increased risk of some of the pharmacokinetic parameters could not be increase the likelihood of breakthrough bleeding and tools, e.g. mammography, should be carried out in risk. Data suggests that the relative risk for ovarian cancer glucose-galactose malabsorption should not take this Tibolone no clinical data on exposed pregnancies are having ovarian cancer diagnosed. determined. Peak plasma levels of the 3α-OH and the 3 spotting. accordance with currently accepted screening practices, with use of Tibolone is similar to the risk associated with QUALITATIVE AND QUANTITATIVE COMPOSITION medicine. available. The potential risk for humans is unknown. Tibol Risk of venous thromboembolism β-OH metabolites are higher but accumulation does not Dosage Adjustment modied to the clinical needs of the individual. use of other types of HRT. Each tablet contains: • Tibolone is not intended for contraceptive use. is contraindicated during breastfeeding. HRT is associated with a 1.3-3-fold increased relative risk of occur. Pediatrics Conditions which need supervision Venous thromboembolism Tibolone (BP)…………………… 2.5 mg • Treatment with Tibolone results in a marked developing venous thromboembolism (VTE), i.e. deep Elimination There is no relevant use of Tibol (Tibolone) in the • If any of the following conditions are present, have • Estrogen or estrogen-progestogen HRT is associated dose-dependent decrease in HDL cholesterol (from E ects on ability to drive and use machines vein thrombosis or pulmonary embolism. The occurrence Excretion of Tibolone is mainly in the form of conjugated paediatric population. occurred previously, and / or have been aggravated with a 1.3-3 fold risk of developing venous DESCRIPTION -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose Tibolone is not known to have any eects on alertness and of such an event is more likely in the rst year of using HRT. (mostly sulfated) metabolites. Part of the administered Elderly during pregnancy or previous hormone treatment, the thromboembolism (VTE), i.e. deep vein thrombosis or Tibol (Tibolone) is a synthetic anabolic steroid with after 2 years). Total triglycerides and lipoprotein(a) levels concentration. Risk of coronary artery disease compound is excreted in the urine, but most is eliminated No dose adjustment is necessary for the elderly. patient should be closely supervised. It should be taken pulmonary embolism. The occurrence of such an event is estrogenic, androgenic and progestogenic activities. are also known to be reduced. The decrease in total The risk of coronary artery disease is slightly increased in via the feces. Administration Requirements into account that these conditions may recur or be more likely in the rst year of HRT than later. Data suggests Tibolone is a 19-nortestosterone derivative and is related cholesterol and VLDL-C levels is not dose-dependent. Adverse Reactions users of combined estrogen-progestogen HRT over the The consumption of food has no signicant eects on the The tablets should be swallowed with some water or other aggravated during treatment with Tibolone, in particular: that the risk of VTE in association with Tibolone is lower structurally to other 19-nortestosterone progestins.It is Levels of LDL-C are unchanged. The clinical implication of age of 60. There is no evidence to suggest that the risk of extent of absorption. drink, preferably at the same time every day. • Leiomyoma (uterine broids) or endometriosis than the risk associated with conventional HRT, but only a the 7α-methyl derivative of noretynodrel. these ndings is not yet known. myocardial infarction with Tibolone is dierent to the risk The pharmacokinetic parameters for Tibolone and its • Risk factors for thromboembolic disorders small proportion of women are current users of Tibolone • Estrogens may cause uid retention, and therefore with other HRT. metabolites are found to be independent of renal Contraindications • Risk factors for estrogen dependent tumors, e.g. and a small increase in risk compared with non-use cannot patients with cardiac or renal dysfunction should be Risk of ischaemic stroke function. • Pregnancy and lactation rst degree heredity for breast cancer be excluded. carefully observed. • The relative risk of ischaemic stroke is not dependent on • Known, past or suspected breast cancer known or • Hypertension • Patients with known thrombophilic states have an • Women with pre-existing hypertriglyceridemia should age or on duration of use, but as the baseline risk is PHARMACEUTICAL INFORMATION suspected estrogen dependent malignant tumors (e.g. • Liver disorders (e.g. liver adenoma) increased risk of VTE and HRT or Tibolone may add to this be followed closely during estrogen replacement or HRT, strongly age-dependent, the overall risk of ischaemic Shelf life endometrial cancer) • Diabetes mellitus with or without vascular involvement risk. HRT is therefore contraindicated in these patients. since rare cases of large increases of plasma triglycerides stroke in women who use HRT or Tibolone will increase 2 years • Undiagnosed genital bleeding • Cholelithiasis • Generally recognized risk factors for VTE include use of CLINICAL INFORMATION leading to pancreatitis are known to occur with estrogen with age. • Untreated endometrial hyperplasia • Migraine or (severe) headache estrogens, older age, major surgery, prolonged Indications therapy in this condition. • The use of estrogen-only and estrogen + progestogen Special Precautions for Storage • Previous or current venous thromboembolism (deep • Systemic lupus erythematosis immobilization, obesity (BMI > 30 kg/m2), • Treatment of estrogen deciency symptoms in • Treatment with Tibolone results in a very minor decrease therapy is associated with an up to 1.5 fold increased • Store below 25°C. venous thrombosis, pulmonary embolism) • A history of endometrial hyperplasia pregnancy/postpartum period, systemic lupus postmenopausal women, more than one year after of thyroid binding globulin (TBG) and total T4. Levels of relative risk of ischaemic stroke. The risk of haemorrhagic • Protect from light and moisture. • Known thrombophilic disorders (e.g. protein C, protein S, • Epilepsy erythematosus (SLE), and cancer. There is no consensus menopause. total T3 are unaltered. Tibolone decreases the level of stroke is not increased during use of HRT. • Keep out of the