Active ingredients: Tibolone
LIVIAL 2.5 mg tablets
Indications Why is Livial used? What is it for?
Livial is a Hormone Replacement Therapy (HRT). Livial contains the active substance tibolone, which belongs to a group of medicines with estrogenic activity. Livial is indicated in postmenopausal women or at least 12 months after their last natural menstruation, in the following cases:
Relief from symptoms that appear after menopause
During menopause, the amount of hormones (estrogen) produced by a woman's body decreases. Reduction in the amount of hormones can cause symptoms such as a feeling of heat in the face, face, neck and chest (hot flashes), night sweats, dryness and fragility of the vaginal mucosa and disorders of the genitourinary system. Livial relieves these symptoms after menopause. Livial will only be prescribed to you by your doctor if your symptoms seriously hinder your normal daily activities.
- Prevention of osteoporosis
After menopause, some women may develop bone fragility with a consequent risk of fractures (osteoporosis). Your doctor, after evaluating whether you have an increased risk of fractures due to osteoporosis and if other medicines are not suitable for you, may prescribe Livial to prevent osteoporosis after menopause.
Contraindications When Livial should not be used
Before starting treatment with Livial, your doctor will inform you about the benefits and possible risks of treatment with Livial. Both before and during treatment, your doctor will assess whether Livial is suitable for you. Based on your general state of health, your doctor will decide on the type and frequency of checks to be performed. If you have a close relative (mother, sister, grandmother) who has suffered from diseases caused by blood clots (venous thrombosis) or breast cancer, you may be at higher risk. For this reason, tell your doctor about any serious illnesses in your family history, and if you notice any changes in your breasts. Likewise, tell your doctor if you have premature menopause.
Do not take Livial
If you have any of the following conditions. If you are not sure about any of the points below talk to your doctor before taking Livial.
- If you are allergic to tibolone or any of the other ingredients of this medicine
- If you have or have had breast cancer, or you are suspected of having it.
- If you have cancer that is sensitive to female hormones (estrogen) such as eg. cancer of the lining of the womb (endometrium) or you are suspected of having it.
- If you have any unusual vaginal bleeding.
- If you have excessive thickening of the lining of the womb (endometrial hyperplasia) which is not being treated.
- If you have or have had a blood clot in a vein (thrombosis), for example in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism).
- If you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency).
- If you have or have recently had a disease caused by blood clots in the arteries, such as a heart attack (angina, myocardial infarction), a cerebrovascular accident (stroke).
- If you have or have had liver disease and your liver function values have not returned to normal.
- If you have a rare blood problem called 'porphyria' which is a family (inherited) disease.
- If you are pregnant or think you are pregnant.
- If you are breastfeeding.
If any of the above conditions appear for the first time while you are taking Livial, stop taking it and consult your doctor immediately.
Precautions for use What you need to know before taking Livial
Talk to your doctor or pharmacist before taking Livial.
Tell your doctor if you have ever had any of the following problems, as they may come back or get worse during treatment with Livial:
- benign tumors inside the uterus (fibroids)
- growth of womb lining outside the womb (endometriosis) or a history of abnormal growth of the womb lining (endometrial hyperplasia)
- risk factors for developing blood clots (see "Blood clots in a vein (thrombosis)")
- increased risk of developing estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
- high blood pressure (hypertension)
- a liver problem, such as a benign liver tumor
- high amount of sugar in the blood (diabetes)
- gallbladder stones
- migraine or severe headache
- 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 impairing hearing (otosclerosis)
- a very high level of fat in the blood (hypertriglyceridaemia) fluid retention caused by heart or kidney problems.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Stop taking Livial and consult a doctor immediately in the following situations:
- the conditions mentioned in the section "Do not take Livial"
- yellowing of the skin and whites of the eye (jaundice). These may be signs of liver disease
- a noticeable increase in blood pressure (symptoms may be headache, fatigue, dizziness)
- migraine (headache) that appears for the first time
- pregnancy
- signs of blood clotting, such as:
- painful swelling and redness of the legs
- sudden chest pain
- breathing difficulties.
Hormone Replacement Therapy (HRT) may increase the risk of the following clinical conditions:
Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)
There have been reports and studies of increased cell growth or cancer of the endometrium in women using Livial. The risk of endometrial cancer increases with duration of use.
