TIBOLONE TABLET

NAME OF THE MEDICINAL PRODUCT

Tibolone Tablet IP 2.5mg,

Tibolone Tablet BP 2.5mg

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2.5 mg tibolone.

PHARMACEUTICAL FORM
Tablet. White to off-white round uncoated tablets of 6 mm diameter with bevelled edge without any marking.

CLINICAL PARTICULARS

Therapeutic indications
•Treatment of oestrogen deficiency symptoms in postmenopausal women, more than one year after menopause.

  • Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

For all women the decision to prescribe Tibolone should be based on an assessment of the individual patient’s overall risks and, particularly in the over 60s, should include consideration of the risk of stroke.

Posology and method of administration

Posology
The dosage is one tablet per day. The tablets should be swallowed with some water or other drink, preferably at the same time every day.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.

A separate progestogen should not be added with Tibolone treatment.

Starting Tibolone
Women experiencing a natural menopause should commence treatment with Tibolone at least 12 months after their last natural bleed. In case of a surgical menopause, treatment with Tibolone may commence immediately. Women being treated with gonadotrophin releasing hormone (GnRH) analogues, for example, for endometriosis, may commence treatment with Tibolone immediately.

Any irregular/unscheduled vaginal bleeding, either on or off HRT, should be investigated to exclude malignancy before starting Tibolone

Switching from a sequential or continuous combined HRT preparation
If changing from a sequential HRT preparation, treatment with Tibolone should start the day following completion of the prior regimen. If changing from a continuous combined HRT preparation, treatment can start at any time.

Missed dose
A missed dose should be taken as soon as remembered, unless it is more than 12 hours overdue. In the latter case, the missed dose should be skipped and the next dose should be taken at the normal time. Missing a dose may increase the likelihood of breakthrough bleeding and spotting.

Paediatric population
There is no relevant use of Tibolone in the paediatric population.

Elderly
No dose adjustment is necessary for the elderly. There is limited experience in treating women over age 65 years.

Method of administration
For oral use

CONTRAINDICATION
– Pregnancy and lactation
– Known, past or suspected breast cancer – Tibolone increased the risk of breast cancer recurrence in placebo controlled trial.
– Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)
– Undiagnosed genital bleeding
– Untreated endometrial hyperplasia
– Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
– Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency,)
– Any history of arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke or Transient Ischemic Attack (TIA))
– Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal
– Porphyria
– Hypersensitivity to the active substance or to any of the excipients

SPECIAL PRECAUTIONS & WARNINGS

For the treatment of postmenopausal symptoms, Tibolone should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and Tibolone should only be continued as long as the benefit outweighs the risk.
The risks of stroke, breast cancer and, in women with an intact uterus, endometrial cancer for each woman should be carefully assessed, in the light of her individual risk factors and bearing in mind the frequency and characteristics of both cancers and stroke, in terms of their response to treatment, morbidity and mortality.
Evidence regarding the risks associated with HRT or tibolone in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow-up
Before initiating or reinstituting HRT or tibolone, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use.
During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse
Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Tibolone, in particular:
– Leiomyoma (uterine fibroids) or endometriosis
– Risk factors for thromboembolic disorders (see below)
– Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer
– Hypertension
– Liver disorders (e.g. liver adenoma)
– Diabetes mellitus with or without vascular involvement
– Cholelithiasis
– Migraine or (severe) headache
– Systemic lupus erythematosus
– A history of endometrial hyperplasia (see below)
– Epilepsy
– Asthma
– Otosclerosis

Reasons for immediate withdrawal of therapy:
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
– Jaundice or deterioration in liver function
– Significant increase in blood pressure
– New onset of migraine-type headache
– Pregnancy

Endometrial hyperplasia and carcinoma
The available data from randomised controlled trials are conflicting, however, observational studies have consistently shown that women who are prescribed Tibolone in normal clinical practice are at an increased risk of having endometrial cancer diagnosed. In these studies risk increased with increasing duration of use. Tibolone increases endometrial wall thickness, as measured by transvaginal ultrasound.

Break-through bleeding and spotting may occur during the first months of treatment.
Women should be advised to report any break-through bleeding or spotting if it is still present after 6 months of treatment, if it starts beyond that time or if it continues after treatment has been discontinued. The woman should be referred for gynaecological investigation, which is likely to include endometrial biopsy to exclude endometrial malignancy.

Breast cancer
Evidence with respect to breast cancer risk in association with tibolone is inconclusive. The Million Women Study (MWS) has identified a significant increase in the risk of breast cancer in association with use of the 2.5mg dose. This risk became apparent within a few years of use and increased with duration of intake, returning to baseline within a few (at most five) years after stopping treatment. These results could not be confirmed in a study using the General Practice Research Database (GPRD).