reach of children. or antithrombin deciency) • Asthma about the possible role of varicose veins in VTE. As in all • Prevention of osteoporosis in postmenopausal women at sex-hormone-binding globulin (SHBG), whereas the levels Other adverse reactions that may be associated with • Any history of arterial thromboembolic disease (e.g. • Otosclerosis postoperative patients, prophylactic measures need be high risk of future fractures who are intolerant of, or of corticoid binding globulin (CBG) and circulating cortisol estrogen/progestogen treatment: To be sold on the prescription of a angina, myocardial infarction, stroke or TIA) Reasons for immediate withdrawal of therapy considered to prevent VTE following surgery. If prolonged contraindicated for, other medicinal products approved are unaected. • Gall bladder disease registered medical practitioner only. • Acute liver disease or a history of liver disease as long as Therapy should be discontinued in case a contraindication immobilisation is to follow elective surgery temporarily for the prevention of osteoporosis. • HRT use does not improve cognitive function. There is • Skin and subcutaneous disorders: chloasma, erythema liver function tests have failed to return to normal is discovered and in the following situations: stopping HRT or Tibolone 4 to 6 weeks earlier is For all women the decision to prescribe Tibol (Tibolone) some evidence of increased risk of probable dementia in multiforme, erythema nodosum, vascular purpura Nature and contents of container • Known hypersensitivity to the active substance • Jaundice or deterioration in liver function recommended. Treatment should not be restarted until should be based on an assessment of the individual women who start using continuous combined or • Probable dementia over the age of 65 Tibol (Tibolone) 2.5 mg tablets are available in a blister • Porphyria • Signicant increase in blood pressure the woman is completely mobilised. patient’s overall risks and, particularly in the over 60s, estrogen-only HRT after the age of 65. pack of 28‘s (1 x 28’s). • New onset of migraine-type headache • In women with no personal history of VTE but with a rst should include consideration of the risk of stroke. Overdose Warnings and Precautions Endometrial hyperplasia and carcinoma degree relative with a history of thrombosis at young age, Interactions The acute toxicity of Tibolone is very low. Therefore, toxic For the treatment of postmenopausal symptoms, • Data suggests that women who are prescribed Tibolone screening may be oered after careful counselling Dosage and Administration • Since Tibolone may increase blood brinolytic activity, it symptoms are not expected to occur, even when several Tibolone should only be initiated for symptoms that in normal clinical practice are at an increased risk of having regarding its limitations (only a proportion of The dosage is one tablet per day. For initiation and may enhance the eect of anticoagulants. This eect may tablets are taken simultaneously. In cases of acute adversely aect quality of life. In all cases, a careful endometrial cancer diagnosed. Risk may be increased thrombophilic defects are identied by screening). If a continuation of treatment of postmenopausal symptoms, be seen with warfarin. Caution should therefore be overdose, nausea, vomiting and vaginal bleeding in appraisal of the risks and benets should be undertaken at with increasing duration of use. Tibolone increases thrombophilic defect is identied which segregates with the lowest eective dose for the shortest duration should exercised during the simultaneous use of Tibolone and females may occur. No specic antidote is known. least annually and Tibolone should only be continued as endometrial wall thickness, as measured by transvaginal thrombosis in family members or if the defect is ‘severe’ be used. A separate progestogen should not be added anticoagulants, especially when starting or stopping Symptomatic treatment can be given if necessary. long as the benet outweighs the risk. ultrasound. (e.g, antithrombin, protein S, or protein C deciencies or a with Tibol (Tibolone) treatment. concurrent Tibolone treatment. If necessary, the dose of The risks of stroke, breast cancer and, in women with an • Break-through bleeding and spotting may occur during combination of defects) HRT or Tibolone is Starting Tibol (Tibolone) warfarin should be adjusted. PHARMACOLOGICAL PROPERTIES intact uterus, endometrial cancer (below) for each woman the rst months of treatment. Women should be advised contraindicated. Women experiencing a natural menopause should • There is limited information regarding pharmacokinetic Pharmacotherapeutic group: ATC code: G03CX01, other should be carefully assessed, in the light of her individual to report any break-through bleeding or spotting if it is • Women already on anticoagulant treatment require commence treatment with Tibol (Tibolone) at least 12 interactions with Tibolone. Data indicates that estrogens risk factors and bearing in mind the frequency and still present after 6 months of treatment, if it starts beyond careful consideration of the benet-risk of use of HRT or months after their last natural bleed. In case of a surgical simultaneous treatment of Tibolone aects Other adverse reactions that may be observed include: Pharmacodynamic properties characteristics of both cancers and stroke, in terms of their that time or if it continues after treatment has been Tibolone. menopause, treatment with Tibol (Tibolone) may pharmacokinetics of the cytochrome P450 3A4 substrate dizziness, rash, seborrheic dermatosis, headache, Following oral administration, Tibolone is rapidly response to treatment, morbidity and mortality. discontinued. The woman should be referred for • If VTE develops after initiating therapy, the drug should commence immediately. midazolam to a moderate extent. Based on this, drug migraine, visual disturbances (including blurred vision), metabolized into three compounds, which all contribute Evidence regarding the risks associated with HRT or gynecological investigation, which is likely to include be discontinued. Patients should be told to contact their Any irregular/unscheduled vaginal bleeding, either on or interactions with other CYP3A4 substrates might be depression, eects on the musculoskeletal system such as to the pharmacodynamic prole