Irregular bleeding
Irregular bleeding or drops of blood (spotting) may occur during the first 3-6 months of treatment with Livial.
However, see your doctor as soon as possible if you have irregular bleeding:
- continues beyond the first 6 months of treatment with Livial
- appears more than 6 months after starting treatment with Livial
- continues after stopping treatment with Livial.
Breast cancer
Evidence suggests that taking combined estrogen and progestogen and possibly estrogen-only HRT increases the risk of breast cancer. This increased risk depends on the duration of HRT. The additional risk of developing cancer is proportional to the duration of treatment.
However, the level of risk returns to normal within a few years (at most 5) of stopping treatment.
Get a regular breast exam. See your doctor immediately if you notice any changes in your breasts, such as:
- dimpling or sagging of the skin
- changes in the nipple
- masses detectable by sight or touch.
Data in comparison
Women taking Livial have a lower risk of developing breast cancer than those taking combined HRT (estrogen and progestogen, two types of hormones) and a comparable risk to women taking estrogen-only HRT.
Ovarian cancer
Ovarian cancer is a rare event. A small increased risk of ovarian cancer has been reported in women who have taken HRT for at least 5 to 10 years.
Data in comparison
In women aged 50 to 69 who have not taken HRT, on average about 2 in 1,000 women will be diagnosed with ovarian cancer over a 5 year period. In women who have taken HRT for 5 years, between 2 and 3 cases in 1,000 users (ie up to 1 additional case). With the use of Livial, the increased risk of ovarian cancer is similar to that seen with other types of HRT.
Effects of HRT on the heart and circulation
The risk of blood clots forming in the veins is about 1.3 to 3 times higher in patients who use HRT than in those who do not, especially during the first year of taking it.
Blood clots can be serious, and if one gets into the lungs, it can cause chest pain, shortness of breath, fainting, or even death.
There is a greater chance of developing blood clots as you age and if you have any of the following conditions, which you will inform your doctor about:
- are pregnant or have recently had a baby
- makes use of estrogen
- you are unable to walk for a long time because you have had a major surgery, accident or illness (see also section, "If you need to have surgery")
- you are severely overweight (BMI (body mass index)> 30 kg / m2)
- have had any bleeding problems that required long-term treatment with a medicine used to prevent blood clots
- a close relative of yours has had blood clots in the legs, lungs or other organs
- you have systemic lupus erythematosus (SLE), a disease of the immune system
- has cancer.
To find out how clot formation occurs in your body, see the section "Stop taking Livial and see a doctor immediately".
Data in comparison
For women aged 50 to 59 who are not taking HRT, a clot in a vein is expected to form in a vein on average in 4 to 7 cases in 1,000 users over a 5-year period.
For women aged 50 to 59 who are taking estrogen-progesterone HRT, a blood clot is expected to form in a vein in 9 to 12 cases in 1,000 users over a 5-year period (i.e. 5 more cases).
The increased risk of a blood clot forming in a vein is less with Livial than with other types of HRT.
Heart disease (heart attack)
HRT or Livial has not been shown to prevent heart attack (angina, myocardial infarction). Women over the age of 60 who use estrogen-progesterone HRT have a slightly higher risk of developing the disease. heart disease compared to those not taking HRT. The risk of heart disease is highly age-dependent, therefore, the number of cases of heart disease due to the use of estrogen-progesterone HRT is very low in next-to-healthy women. at menopause, but it will get higher with increasing age.
In the current state of clinical knowledge, the risk of myocardial infarction associated with the use of Livial is comparable to that associated with other types of HRT.
Stroke
Recent research suggests HRT and Livial increase the risk of having a stroke. The increased risk was mainly seen in postmenopausal elderly women over 60 years of age.
D.ati in comparison
For women aged 50 to 59 who are not taking Livial, over 5 years, approximately 3 in 1,000 stroke cases and 7 in 1,000 are expected for women in the same age group taking Livial ( i.e. 4 more cases).
For women between the ages of 60 and 69 who are not taking Livial, over 5 years, approximately 11 out of 1,000 stroke cases are expected and 24 out of 1,000 cases for women in the same age group taking Livial ( i.e. 13 more cases).
Other conditions
HRT does not prevent memory loss. There is some evidence of an increased risk of memory loss in women who start using HRT after the age of 65.