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer
Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the Women’s Health Initiative (WHI) trial, suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk.

In the Million Women Study it was shown that the relative risk for ovarian cancer with use of tibolone was similar to the risk associated with use of other types of HRT.

Venous thromboembolism
Oestrogen or oestrogen-progestogen HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8). In an epidemiological study using a UK database, the risk of VTE in association with tibolone was lower than the risk associated with conventional HRT, but only a small proportion of women were current users of tibolone and a small increase in risk compared with non-use cannot be excluded.

Patients with known thrombophilic states have an increased risk of VTE and HRT or tibolone may add to this risk. HRT is therefore contraindicated in these patients.
Generally recognized risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT or tibolone 4 to 6 weeks earlier is recommended, if possible. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g, antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT or tibolone is contraindicated.
Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT or tibolone.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctor immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT. In an epidemiological study using the GPRD no evidence was found of protection against myocardial infarction in postmenopausal women who received tibolone.

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

Other conditions
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Tibolone is not intended for contraceptive use.
Treatment with Tibolone results in a marked dose-dependent decrease in HDL cholesterol (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known.
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

Treatment with Tibolone results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Tibolone decreases the level of sexhormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected.
HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

Interaction with other medicinal products and other forms of interaction

Since Tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants. This effect has been demonstrated with warfarin. Caution should therefore be exercised during the simultaneous use of Tibolone and anticoagulants, especially when starting or stopping concurrent Tibolone treatment. If necessary, the dose of warfarin should be adjusted.
There is limited information regarding pharmacokinetic interactions with tibolone. An in vivo study showed that simultaneous treatment of tibolone affects pharmacokinetics of the cytochrome P450 3A4 substrate midazolam to a moderate extent. Based on this, drug interactions with other CYP3A4 substrates might be expected.
CYP3A4 inducing compounds such as barbiturates, carbamazepine, hydantoins and rifampicin may enhance the metabolism of tibolone and thus affect its therapeutic effect.
Herbal preparations containing St.John`s wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestogens via CYP3A4. Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

Fertility, pregnancy and lactation

Pregnancy

Tibolone is contraindicated during pregnancy. If pregnancy occurs during medication with Tibolone, treatment should be withdrawn immediately. For Tibolone no clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Breastfeeding
Tibolone is contraindicated during lactation.

Fertility
In animal studies, Tibolone had anti-fertility activities by virtue of its hormonal properties.

Effects on ability to drive and use machines
Tibolone is not known to have any effects on alertness and concentration.

Table 1: Undesirable effect of tibolone
System Organ Class Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Metabolism and nutrition disorders Oedema**
Gastrointestinal disorders Lower abdominal pain Abdominal discomfort**
Skin and subcutaneous tissue disorders Abnormal hair growth Acne Pruritus**
Reproductive system and breast disorders Vaginal discharge

Endometrial was thickening

Postmenopausal haemorrhage

Breast tenderness

Genital pruritus

Vaginal candidiasis

Vaginal haemorrhage

Pelvic pain

Cervical dysplasia

Genital discharge

Vulvovaginitis

Breast discomfort

Fungal infection

Vaginal mycosis

Nipple pain

Investigations Weight increase

Abnormal cervical smear*

UNDESIRABLE EFFECTS
This section describes undesirable effects, which were registered in 21 placebo-controlled studies (including the LIFT study), with 4079 women receiving therapeutic doses (1.25 or 2.5 mg) of Tibolone and 3476 women receiving placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. Table 1 shows the undesirable effects that occurred statistically significantly more frequently during treatment with Tibolone than with placebo.
*The majority consisted of benign changes. Cervix pathology (cervical carcinoma) was not increased with Tibolone compared to placebo.

**These adverse reactions were identified through post-marketing surveillance. The frequency category was estimated based on relevant clinical trials.

In market use, other undesirable effects that have been observed include: dizziness, rash, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), depression, effects on the musculoskeletal system such as arthralgia or myalgia and changes in liver function parameters.

Breast cancer
An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.

Any increased risk in users of oestrogen-only and tibolone therapies is substantially lower than seen in users of oestrogen-progestogen combinations.

The level of risk is dependent on the duration of use.
Results of the largest epidemiological study (Million Women Study) are presented.

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT or tibolone.