of Tibolone. Two of the Tibolone in the treatment of premature menopause is endometrial biopsy to exclude endometrial malignancy. doctors immediately when they are aware of a potential o HRT, should be investigated to exclude malignancy expected. arthralgia or myalgia and changes in liver function metabolites (3α-OH-Tibolone and 3β-OH-Tibolone) have limited. Due to the low level of absolute risk in younger Breast cancer thromboembolic symptom (e.g. painful swelling of a leg, before starting Tibol (Tibolone). • CYP3A4 inducing compounds such as barbiturates, parameters. estrogenic-like activities, whereas the third metabolite ( ∆ women, however, the balance of benets and risks for • Evidence with respect to breast cancer risk in association sudden pain in the chest, dyspnea). Switching from a sequential or continuous combined carbamazepine, hydantoins and rifampicin may enhance Breast cancer 4-isomer of Tibolone) has progestogenic and these women may be more favourable than in older with Tibolone is inconclusive. Data suggests a signicant Coronary artery disease (CAD) HRT preparation the metabolism of Tibolone and thus aect its therapeutic An up to 2-fold increased risk of having breast cancer androgenic-like activities. women. increase in the risk of breast cancer in association with use There is no evidence of protection against myocardial If changing from a sequential HRT preparation, treatment eect. diagnosed may be observed in women taking combined Tibolone substitutes for the loss of estrogen production in Medical examination/follow-up of the 2.5mg dose. This risk may become apparent within infarction in women with or without existing CAD who with Tibol (Tibolone) should start the day following • Herbal preparations containing St. John`s wort oestrogen-progestogen therapy for more than 5 years. postmenopausal women and alleviates menopausal • Before initiating or reinstituting HRT or Tibolone, a a few years of use and increased with duration of intake, received combined estrogen-progestogen or completion of the prior regimen. If changing from a (Hypericum Perforatum) may induce the metabolism of Any increased risk in users of oestrogen-only and Tibolone complete personal and family medical history should be returning to baseline within a few (at most ve) years after estrogen-only HRT. therapies is substantially lower than in users of 2 oestrogen-progestogen combinations. The level of risk is symptoms. Tibolone prevents bone loss following Ischaemic stroke oestrogens and progestogens via CYP3A4. Clinically, an dependent on the duration of use. menopause or ovariectomy. continuous-combined HRT preparation, treatment can taken. Physical (including pelvic and breast) examination stopping treatment • Tibolone increases the risk of ischaemic stroke from the increased metabolism of oestrogens and progestogens Endometrial cancer risk Pharmacokinetic properties start at any time. should be guided by this and by the contraindications and Ovarian cancer rst year of treatment. The baseline risk of stroke is may lead to decreased eect and changes in the uterine Postmenopausal women with a uterus Absorption and biotransformation Missed dose warnings for use. During treatment, periodic check-ups • Ovarian cancer is much rarer than breast cancer. strongly age-dependent and so the eect of Tibolone is bleeding prole. The endometrial cancer risk is about 5 in every 1000 Following oral administration, Tibolone is rapidly and A missed dose should be taken as soon as remembered, are recommended of a frequency and nature adapted to Long-term (at least 5-10 years) use of estrogen-only HRT greater with older age. Pregnancy and Breastfeeding women with a uterus not using HRT or Tibolone. extensively absorbed. Due to rapid metabolism, the unless it is more than 12 hours overdue. In the latter case, the individual woman. Women should be advised what products may be associated with a slightly increased risk Other conditions Tibolone is contraindicated during pregnancy. If Ovarian cancer plasma levels of Tibolone are very low. The plasma levels the missed dose should be skipped and the next dose changes in their breasts should be reported to their doctor of ovarian cancer. Data suggest that the long-term use of • Patients with rare hereditary problems of galactose pregnancy occurs during medication with Tibolone, Use of estrogen-only or combined estrogen-progestogen of the ∆4-isomer of Tibolone are also very low. Therefore should be taken at the normal time. Missing a dose may or nurse. Investigations, including appropriate imaging combined HRTs may confer a similar or slightly smaller intolerance, the Lapp lactase deciency or treatment should be withdrawn immediately. For HRT may be associated with a slightly increased risk of some of the pharmacokinetic parameters could not be increase the likelihood of breakthrough bleeding and tools, e.g. mammography, should be carried out in risk. Data suggests that the relative risk for ovarian cancer glucose-galactose malabsorption should not take this Tibolone no clinical data on exposed pregnancies are having ovarian cancer diagnosed. determined. Peak plasma levels of the 3α-OH and the 3 spotting. accordance with currently accepted screening practices, with use of Tibolone is similar to the risk associated with QUALITATIVE AND QUANTITATIVE COMPOSITION medicine. available. The potential risk for humans is unknown. Tibol Risk of venous thromboembolism β-OH metabolites are higher but accumulation does not Dosage Adjustment modied to the clinical needs of the individual. use of other types of HRT. Each tablet contains: • Tibolone is not intended for contraceptive use. is contraindicated during breastfeeding. HRT is associated with a 1.3-3-fold increased relative risk of occur. Pediatrics Conditions which need supervision Venous thromboembolism Tibolone (BP)…………………… 2.5 mg • Treatment with Tibolone results in a marked developing venous thromboembolism (VTE), i.e. deep Elimination There is no relevant use of Tibol (Tibolone) in the • If any of the following conditions are present, have • Estrogen or estrogen-progestogen HRT is associated dose-dependent decrease in HDL cholesterol (from E ects on ability to drive and use machines vein thrombosis or pulmonary embolism. The occurrence Excretion of Tibolone is mainly in the form of conjugated paediatric population. occurred