Interactions Which drugs or foods may change the effect of Livial
Some medicines listed below may interfere with the effect of Livial, causing irregular bleeding:
- medicines for excessive blood clotting (such as warfarin)
- medicines to treat epilepsy (such as phenobarbital, phenytoin and carbamazepine)
- medicines to treat tuberculosis (such as rifampicin)
- herbal preparations containing St. John's wort (Hypericum perforatum).
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Livial with food and drink
Livial can normally be taken with food and drink
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Livial is only indicated for postmenopausal women.
Livial is not a contraceptive. If it has been less than 12 months since your last period or if you are under the age of 50, you may still need to use a contraceptive system in order to avoid pregnancy. Ask your doctor for advice.
Driving and using machines
Livial has no known effect on the ability to drive or use machines.
Livial contains lactose
Livial tablets contain lactose. If you have been told by your doctor that you have "intolerance to some sugars, consult your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Livial: Posology
Always take this medicine exactly as your doctor or pharmacist has told you.
If in doubt, consult your doctor or pharmacist. Livial must be taken orally. The recommended dose is one tablet a day. Livial tablets should be swallowed with water or another drink. Take the tablet at the same time each day.
The days of the week are indicated on the Livial tablet container (blister). Start the treatment by taking the tablet marked with the day of the week. For example, if it were Monday, take one tablet marked Monday on the top line of the strip. Follow the days of the week until the blister is empty. Start a new strip the next day. Do not leave any voids in the blister.
Livial must not be taken until twelve months have passed since the last spontaneous menstruation. If Livial is taken earlier, the chance of irregular vaginal bleeding may increase.
Your doctor will prescribe the lowest dose to treat your symptoms for the shortest time needed. Consult your doctor if you have the impression that this dose is too strong or too low.
Overdose What to do if you have taken too much Livial
If you take more Livial than you should
If you have taken too much Livial, contact your doctor or pharmacist immediately. If several tablets are taken at the same time, there is no major cause for concern. However, you must report this to your doctor immediately. Signs of overdose may include feeling sick or vaginal bleeding.
If you forget to take Livial
If you have forgotten to take a tablet, take it as soon as you remember, unless it is more than 12 hours after taking the last tablet. If it has been more than 12 hours, do not take the forgotten tablet and take the next tablet at the usual time.
Do not take a double dose to make up for a forgotten dose.
If you need to have surgery
If you are going to have surgery, tell your anesthetist about your current treatment with Livial. You may need to stop taking Livial about 4-6 weeks before your operation in order to reduce the risk of a blood clot (see section, "Blood clots in a vein (thrombosis)") Ask your doctor when you can resume treatment with Livial.
If you stop taking Livial
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Livial
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of these side effects are mild.
The following conditions are reported more frequently in women who use HRT than in women who do not:
- breast cancer
- abnormal growth of the lining of the womb (endometrial hyperplasia) or cancer of the endometrium
- ovarian cancer
- formation of blood clots in the legs or lungs (venous thromboembolism)
- heart disease
- stroke
- probable memory loss if HRT is started after the age of 65.
For more information on these side effects, see section 2.
Common side effects seen in clinical studies (affecting up to 1 in 10 women) are:
- vaginal bleeding or discharge
- abdominal or pelvic pain
- weight gain
- breast pain
- abnormal hair growth
- vaginal symptoms such as discharge, itching, irritation, inflammation (vulvovaginitis), candida infection.
Uncommon side effects (affecting up to 1 in 100 women) are:
- acne
- nipple pain or breast discomfort
- vaginal infections (vaginal mycosis).
Other side effects observed with Livial in therapeutic use were:
- dizziness, headache, migraine, depression
- skin rash or itching
- visual disturbances
- gastro-intestinal disorders
- fluid retention
- joint pain, muscle pain
- impaired liver function.
There have been reports of breast cancer and abnormal cell growth or carcinoma of the uterine lining in women taking Livial.
Contact your doctor if you experience vaginal bleeding or discharge or if any of the above side effects become bothersome or persistent.
The following side effects have been reported with other hormone replacement therapies:
- disorders of the gallbladder
- various skin disorders:
- discoloration of the skin (skin), especially of the face or neck, known as "pregnancy patches" (chloasma)
- painful red skin nodules (erythema nodosum)
- rash with target-shaped redness or ulceration (erythema multiforme).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Store below 25 ° C. Do not freeze.