The randomised placebo controlled trial that included women who had not been screened for endometrial abnormalities at baseline, and therefore reflected clinical practice, identified the highest risk of endometrial cancer (LIFT study, mean age 68 years). In this study, no cases of endometrial cancer were diagnosed in the placebo group (n=1,773) after 2.9 years compared with 4 cases of endometrial cancer in the Tibolone group (n=1,746). This corresponds to a diagnosis of 0.8 additional case of endometrial cancer in every 1000 women who used Tibolone for one year in this

Ovarian cancer
Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed .

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

In the Million Women Study, taking 5 years of tibolone resulted in 1 extra case per 2500 users. HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT.

Results of the WHI studies are presented.

Table 2-Million Women study- Estimated additional risk of breast cancer after 5 years’ use
Age range

(Years)

Additional cases per 1000 never-users of HRT over a 5 year period (*2) Risk ratio (95% CI) (*3) Additional cases per 1000 HRT users over 5 years (95% CI)
Estrogen-only HRT
50-65 9-12 1.2 1-2 (0-3)
Combined estrogen-progestagen
50-65 9-12 1.7 6 (5-7)
Tibolone
50-65 9-12 1.3 3 (0-6)
*2: Taken from baseline incidence rates in developed countries

*3: Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of use

Table 3- WHI studies-Additional risk of  VTE over 5 years’ use
Age range (years) Incidence per 1000 women in placebo arm over 5 years Risk ratio (95% CI) Additional cases per 1000 HRT users
Oral estrogen-only (*4)
50-59 7 1.2 (0.6-2.4) 1 (-3-10)
Oral combined estrogen-progesteron
50-59 4 2.3 (1.2–4.3) 5 (1-13)

4: Study in women with no uterus
Risk of coronary artery disease
– The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen HRT over the age of 60. There is no evidence to suggest that the risk of myocardial infarction with tibolone is different to the risk with other HRT.

Risk of ischaemic stroke
– The relative risk of ischaemic stroke is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of ischaemic stroke in women who use HRT or tibolone will increase with age, see section 4.4.
– The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
– A 2.9 year randomised controlled study has estimated a 2.2-fold increase in the risk of stroke in women (mean age 68 years) who used 1.25 mg Tibolone (28/2249) compared with placebo (13/2257). The majority (80%) of strokes were ischaemic.
The baseline risk of stroke is strongly age-dependent. Thus, the baseline incidence over a 5 year period is estimated to be 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years.
– For women who use Tibolone for 5 years, the number of additional cases would be expected to be about 4 per 1000 users aged 50-59 years and 13 per 1000 users aged 60-69 years.

Age range

(years)

Incidence per 1000 women in placebo arm over 5 years Risk ratio (95%CI) Additional cases per 1000 HRT users over 5 years
50-59 8 1.3 (1.1-1.6) 3 (1-5)

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:
– Gall bladder disease
– Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura
– Probable dementia over the age of 65

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via theYellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard

Overdose
The acute toxicity of tibolone in animals is very low. Therefore, toxic symptoms are not expected to occur, even when several tablets are taken simultaneously. In cases of acute overdose, nausea, vomiting and vaginal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary

Pharmacological properties

Pharmacodynamic properties

Pharmacotherapeutic group: ATC code: G03CX01, other estrogens
Following oral administration, tibolone is rapidly metabolised into three compounds, which all contribute to the pharmacodynamic profile of Tibolone. Two of the metabolites (3α-OH-tibolone and 3β-OH-tibolone) have oestrogenic-like activities, whereas the third metabolite (4Δ-isomer of tibolone) has progestogenic and androgenic-like activities.
Tibolone substitutes for the loss of oestrogen production in postmenopausal women and alleviates menopausal symptoms. Tibolone prevents bone loss following menopause or ovariectomy.

Clinical trial information of Tibolone:
Relief of oestrogen-deficiency symptoms.
Relief of menopausal symptoms generally occurs during the first few weeks of treatment.

Effects on the endometrium and bleeding patterns.
There have been reports of endometrial hyperplasia and endometrial cancer in patients treated with Tibolone.
Amenorrhea has been reported in 88% of women using Tibolone 2.5 mg after 12 months of treatment. Breakthrough bleeding and/or spotting has been reported in 32.6% of women during the first 3 months of treatment, and in 11.6% of women after 11-12 months of use.