previously, and / or have been aggravated with a 1.3-3 fold risk of developing venous DESCRIPTION -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose Tibolone is not known to have any eects on alertness and of such an event is more likely in the rst year of using HRT. (mostly sulfated) metabolites. Part of the administered Elderly during pregnancy or previous hormone treatment, the thromboembolism (VTE), i.e. deep vein thrombosis or Tibol (Tibolone) is a synthetic anabolic steroid with after 2 years). Total triglycerides and lipoprotein(a) levels concentration. Risk of coronary artery disease compound is excreted in the urine, but most is eliminated No dose adjustment is necessary for the elderly. patient should be closely supervised. It should be taken pulmonary embolism. The occurrence of such an event is estrogenic, androgenic and progestogenic activities. are also known to be reduced. The decrease in total The risk of coronary artery disease is slightly increased in via the feces. Administration Requirements into account that these conditions may recur or be more likely in the rst year of HRT than later. Data suggests Tibolone is a 19-nortestosterone derivative and is related cholesterol and VLDL-C levels is not dose-dependent. Adverse Reactions users of combined estrogen-progestogen HRT over the The consumption of food has no signicant eects on the The tablets should be swallowed with some water or other aggravated during treatment with Tibolone, in particular: that the risk of VTE in association with Tibolone is lower structurally to other 19-nortestosterone progestins.It is Levels of LDL-C are unchanged. The clinical implication of age of 60. There is no evidence to suggest that the risk of extent of absorption. drink, preferably at the same time every day. • Leiomyoma (uterine broids) or endometriosis than the risk associated with conventional HRT, but only a the 7α-methyl derivative of noretynodrel. these ndings is not yet known. myocardial infarction with Tibolone is dierent to the risk The pharmacokinetic parameters for Tibolone and its • Risk factors for thromboembolic disorders small proportion of women are current users of Tibolone System organ class Common Uncommon Rare • Estrogens may cause uid retention, and therefore with other HRT. metabolites are found to be independent of renal Contraindications • Risk factors for estrogen dependent tumors, e.g. and a small increase in risk compared with non-use cannot patients with cardiac or renal dysfunction should be Risk of ischaemic stroke function. • Pregnancy and lactation rst degree heredity for breast cancer be excluded. Metabolism and Oedema carefully observed. nutrition disorders • The relative risk of ischaemic stroke is not dependent on • Known, past or suspected breast cancer known or • Hypertension • Patients with known thrombophilic states have an • Women with pre-existing hypertriglyceridemia should Gastrointestinal Lower age or on duration of use, but as the baseline risk is PHARMACEUTICAL INFORMATION suspected estrogen dependent malignant tumors (e.g. • Liver disorders (e.g. liver adenoma) increased risk of VTE and HRT or Tibolone may add to this be followed closely during estrogen replacement or HRT, disorders abdominal pain strongly age-dependent, the overall risk of ischaemic Shelf life endometrial cancer) • Diabetes mellitus with or without vascular involvement risk. HRT is therefore contraindicated in these patients. since rare cases of large increases of plasma triglycerides Skin and Abnormal hair Acne Pruritus stroke in women who use HRT or Tibolone will increase 2 years • Undiagnosed genital bleeding • Cholelithiasis • Generally recognized risk factors for VTE include use of CLINICAL INFORMATION leading to pancreatitis are known to occur with estrogen subcutaneous growth with age. • Untreated endometrial hyperplasia • Migraine or (severe) headache estrogens, older age, major surgery, prolonged Indications therapy in this condition. tissue disorders • The use of estrogen-only and estrogen + progestogen Special Precautions for Storage • Previous or current venous thromboembolism (deep • Systemic lupus erythematosis immobilization, obesity (BMI > 30 kg/m2), • Treatment of estrogen deciency symptoms in • Treatment with Tibolone results in a very minor decrease Reproductive Vaginal Breast therapy is associated with an up to 1.5 fold increased • Store below 25°C. venous thrombosis, pulmonary embolism) • A history of endometrial hyperplasia pregnancy/postpartum period, systemic lupus postmenopausal women, more than one year after of thyroid binding globulin (TBG) and total T4. Levels of system and breast discharge discomfort relative risk of ischaemic stroke. The risk of haemorrhagic • Protect from light and moisture. • Known thrombophilic disorders (e.g. protein C, protein S, • Epilepsy erythematosus (SLE), and cancer. There is no consensus menopause. total T3 are unaltered. Tibolone decreases the level of disorders Endometrial Fungal stroke is not increased during use of HRT. • Keep out of the reach of children. or antithrombin deciency) • Asthma about the possible role of varicose veins in VTE. As in all • Prevention of osteoporosis in postmenopausal women at sex-hormone-binding globulin (SHBG), whereas the levels wall thickening infection Other adverse reactions that may be associated with • Any history of arterial thromboembolic disease (e.g. • Otosclerosis postoperative patients, prophylactic measures need be Postmenopausal Vaginal high risk of future fractures who are intolerant of, or of corticoid binding globulin (CBG) and circulating cortisol estrogen/progestogen treatment: To be sold on the prescription of a angina, myocardial infarction, stroke or TIA) Reasons for immediate withdrawal of therapy considered to prevent VTE following surgery. If prolonged haemorrhage mycosis contraindicated for, other medicinal products approved are unaected. • Gall bladder disease registered medical practitioner only. • Acute liver disease or a history of liver disease as long as Therapy should be discontinued in case a contraindication immobilisation is to follow elective surgery temporarily Breast Nipple pain for the prevention of osteoporosis. • HRT use does not improve cognitive function. There is • Skin and subcutaneous disorders: chloasma, erythema liver function tests have failed to return