Keep the tablets in the original packaging.
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.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Livial contains
- The active ingredient is: tibolone 2.5 mg.
- The other ingredients are: potato starch, lactose, ascorbyl palmitate and magnesium stearate.
What Livial looks like and contents of the pack
Livial 2.5 mg tablets are white, round and flat and debossed with "MK2" on one side and "Organon *" on the other side. They are available in PVC / Aluminum blisters of 30 tablets. Each blister is packaged in a box.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LIVIAL 2.5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Active ingredient: tibolone 2.5 mg
Excipients with known effect: lactose 100 mg
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets
White, round flat tablets with rounded ends, 6 mm in diameter, coded "MK" on 2 on one side and "Organon *" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
• Treatment of estrogen deficiency symptoms in postmenopausal women, more than one year after menopause.
• Prevention of osteoporosis in postmenopausal women, at high risk of future fractures who have intolerances or contraindications to other medicines authorized for the prevention of osteoporosis.
For all women, the decision to prescribe Livial should be based on an assessment of the patient's overall individual risks, particularly in women over 60 years of age, the risk of stroke should be considered (see sections 4.4 and 4.8).
04.2 Posology and method of administration
Dosage
The dosage is one tablet per day. No dosage adjustment is necessary in elderly patients. Livial tablets should be swallowed with a glass of water or other beverage, preferably at the same time of day.
To initiate and continue treatment of postmenopausal symptoms, the lowest effective dose should be used, for the shortest time possible (see also section 4.4).
A progestogen should not be added to treatment with Livial.
Method of administration
Start therapy with LIVIAL
Women with spontaneous menopause should start treatment with Livial at least 12 months after the last spontaneous menstrual cycle. In the case of (surgically) induced menopause, treatment with Livial can begin immediately.
An assessment should be made before starting Livial for any irregular or unexpected vaginal bleeding, both within and outside HRT, for which there is no known cause (see section 4.3).
Changing from sequential or continuous hormone replacement therapy (HRT)
If the woman is coming from HRT with a sequential preparation, Livial treatment should start the day after the completion of the previous therapy.
If the woman is coming from HRT with a continuous-combination preparation, treatment can start at any time.
Forgotten tablet
A forgotten tablet should be taken as soon as you remember, unless more than 12 hours have passed since the time you usually take Livial. In the latter circumstance, the missed dose should not be taken and the next tablet should be taken as usual.
Forgetting a tablet may increase the chance of breakthrough bleeding and spotting.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Pregnancy and breastfeeding
• Past, suspected or known breast cancer. In a placebo-controlled study, Livial increased the risk of breast cancer returning
• Known or suspected estrogen-dependent malignant tumors (eg endometrial cancer)
• Undiagnosed genital bleeding
• Untreated endometrial hyperplasia
• Current or previous venous thromboembolism (eg deep vein thrombosis, pulmonary embolism)
• Known thrombophilic disorders (eg protein C, protein S, or antithrombin deficiency, see section 4.4)
• History of arterial thromboembolic disease (eg angina, myocardial infarction, stroke or transient ischemic attack)
• Acute liver disease or history of liver disease, until liver function tests have returned to normal
• Porphyria.
04.4 Special warnings and appropriate precautions for use
For the treatment of postmenopausal symptoms, Livial should only be started if the symptoms adversely affect the quality of life. In any case, a careful evaluation of the risks and benefits must be carried out at least annually and Livial must be continued only as long as the benefit obtained outweighs the risk.
The risk of stroke, breast cancer and, in non-hysterectomised women, endometrial cancer (see below and section 4.8) should be carefully weighed for each individual woman, in light of individual risk factors and taking into account the frequency and characteristics of both forms of cancer and stroke, in terms of responsiveness to treatment, morbidity and mortality.
There is limited evidence regarding the risk associated with HRT or tibolone in the treatment of premature menopause. However, due to the low level of absolute risk in younger women, the balance of benefits and risks for these women may be more favorable than to older women.
Medical examination and subsequent checks
A complete family and personal medical history should be taken by the physician before initiating or resuming HRT or tibolone. A general examination (including pelvic and breast examination), guided by medical history and contraindications, should also be done. warnings for use.