Prevention of osteoporosis
Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

In the LIFT study, Tibolone reduced the number of women (mean age 68 years) with new vertebral fractures compared to placebo during the 3 years of treatment (ITT: Tibolone to placebo odds ratio 0.57; 95% CI [0.42, 0.78]).
After 2 years of treatment with Tibolone (2.5 mg), the increase in lumbar spine bone mineral density (BMD) was 2.6 ± 3.8%. The percentage of women who maintained or gained BMD in lumbar zone during treatment was 76%. A second study confirmed these results.
Tibolone (2.5 mg) also had an effect 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% at the total hip. The percentage of women who maintained or gained 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 gained BMD in the hip region during treatment was 84.7%.

Effects on the breast
In clinical studies mammographic density is not increased in women treated with Tibolone compared to placebo.

Pharmacokinetic properties

Absorption and biotransformation
Following oral administration, tibolone is rapidly and extensively absorbed. Due to rapid metabolism, the plasma levels of tibolone are very low. The plasma levels of the Δ4-isomer of tibolone are also very low. Therefore some of the pharmacokinetic parameters could not be determined. Peak plasma levels of the 3α-OH and the 3β-OH metabolites are higher but accumulation does not occur.

 


Tibolone
3α-OH

metaboline

3β-OH

metabolite

Δ 4 Isomer
SD MD SD MD SD MD SD MD
Cmax

(mg/ml)

1,37 1,72 14,23 14,15 3,43 3,75 0,47 0,43
Caverage 1,88
Tmax (h) 1,08 1,19 1,21 1,15 1,37 1,35 1,64 1,65
T1/2 (h) 5,78 7,71 5,87
Cmin (ng/ml) 0,23
AUC 0-24

(ng/ml.h)

52,23 44,73 16,23 9,20

SD = single dose ; MD = multiple dose

Elimination

Excretion of tibolone is mainly in the form of conjugated (mostly sulfated) metabolites. Part of the administered compound is excreted in the urine, but most is eliminated via the faeces.

The consumption of food has no significant effects on the extent of absorption.

Other special populations

The pharmacokinetic parameters for tibolone and its metabolites were found to be independent of renal function.

Preclinical safety data

In animal studies, tibolone had anti-fertility and embryotoxic activities by virtue of its hormonal properties. Tibolone was not teratogenic in mice and rats. It displayed teratogenic potential in the rabbit at near-abortive dosages. Tibolone is not genotoxic under in vivo conditions. Although a carcinogenic effect was seen in certain strains of rat (hepatic tumours) and mouse (bladder tumours), the clinical relevance of this is uncertain.

Pharmaceutical particulars

List of excipients
Tibolone contains:
– lactose monohydrate
– mannitol
– potato starch
– magnesium stearate
– ascorbyl palmitate

Incompatibilities

Not applicable.

 Shelf life

2 years.

Special precautions for storage
This medicinal product does not require any special temperature storage conditions.

Store in the original package, in order to protect from light and moisture.

Nature and contents of container
Push-through pack of transparent PVC-Alu tablets pack sizes: cardboard boxes containing 1, 3 or 6 blisters with 28 or 30 tablets.

Not all pack size may be marketed.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORISATION HOLDER

TAJ PHARMA CIS LTD.
Marksistsky lane 6, office 221, Moscow, 109147, Russia

MANUFACTURER:

Manufactured in India by:
TAJ PHARMACEUTICALS LTD,
220, Mahagujarat Ind. Estate,  Moraiya,

Tal. Sanand , Dist. Ahmedabad,

Gujarat, INDIA.

What is in this leaflet

In this leaflet:

  1. What Tibolone is and what it is used for
  2. What you need to know before you take Tibolone
  3. How to take Tibolone
  4. Possible side effects
  5. How to store Tibolone
  6. Contents of the pack and other information

  7. What Tibolone is and what it is used for

The active substance is: tibolone.This medicine is a Hormone Replacement Therapy (HRT). It contains tibolone, a substance that has favourable effects on different tissues in the body, such as brain, vagina and bone

. This medicine is used in postmenopausal women with at least 12 months(1 year)since their last natural period.

This medicine is used for:

Relief of symptoms occurring after menopause

During the menopause, the amount of the oestrogen produced by a woman’s body drops. This can cause symptoms such as hot face, neck and chest (“hot flushes”). Tibolone alleviates these symptoms after menopause. You will only be prescribed this medicine if your symptoms seriously hinder your daily life.

Prevention of osteoporosis

After the menopause some women may develop fragile bones (osteoporosis). You should discuss all available options with your doctor.

If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you, you can use Tibolone to prevent osteoporosis after menopause.