to normal is discovered and in the following situations: stopping HRT or Tibolone 4 to 6 weeks earlier is tenderness For all women the decision to prescribe Tibol (Tibolone) some evidence of increased risk of probable dementia in multiforme, erythema nodosum, vascular purpura Nature and contents of container • Known hypersensitivity to the active substance • Jaundice or deterioration in liver function recommended. Treatment should not be restarted until Genital pruritus should be based on an assessment of the individual women who start using continuous combined or • Probable dementia over the age of 65 Tibol (Tibolone) 2.5 mg tablets are available in a blister • Porphyria • Signicant increase in blood pressure the woman is completely mobilised. Vaginal patient’s overall risks and, particularly in the over 60s, estrogen-only HRT after the age of 65. pack of 28‘s (1 x 28’s). • New onset of migraine-type headache • In women with no personal history of VTE but with a rst candidiasis should include consideration of the risk of stroke. Overdose Warnings and Precautions Endometrial hyperplasia and carcinoma degree relative with a history of thrombosis at young age, Vaginal Interactions The acute toxicity of Tibolone is very low. Therefore, toxic For the treatment of postmenopausal symptoms, • Data suggests that women who are prescribed Tibolone screening may be oered after careful counselling haemorrhage Dosage and Administration • Since Tibolone may increase blood brinolytic activity, it Pelvic pain symptoms are not expected to occur, even when several Tibolone should only be initiated for symptoms that in normal clinical practice are at an increased risk of having regarding its limitations (only a proportion of The dosage is one tablet per day. For initiation and may enhance the eect of anticoagulants. This eect may Cervical tablets are taken simultaneously. In cases of acute adversely aect quality of life. In all cases, a careful endometrial cancer diagnosed. Risk may be increased thrombophilic defects are identied by screening). If a continuation of treatment of postmenopausal symptoms, be seen with warfarin. Caution should therefore be dysplasia overdose, nausea, vomiting and vaginal bleeding in appraisal of the risks and benets should be undertaken at with increasing duration of use. Tibolone increases thrombophilic defect is identied which segregates with the lowest eective dose for the shortest duration should exercised during the simultaneous use of Tibolone and Genital females may occur. No specic antidote is known. least annually and Tibolone should only be continued as endometrial wall thickness, as measured by transvaginal thrombosis in family members or if the defect is ‘severe’ be used. A separate progestogen should not be added anticoagulants, especially when starting or stopping discharge Symptomatic treatment can be given if necessary. long as the benet outweighs the risk. ultrasound. (e.g, antithrombin, protein S, or protein C deciencies or a with Tibol (Tibolone) treatment. concurrent Tibolone treatment. If necessary, the dose of Vulvovaginitis The risks of stroke, breast cancer and, in women with an • Break-through bleeding and spotting may occur during combination of defects) HRT or Tibolone is Starting Tibol (Tibolone) warfarin should be adjusted. Investigations Weight increase PHARMACOLOGICAL PROPERTIES intact uterus, endometrial cancer (below) for each woman the rst months of treatment. Women should be advised contraindicated. Women experiencing a natural menopause should • There is limited information regarding pharmacokinetic Abnormal Pharmacotherapeutic group: ATC code: G03CX01, other should be carefully assessed, in the light of her individual to report any break-through bleeding or spotting if it is • Women already on anticoagulant treatment require cervical smear commence treatment with Tibol (Tibolone) at least 12 interactions with Tibolone. Data indicates that estrogens risk factors and bearing in mind the frequency and still present after 6 months of treatment, if it starts beyond careful consideration of the benet-risk of use of HRT or months after their last natural bleed. In case of a surgical simultaneous treatment of Tibolone aects Other adverse reactions that may be observed include: Pharmacodynamic properties characteristics of both cancers and stroke, in terms of their that time or if it continues after treatment has been Tibolone. menopause, treatment with Tibol (Tibolone) may pharmacokinetics of the cytochrome P450 3A4 substrate dizziness, rash, seborrheic dermatosis, headache, Following oral administration, Tibolone is rapidly response to treatment, morbidity and mortality. discontinued. The woman should be referred for • If VTE develops after initiating therapy, the drug should commence immediately. midazolam to a moderate extent. Based on this, drug migraine, visual disturbances (including blurred vision), metabolized into three compounds, which all contribute Evidence regarding the risks associated with HRT or gynecological investigation, which is likely to include be discontinued. Patients should be told to contact their Any irregular/unscheduled vaginal bleeding, either on or interactions with other CYP3A4 substrates might be depression, eects on the musculoskeletal system such as to the pharmacodynamic prole of Tibolone. Two of the Tibolone in the treatment of premature menopause is endometrial biopsy to exclude endometrial malignancy. doctors immediately when they are aware of a potential o HRT, should be investigated to exclude malignancy expected. arthralgia or myalgia and changes in liver function metabolites (3α-OH-Tibolone and 3β-OH-Tibolone) have limited. Due to the low level of absolute risk in younger Breast cancer thromboembolic symptom (e.g. painful swelling of a leg, before starting Tibol (Tibolone). • CYP3A4 inducing compounds such as barbiturates, parameters. estrogenic-like activities, whereas the third metabolite ( ∆ women, however, the balance of benets and risks for • Evidence with respect to breast cancer risk in association sudden pain in the chest, dyspnea). Switching from a sequential or continuous combined carbamazepine, hydantoins and rifampicin may enhance Breast cancer 4-isomer of Tibolone) has progestogenic and these women may be more favourable than in older with Tibolone is inconclusive. Data suggests a