During treatment, periodic clinical checks of a nature and frequency adapted to the individual case are recommended. Women should be advised to report any changes in their breasts to their doctor (see "Breast Cancer" below).
Clinical investigations, including "appropriate diagnostic imaging, eg mammography, should be performed in line with currently accepted clinical protocols and adapted to the clinical needs of the individual case."
Conditions that require special control
If any of the following conditions are present, or have been present in the past, and / or have been aggravated by pregnancy or previous hormonal treatment, the patient should be followed closely. Please note that these conditions may recur or worsen during treatment with Livial:
• Leiomyoma (uterine fibroids) or endometriosis
• Risk factors for thromboembolic disease (see below)
• Risk factors for estrogen-dependent cancers, eg. first degree heredity for breast cancer
• Hypertension
• Hepatopathies (eg hepatic adenoma)
• Diabetes mellitus with or without vascular involvement
• Cholelithiasis
• Migraine or headache (severe)
• Systemic lupus erythematosus
• History of endometrial hyperplasia (see below)
• Epilepsy
• Bronchial asthma
• Otosclerosis
Indications for an "immediate suspension of treatment:
Treatment must be stopped immediately if a contraindication is highlighted and in the following cases:
• Jaundice or deterioration of liver function
• Significant increase in blood pressure
• Onset of migraine-type headache
Hyperplasia of the endometrium and carcinoma
• The available data obtained from controlled, randomized clinical trials are contradictory; however, observational studies have consistently shown that women who are prescribed Livial in normal clinical practice have an increased risk of having endometrial cancer diagnosed (see also section 4.8). In these studies, the risk increased as the duration of treatment increased. Use. Tibolone increases the thickness of the endometrial wall, measured with trans-vaginal ultrasound.
• Breakthrough bleeding and spotting may occur during the first months of treatment (see section 5.1). Women should be advised to report any breakthrough bleeding or spotting that was still present after 6 months of treatment, starting after this period or continuing after treatment has been stopped. The woman should be referred for a gynecological check-up which possibly includes a biopsy of the endometrium, to rule out malignant forms of the endometrium.
Breast cancer
• The evidence regarding the risk of breast cancer in association with tibolone is not conclusive. The Million Women Study (MWS), has identified a significant increase in the risk of breast cancer in association with the use of a dose of 2, 5 mg. The risk became apparent within a few years of use and increased with the duration of intake, returning instead to baseline within a few years (maximum five) after discontinuation of treatment, see section 4.8. These results could not be confirmed in a study referring to the General Practice Research Database (GPRD).
Ovarian cancer
• Ovarian cancer is much rarer than breast cancer. Long-term use (at least 5-10 years) of estrogen-only HRT has been associated with a slightly increased risk of ovarian cancer (see section 4.8). Some studies including the Women 's Health Initiative (WHI) study ) suggest that long-term use of combined HRT may confer a similar risk, or a slightly lower risk (see section 4.8). The Million Women Study showed that the relative risk of ovarian cancer with the use of tibolone was similar to the risk associated with the use of other types of HRT.
Venous thromboembolism
• Estrogen or estrogen-progestogen HRT is associated with a 1.3-3 fold increased risk of developing venous thromboembolism (VTE), ie deep vein thrombosis or pulmonary embolism. This event is more likely to occur in the first year of HRT than in subsequent years (see section 4.8). In an epidemiological study using a UK database, the risk of VTE in combination with tibolone was lower than the risk associated with conventional HRT, but only a small proportion of women currently used tibolone and a small increase cannot be excluded. risk versus non-use.
• Patients with known thrombophilic states have an increased risk of VTE and HRT or tibolone may increase this risk. Therefore HRT is contraindicated in these patients (see section 4.3).
• Generally recognized risk factors for VTE include estrogen use, older age, major surgery, prolonged immobilization, obesity (BMI> 30 kg / m2), pregnancy / postpartum period , systemic lupus erythematosus (SLE) and cancer. There is no consensus on the possible role of varicose veins in VTE. As in all patients who are in the postoperative period, prophylactic measures should be considered to prevent postoperative VTE episodes. If prolonged immobilization is to follow elective surgery, temporary discontinuation of HRT or tibolone 4-6 weeks prior to surgery is recommended. Treatment should not be resumed until the patient is completely mobilized.
• In women who do not have a personal history of VTE but with a first degree family member with a history of thrombosis at a young age, screening may be proposed after "careful advice on its limitations (only a proportion of thrombophilic defects are identified by screening). If family members have identified a thrombophilic defect that segregates with thrombosis or if the defect is "severe (eg antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT or tibolone are contraindicated.
• Women who are already on anticoagulant therapy require "careful consideration of the benefit-risk balance of using HRT or tibolone.
• If venous thromboembolism develops after initiation of therapy, the drug should be discontinued. Patients should be advised to contact their physician immediately in case of symptoms potentially due to venous thromboembolism (eg. painful, sudden chest pain, dyspnoea).
Coronary heart disease (CAD)
• Randomized controlled trials have shown no protection against myocardial infarction in women with or without CAD who received estrogen-progestogen or estrogen-only HRT. In an epidemiological study using GPRD it was not No evidence of protection against myocardial infarction was found in postmenopausal women receiving tibolone.
Ischemic stroke
• Tibolone increases the risk of ischemic stroke from the first year of treatment (see section 4.8). The baseline risk of stroke is strongly correlated with age and therefore the effect of tibolone is greater with increasing age.
Other conditions
• Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Livial is not intended to be used for contraception.
• Treatment with Livial shows a marked dose-dependent decrease in HDL-cholesterol levels (from -16.7% with the 1.25 mg dose to -21.8% with the 2.5 mg dose after two years ). Total triglyceride and lipoprotein (s) levels were also reduced. The decrease in total cholesterol and VLDL-C cholesterol levels was not dose dependent; LDL-C levels were unchanged. The clinical implications of these findings are unknown.
• Estrogen can cause fluid retention and therefore patients with renal or cardiac dysfunction should be carefully observed.
• Women with pre-existing hypertriglyceridaemia should be followed closely while taking estrogen alone or with HRT. Rare cases of pancreatitis following a marked increase in plasma triglycerides have been reported in women with pre-existing hypertriglyceridaemia receiving estrogen-only therapy.
• Treatment with Livial causes a slight decrease in thyroglobulin (TBG) and total T4; the levels of T3 are unaltered. Livial also reduces the levels of sex hormone binding globulin (SHBG), but does not affect those of corticoid hormone binding globulin (CBG) and circulating cortisol.
• The use of HRT does not improve cognitive function. There is some evidence of an increased risk of probable dementia in women who have started combination treatment or estrogen-only HRT after the age of 65.
04.5 Interactions with other medicinal products and other forms of interaction
Since Livial can increase the fibrinolytic activity of the blood, it can increase the effect of anticoagulants. This effect has been demonstrated with warfarin. Therefore, the simultaneous use of Livial and anticoagulants should be done with caution; especially when starting or stopping concomitant treatment with Livial. If necessary, the dose of warfarin should be adjusted.
There is "limited" information on pharmacokinetic interactions with tibolone. A study in vivo showed that concomitant treatment with tibolone moderately affects the pharmacokinetics of cytochrome P450 substrate 3A4 midazolam. Based on this finding, interaction with other CYP3A4 substrates can be expected.
CYP3A4 inducing compounds such as barbiturates, carbamazepine, hydantoin and rifampicin may increase the metabolism of tibolone and consequently affect its therapeutic effect.
Herbal medicinal preparations containing St. John's wort (Hypericum Perforatum) can induce the metabolism of estrogens and progestogens via CYP3A4. Clinically, an increase in estrogen and progestogen metabolism may lead to a decrease in effect. and changes in the uterine bleeding profile.
04.6 Pregnancy and lactation
Pregnancy
Livial is contraindicated in pregnancy (see section 4.3). If pregnancy occurs during treatment with Livial, treatment should be stopped immediately.
There are no clinical data on the use of Livial in pregnant women.
Studies in animals have shown some reproductive toxicity (see section 5.3). The potential risk in humans is unknown.
Pregnancy
Livial is contraindicated during lactation (see section 4.3).
04.7 Effects on ability to drive and use machines
Livial has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
It describes the undesirable effects recorded during 21 placebo-controlled studies (including the LIFT study), involving 4,079 women who received therapeutic doses of Livial (1.25 or 2.5 mg) and 3,476 women who received it. placebo. The duration of these treatments ranged from 2 months to 4.5 years. Table 1 shows the undesirable effects that occurred statistically significantly more frequently during treatment with Livial compared to
placebo.