signicant Coronary artery disease (CAD) HRT preparation the metabolism of Tibolone and thus aect its therapeutic An up to 2-fold increased risk of having breast cancer androgenic-like activities. women. increase in the risk of breast cancer in association with use There is no evidence of protection against myocardial If changing from a sequential HRT preparation, treatment eect. diagnosed may be observed in women taking combined Tibolone substitutes for the loss of estrogen production in Medical examination/follow-up of the 2.5mg dose. This risk may become apparent within infarction in women with or without existing CAD who with Tibol (Tibolone) should start the day following • Herbal preparations containing St. John`s wort oestrogen-progestogen therapy for more than 5 years. postmenopausal women and alleviates menopausal • Before initiating or reinstituting HRT or Tibolone, a a few years of use and increased with duration of intake, received combined estrogen-progestogen or completion of the prior regimen. If changing from a (Hypericum Perforatum) may induce the metabolism of Any increased risk in users of oestrogen-only and Tibolone complete personal and family medical history should be returning to baseline within a few (at most ve) years after estrogen-only HRT. therapies is substantially lower than in users of 3 oestrogen-progestogen combinations. The level of risk is symptoms. Tibolone prevents bone loss following Ischaemic stroke oestrogens and progestogens via CYP3A4. Clinically, an dependent on the duration of use. menopause or ovariectomy. continuous-combined HRT preparation, treatment can taken. Physical (including pelvic and breast) examination stopping treatment • Tibolone increases the risk of ischaemic stroke from the increased metabolism of oestrogens and progestogens Endometrial cancer risk Pharmacokinetic properties start at any time. should be guided by this and by the contraindications and Ovarian cancer rst year of treatment. The baseline risk of stroke is may lead to decreased eect and changes in the uterine Postmenopausal women with a uterus Absorption and biotransformation Missed dose warnings for use. During treatment, periodic check-ups • Ovarian cancer is much rarer than breast cancer. strongly age-dependent and so the eect of Tibolone is bleeding prole. The endometrial cancer risk is about 5 in every 1000 Following oral administration, Tibolone is rapidly and A missed dose should be taken as soon as remembered, are recommended of a frequency and nature adapted to Long-term (at least 5-10 years) use of estrogen-only HRT greater with older age. Pregnancy and Breastfeeding women with a uterus not using HRT or Tibolone. extensively absorbed. Due to rapid metabolism, the unless it is more than 12 hours overdue. In the latter case, the individual woman. Women should be advised what products may be associated with a slightly increased risk Other conditions Tibolone is contraindicated during pregnancy. If Ovarian cancer plasma levels of Tibolone are very low. The plasma levels the missed dose should be skipped and the next dose changes in their breasts should be reported to their doctor of ovarian cancer. Data suggest that the long-term use of • Patients with rare hereditary problems of galactose pregnancy occurs during medication with Tibolone, Use of estrogen-only or combined estrogen-progestogen of the ∆4-isomer of Tibolone are also very low. Therefore should be taken at the normal time. Missing a dose may or nurse. Investigations, including appropriate imaging combined HRTs may confer a similar or slightly smaller intolerance, the Lapp lactase deciency or treatment should be withdrawn immediately. For HRT may be associated with a slightly increased risk of some of the pharmacokinetic parameters could not be increase the likelihood of breakthrough bleeding and tools, e.g. mammography, should be carried out in risk. Data suggests that the relative risk for ovarian cancer glucose-galactose malabsorption should not take this Tibolone no clinical data on exposed pregnancies are having ovarian cancer diagnosed. determined. Peak plasma levels of the 3α-OH and the 3 spotting. accordance with currently accepted screening practices, with use of Tibolone is similar to the risk associated with QUALITATIVE AND QUANTITATIVE COMPOSITION medicine. available. The potential risk for humans is unknown. Tibol Risk of venous thromboembolism β-OH metabolites are higher but accumulation does not Dosage Adjustment modied to the clinical needs of the individual. use of other types of HRT. Each tablet contains: • Tibolone is not intended for contraceptive use. is contraindicated during breastfeeding. HRT is associated with a 1.3-3-fold increased relative risk of occur. Pediatrics Conditions which need supervision Venous thromboembolism Tibolone (BP)…………………… 2.5 mg • Treatment with Tibolone results in a marked developing venous thromboembolism (VTE), i.e. deep Elimination There is no relevant use of Tibol (Tibolone) in the • If any of the following conditions are present, have • Estrogen or estrogen-progestogen HRT is associated dose-dependent decrease in HDL cholesterol (from E ects on ability to drive and use machines vein thrombosis or pulmonary embolism. The occurrence Excretion of Tibolone is mainly in the form of conjugated paediatric population. occurred previously, and / or have been aggravated with a 1.3-3 fold risk of developing venous DESCRIPTION -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose Tibolone is not known to have any eects on alertness and of such an event is more likely in the rst year of using HRT. (mostly sulfated) metabolites. Part of the administered Elderly during pregnancy or previous hormone treatment, the thromboembolism (VTE), i.e. deep vein thrombosis or Tibol (Tibolone) is a synthetic anabolic steroid with after 2 years). Total triglycerides and lipoprotein(a) levels concentration. Risk of coronary artery disease compound is excreted in the urine, but most is eliminated No dose adjustment is necessary for the elderly. patient should be closely supervised. It should be taken pulmonary embolism. The occurrence of such an event is estrogenic, androgenic and progestogenic activities. are also known to be reduced. The decrease in total The risk of coronary artery disease is slightly increased in via the feces. Administration Requirements into