Table 1 Undesirable effects of Livial
* In most cases these were benign changes. There was no increase in cervical disease (cervical cancer) in women treated with tibolone compared to placebo.
** These adverse reactions were identified through post-marketing surveillance. The frequency category was estimated based on relevant clinical studies.
In common therapeutic use other observed side effects include:
dizziness, rash, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), depression, effects on skeletal muscles such as arthralgia or myalgia and changes in liver function parameters.
Breast cancer risk
• An up to 2-fold increased risk of being diagnosed with breast cancer is reported in women taking combined estrogen-progestogen therapy for more than 5 years.
The increased risk in estrogen-only users and tibolone is substantially lower than that seen in users of estrogen-progestogen combinations.
• The level of risk depends on the duration of use (see section 4.4).
• The results of the largest epidemiological study (MWS) are presented.
Table 2 Million Women study - Estimated additional risk of breast cancer after 5 years of use
Endometrial cancer risk
The risk of endometrial cancer is 5 in every 1,000 women with a uterus that does not use HRT or tibolone.
The randomized placebo-controlled clinical trial that included women who had never undergone basic screening for endometrial abnormalities, and thus reflected clinical practice, identified the highest risk of endometrial cancer (LIFT study, mean age 68 years). In this study, no cases of cancer were diagnosed in the placebo group (n = 1,773) after 2.9 years, compared with 4 cases of endometrial cancer diagnosed in the Livial group (n = 1,746). This corresponds to a diagnosis 0.8 additional cases of endometrial cancer per 1,000 women who used Livial for one year in this study (see section 4.4).
Risk of ischemic stroke
• The relative risk of ischemic stroke is not dependent on age or duration of use, but as the baseline risk is highly age-dependent, the overall risk of ischemic stroke in women using HRT or Tibolone will increase with age. see section 4.4.
• A 2.9-year randomized controlled trial estimated a 2.2-fold increase in the risk of stroke in women (mean age 68 years) using 1.25 mg of Livial (28 / 2,249), compared to placebo (13 /2.257). Most strokes (80%) were of the ischemic type.
• The baseline risk of stroke is highly age-dependent. Therefore, the baseline incidence over a 5-year period is estimated to be 3 per 1,000 women aged 50-59 and 11 per 1,000 women aged 60-69. of age.
• For women using Livial for 5 years, the number of additional cases expected should be approximately 4 per 1,000 women aged 50-59 and 13 per 1,000 women aged 60-69.
Other adverse reactions have been reported in association with estrogen and estrogen-progestogen treatment:
• Long-term use of estrogen-only and combined estrogen-progestogen HRT was associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 additional case for 2,500 users. This study showed that the relative risk of ovarian cancer with tibolone was similar to the risk with other types of HRT.
• HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), eg. deep vein thrombosis or pulmonary embolism. This event is more likely to occur in the first year of HRT use (see section 4.4).
The results of the WHI studies are reported:
Table 3 WHI Studies - Additional risk of VTE over 5 years of use
4 * Study in women with no uterus
- The risk of coronary heart disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60 (see section 4.4). There is no evidence to suggest that the risk of myocardial infarction with tibolone is different from the risk with other HRT.
- Cholecystopathies.
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
- Probable dementia after 65 years of age (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
The acute toxicity of tibolone in animals is very low therefore toxic symptoms are not expected to occur if several tablets are taken simultaneously; in cases of acute overdose, nausea, vomiting and, in females, vaginal bleeding may occur. No specific antidote is known. Symptomatic treatment can be implemented if necessary.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Drug therapeutic category: other estrogens ATC: G03 CX01
After oral administration, tibolone is rapidly metabolised to three compounds which contribute to Livial's pharmacodynamic profile. Two of these metabolites (3a-OH-tibolone and 3b-OH-tibolone) possess "estrogenic activity, while the third metabolite (isomer-D4 of tibolone) possesses" progestogenic and androgenic activity.
Livial replaces the lack of estrogen production in postmenopausal women and relieves menopausal symptoms. Livial prevents bone loss following menopause and oophorectomy.
Education in vitro:
Education in vitro suggest that tibolone exerts tissue-selective effects, due to local metabolism and local effects on enzymatic systems. The δ4 isomer is formed mainly in the endometrial tissue and in the breast; tibolone inhibits the sulfatase enzyme thus reducing the levels of 3-hydroxy-tibolone metabolites in this tissue. The clinical relevance of these studies is unknown (see section 4.8).
Information on clinical studies with Livial:
• Relief of estrogen deficiency symptoms:
- Relief of menopausal symptoms generally occurs during the first few weeks of treatment.
• Effects on the endometrium and bleeding profile:
- There have been reports of endometrial hyperplasia and endometrial cancer in patients treated with Livial (see sections 4.4 and 4.8).
- Amenorrhea was reported in 88% of women using Livial 2.5 mg after 12 months of treatment. Breakthrough bleeding and / or spotting was reported in 32.6% of women during the first three months of treatment and in 11.6% of women after 11-12 months of use.
• Prevention of osteoporosis:
- Estrogen deficiency in menopause is associated with an increased turnover of bone metabolism and a reduction in bone mass. The protection appears to be effective for the duration of the treatment. After stopping HRT, bone mass decreases at a similar rate to that seen in untreated women.
- In the LIFT study, Livial reduced the number of women (mean age 68 years) with new vertebral fractures compared to placebo, during the three years of treatment (ITT: Livial versus placebo odds ratio 0.57; 95% CI [0, 42, 0.78]).
- After 2 years of treatment with Livial 2.5 mg, the increase in bone mineral density in the lumbar spine (BMD) was 2.6 + 3.8%. The percentage of women who had maintained or increased BMD in the lumbar region during treatment was 76% A second study confirmed these results.
- Livial (2.5 mg) also showed effects on hip BMD. In one study, the increase after 2 years was 0.7 + 3.9% at the femoral neck and 1.7 + 3, 0% total hip. The percentage of women who maintained or increased their BMD in the hip region during treatment was 72.5%. A second study showed that the increase after 2 years was 1.3 + 5.1% at the femoral neck and 2.9 + 3.4% at the total hip. The percentage of women who maintained or increased their BMD in the hip region during treatment was 84.7%.
• Effects on the breast:
In clinical studies, mammography density was not increased in women treated with Livial compared to placebo.
05.2 Pharmacokinetic properties
After oral administration, tibolone is rapidly and extensively absorbed. Due to the rapid metabolism, the plasma levels of tibolone are very low. Plasma levels of the δ4-isomer are also very low. Therefore, it is not possible to determine some of the pharmacokinetic parameters. The plasma peak levels of the 3-alpha-OH and 3-beta-OH metabolites are higher but there is no accumulation.
Table 4 - Pharmacokinetic parameters of Livial (2.5 mg)
SD = single dose; DM = multiple dose
The excretion of tibolone occurs mainly in the form of conjugated metabolites (mostly sulfates). Some of the administered compound is excreted in the urine, but most is excreted in the faeces.
Food has no significant effect on the extent of absorption.
The pharmacokinetic parameters of tibolone and its metabolites were independent of renal function.
05.3 Preclinical safety data
In animal studies, Tibolone has shown anti-fertility and embryotoxic activity, by virtue of its hormonal characteristics. Tibolone was not teratogenic in mice and rats; it showed teratogenic potential in rabbits at abortive-like doses (see section 4.6). In vivo tibolone was not genotoxic. Although a carcinogenic effect has been observed in some strains of rats (liver tumors) and mice (gallbladder tumors), the clinical relevance of these effects is uncertain.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Livial 2.5 mg tablets contain potato starch, magnesium stearate, ascorbyl palmitate and lactose.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store below 25 ° C. Do not freeze.
Store the tablets in the original package.
06.5 Nature of the immediate packaging and contents of the package
Livial 2.5 mg tablets packed in colored PVC / aluminum blisters with a heat-sealed coating on the part in contact with the tablets. Available packaging: cardboard box containing 1 blister with 30 white tablets each containing 2.5 mg of tibolone.
06.6 Instructions for use and handling
No special instructions.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
N.V. Organon, Kloosterstraat 6, 5349 AB Oss (The Netherlands)
Representative in Italy:
MSD Italia S.r.l.
Via Vitorchiano, 151
00189 Rome
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 028035018
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 30.09.1991
Date of most recent renewal: May 2005
10.0 DATE OF REVISION OF THE TEXT
November 2014