account that these conditions may recur or be more likely in the rst year of HRT than later. Data suggests Tibolone is a 19-nortestosterone derivative and is related cholesterol and VLDL-C levels is not dose-dependent. Adverse Reactions users of combined estrogen-progestogen HRT over the The consumption of food has no signicant eects on the The tablets should be swallowed with some water or other aggravated during treatment with Tibolone, in particular: that the risk of VTE in association with Tibolone is lower structurally to other 19-nortestosterone progestins.It is Levels of LDL-C are unchanged. The clinical implication of age of 60. There is no evidence to suggest that the risk of extent of absorption. drink, preferably at the same time every day. • Leiomyoma (uterine broids) or endometriosis than the risk associated with conventional HRT, but only a the 7α-methyl derivative of noretynodrel. these ndings is not yet known. myocardial infarction with Tibolone is dierent to the risk The pharmacokinetic parameters for Tibolone and its • Risk factors for thromboembolic disorders small proportion of women are current users of Tibolone • Estrogens may cause uid retention, and therefore with other HRT. metabolites are found to be independent of renal Contraindications • Risk factors for estrogen dependent tumors, e.g. and a small increase in risk compared with non-use cannot patients with cardiac or renal dysfunction should be Risk of ischaemic stroke function. • Pregnancy and lactation rst degree heredity for breast cancer be excluded. carefully observed. • The relative risk of ischaemic stroke is not dependent on • Known, past or suspected breast cancer known or • Hypertension • Patients with known thrombophilic states have an • Women with pre-existing hypertriglyceridemia should age or on duration of use, but as the baseline risk is PHARMACEUTICAL INFORMATION suspected estrogen dependent malignant tumors (e.g. • Liver disorders (e.g. liver adenoma) increased risk of VTE and HRT or Tibolone may add to this be followed closely during estrogen replacement or HRT, strongly age-dependent, the overall risk of ischaemic Shelf life endometrial cancer) • Diabetes mellitus with or without vascular involvement risk. HRT is therefore contraindicated in these patients. since rare cases of large increases of plasma triglycerides stroke in women who use HRT or Tibolone will increase 2 years • Undiagnosed genital bleeding • Cholelithiasis • Generally recognized risk factors for VTE include use of CLINICAL INFORMATION leading to pancreatitis are known to occur with estrogen with age. • Untreated endometrial hyperplasia • Migraine or (severe) headache estrogens, older age, major surgery, prolonged Indications therapy in this condition. • The use of estrogen-only and estrogen + progestogen Special Precautions for Storage • Previous or current venous thromboembolism (deep • Systemic lupus erythematosis immobilization, obesity (BMI > 30 kg/m2), • Treatment of estrogen deciency symptoms in • Treatment with Tibolone results in a very minor decrease therapy is associated with an up to 1.5 fold increased • Store below 25°C. venous thrombosis, pulmonary embolism) • A history of endometrial hyperplasia pregnancy/postpartum period, systemic lupus postmenopausal women, more than one year after of thyroid binding globulin (TBG) and total T4. Levels of relative risk of ischaemic stroke. The risk of haemorrhagic • Protect from light and moisture. • Known thrombophilic disorders (e.g. protein C, protein S, • Epilepsy erythematosus (SLE), and cancer. There is no consensus menopause. total T3 are unaltered. Tibolone decreases the level of stroke is not increased during use of HRT. • Keep out of the reach of children. or antithrombin deciency) • Asthma about the possible role of varicose veins in VTE. As in all • Prevention of osteoporosis in postmenopausal women at sex-hormone-binding globulin (SHBG), whereas the levels Other adverse reactions that may be associated with • Any history of arterial thromboembolic disease (e.g. • Otosclerosis postoperative patients, prophylactic measures need be high risk of future fractures who are intolerant of, or of corticoid binding globulin (CBG) and circulating cortisol estrogen/progestogen treatment: To be sold on the prescription of a angina, myocardial infarction, stroke or TIA) Reasons for immediate withdrawal of therapy considered to prevent VTE following surgery. If prolonged contraindicated for, other medicinal products approved are unaected. • Gall bladder disease registered medical practitioner only. • Acute liver disease or a history of liver disease as long as Therapy should be discontinued in case a contraindication immobilisation is to follow elective surgery temporarily for the prevention of osteoporosis. • HRT use does not improve cognitive function. There is • Skin and subcutaneous disorders: chloasma, erythema liver function tests have failed to return to normal is discovered and in the following situations: stopping HRT or Tibolone 4 to 6 weeks earlier is For all women the decision to prescribe Tibol (Tibolone) some evidence of increased risk of probable dementia in multiforme, erythema nodosum, vascular purpura Nature and contents of container • Known hypersensitivity to the active substance • Jaundice or deterioration in liver function recommended. Treatment should not be restarted until should be based on an assessment of the individual women who start using continuous combined or • Probable dementia over the age of 65 Tibol (Tibolone) 2.5 mg tablets are available in a blister • Porphyria • Signicant increase in blood pressure the woman is completely mobilised. patient’s overall risks and, particularly in the over 60s, estrogen-only HRT after the age of 65. pack of 28‘s (1 x 28’s). • New onset of migraine-type headache • In women with no personal history of VTE but with a rst should include consideration of the risk of stroke. Overdose Warnings and Precautions Endometrial hyperplasia and carcinoma degree relative with a history of thrombosis at young age, Interactions The acute toxicity of Tibolone is very low. Therefore, toxic For the treatment of postmenopausal symptoms, • Data suggests that women who are prescribed Tibolone screening may be oered after careful counselling MANUFACTURED BY Dosage and Administration • Since Tibolone may increase blood brinolytic activity, it symptoms are not expected to occur, even when several Tibolone should only be initiated for symptoms that in normal clinical practice are at an increased risk of having regarding its limitations (only a proportion of OBS Pakistan (Pvt.) Ltd. The dosage is one tablet per day. For initiation and may enhance the eect of anticoagulants. This eect may tablets are taken simultaneously. In cases of acute adversely aect quality of life. In all cases, a careful endometrial cancer diagnosed. Risk may be increased thrombophilic defects are identied by screening). If a C-14, Manghopir Road, S.I.T.E., Karachi-75700, continuation of treatment of postmenopausal symptoms, be seen with warfarin. Caution should therefore be overdose, nausea, vomiting and vaginal bleeding in appraisal of the risks and benets should be undertaken at with increasing duration of use. Tibolone increases thrombophilic defect is identied which segregates with Pakistan. the lowest eective dose for the shortest duration should exercised during the simultaneous use of Tibolone and females may occur. No specic antidote is known. least annually and Tibolone should only be continued as endometrial wall thickness, as measured by transvaginal thrombosis in family members or if the defect is ‘severe’ be used. A separate progestogen should not be added anticoagulants, especially when starting or stopping Symptomatic treatment can be given if necessary. long as the benet outweighs the risk. ultrasound. (e.g, antithrombin, protein S, or protein C deciencies or a MANUFACTURED FOR with Tibol (Tibolone) treatment. concurrent Tibolone treatment. If necessary, the dose of The risks of stroke, breast cancer and, in women with an • Break-through bleeding and spotting may occur during combination of defects) HRT or Tibolone is Starting Tibol (Tibolone) warfarin should be adjusted. PHARMACOLOGICAL PROPERTIES intact uterus, endometrial cancer (below) for each woman the rst months of treatment. Women should be advised contraindicated. Women experiencing a natural menopause should • There is limited information regarding pharmacokinetic Pharmacotherapeutic group: ATC code: G03CX01, other should be carefully assessed, in the light of her individual to report any break-through bleeding or spotting if it is • Women already on anticoagulant treatment require commence treatment with Tibol (Tibolone) at least 12 interactions with Tibolone. Data indicates that estrogens risk factors and bearing in mind the frequency and still present after 6 months of treatment, if it starts beyond careful consideration of the benet-risk of use of HRT or months after their last natural bleed. In case of a surgical simultaneous treatment of Tibolone aects Other adverse reactions that may be observed include: Pharmacodynamic properties Aspin Pharma (Pvt.) Ltd. characteristics of both cancers and stroke, in terms of their that time or if it continues after treatment has been Tibolone. menopause, treatment with Tibol (Tibolone) may pharmacokinetics of the cytochrome P450 3A4 substrate dizziness, rash, seborrheic dermatosis, headache, Following oral administration, Tibolone is rapidly Plot No. 10 & 25, Sector No. 20, response to treatment, morbidity and mortality. discontinued. The woman should be referred for • If VTE develops after initiating therapy, the drug should commence immediately. midazolam to a moderate extent. Based on this, drug migraine, visual disturbances (including blurred vision), metabolized into three compounds, which all contribute Korangi Industrial Area, Karachi-74900, Pakistan. Evidence regarding the risks associated with HRT or gynecological investigation, which is likely to include be discontinued. Patients should be told to contact their Any irregular/unscheduled vaginal bleeding, either on or interactions with other CYP3A4 substrates might be depression, eects on the musculoskeletal system such as to the pharmacodynamic prole of Tibolone. Two of the www.aspin.com.pk Tibolone in the treatment of premature menopause is endometrial biopsy to exclude endometrial malignancy. doctors immediately when they are aware of a potential o HRT, should be investigated to exclude malignancy expected. arthralgia or myalgia and changes in liver function metabolites (3α-OH-Tibolone and 3β-OH-Tibolone) have limited. Due to the low level of absolute risk in younger Breast cancer thromboembolic symptom (e.g. painful swelling of a leg, before starting Tibol (Tibolone). • CYP3A4 inducing compounds such as barbiturates, parameters. estrogenic-like activities, whereas the third metabolite ( ∆ REVISION DATE women, however, the balance of benets and risks for • Evidence with respect to breast cancer risk in association sudden pain in the chest, dyspnea). Switching from a sequential or continuous combined carbamazepine, hydantoins and rifampicin may enhance Breast cancer 4-isomer of Tibolone) has progestogenic and February 2020 these women may be more favourable than in older with Tibolone is inconclusive. Data suggests a signicant Coronary artery disease (CAD) HRT preparation the metabolism of Tibolone and thus aect its therapeutic An up to 2-fold increased risk of having breast cancer androgenic-like activities. women. increase in the risk of breast cancer in association with use There is no evidence of protection against myocardial If changing from a sequential HRT preparation, treatment eect. diagnosed may be observed in women taking combined Tibolone substitutes for the loss of estrogen production in Medical examination/follow-up of the 2.5mg dose. This risk may become apparent within infarction in women with or without existing CAD who with Tibol (Tibolone) should start the day following • Herbal preparations containing St. John`s wort oestrogen-progestogen therapy for more than 5 years. postmenopausal women and alleviates menopausal • Before initiating or reinstituting HRT or Tibolone, a a few years of use and increased with duration of intake, received combined estrogen-progestogen or PIL-TI-0220/2 completion of the prior regimen. If changing from a (Hypericum Perforatum) may induce the metabolism of Any increased risk in users of oestrogen-only and Tibolone 4 complete personal and family medical history should be returning to baseline within a few (at most ve) years after estrogen-only HRT. therapies is substantially lower than in users of