There are three different kinds of HRT:

  • Oestrogen-only HRT
  • Combined HRT, containing two kinds of female hormone, an oestrogen and a progestogen

.•Tibolone,which contains a substance called tibolone

Tibolone is different from other HRT. Instead of actual hormones (such as oestrogen and

progestogen) it contains tibolone. Your body breaks down tibolone to make hormones. Its effects and benefits are similar to combined HRT

  1. What you need to know before you take Tibolone

Medical History and regular check-ups

The use of HRT or Tibolone carries risks that need to be considered when deciding whether to start

taking it, or whether to carry on taking it. This is especially important if you are more than 60

years old.

The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause the risks of using HRT or Tibolone may be different.

Please talk to your doctor.

Before you start taking or restart HRT or Tibolone

Your doctor will ask about your own and your family’s medical history. Your doctor may decide to perform a physical examination.

This may include an examination of your breast

s and /or an internal examination, if necessary

Tell your doctor

if you have any medical problems or illnesses.

Regular check-ups

Once you have started on Tibolone, you should see your doctor for regular check-ups

(at least once a year). At these check -ups, discuss with your doctor the benefits and risks of continuing with Tibolone.Go for regular breast screening, as recommended by your doctor.

Be sure to

  • go for regular breast screening and

cervical smear tests.

  • regularlycheck your breasts for any changes such as dimpling of the skin, changes in the

nipple, or any lumps you can see or feel

Some women should not take Tibolone

Do not take Tibolone

If any of the following applies to you. If you are not sure about any of the points below, talk to your doctor before taking Tibolone

  • If you have or have ever had breast cancer, or if you are suspected of having it
  • If you have cancer which is sensitive to oestrogens, such as cancer of the womb lining

(endometrium), or if you are suspected of having it

  • If you have any unexplained vaginal bleeding
  • If you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated.
  • If you have or have ever had a blood clot in a vein (thrombosis), such as in the legs (deep

venous thrombosis) or the lungs (pulmonary embolism)

  • If you have a blood clotting disorder

(such as protein C, protein S, or antithrombin

deficiency)

  • If you have or recently have had a disease caused by blood clots in the arteries, such as a

heart attack, stroke or angina

  • If you have or have ever had a liver disease

and your liver function tests have not returned to

normal

  • If you have a rare blood problem called “porphyria” which is passed down in families

(inherited)

  • If you are allergic to tiboloneor any of the other ingredients of this medicine
  • If you are pregnant or think you might be pregnant.
  • If you are breastfeeding

. If any of the above conditions appear for the first time while taking Tibolone, stop taking it at once and consult your doctor immediately.

If you have started the menopause you should not take Tibolone until 12 months after your last

natural period.

If you take it sooner than this you may have irregular bleeding.

Warning and precautions

Talk to your docto, pharmacist or nurse before taking Tibolone.

If you have ever had any of the following problems, tell your doctor before you start the

treatment, as these may return or become worse during treatment with Tibolone. If so, you should

see your doctor more often for check-ups:

  • fibroids inside your womb
  • growth of the womb lining outside your womb (endometriosis) or a history of excessive

growth of the womb lining (endometrial hyperplasia)

  • increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”)
  • increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
  • high blood pressure
  • a liver disorder, such as a benign liver tumour
  • diabetes
  • gallstones
  • migraine or severe headaches
  • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
  • epilepsy
  • asthma
  • a disease affecting the eardrum and hearing (otosclerosis)
  • a very high level of fat in your blood (triglycerides)
  • fluid retention due to cardiac or kidney problem

Stop taking Tibolone and see a doctor immediately
If you notice any of the following when taking Tibolone:

  • any of the conditions mentioned in the “Do not take Tibolone” section
  • yellowing of your skin or the whites of your eyes (jaundice). These may be signs of a liver disease
  • a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness)
  • migraine-like headaches which happen for the first time
  • if you become pregnant
  • if you notice signs of a blood clot, such as:
    • painful swelling and redness of the legs
    • sudden chest pain
    • difficulty in breathing

For more information, see “Blood clots in a vein (thrombosis)”.

Note: Tibolone is not a contraceptive. If it is less than 12 months since your last menstrual period or you are under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your doctor for advice.

HRT and Cancer
Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of the womb (endometrial cancer)
There have been reports of an increased cell growth or cancer of the lining of the womb in women using Tibolone. The risk of cancer of the lining of the womb increases the longer you take the medicine.

Irregular bleeding
You may have irregular bleeding or drops of blood (spotting) during the first 3-6 months of taking Tibolone. But if the bleeding or spotting:

  • Carries on for more than the first 6 months
  • Starts after you have been taking Tibolone for more than 6 months
  • Carries on even after you’ve stopped taking Tibolone
  • see your doctor as soon as possible.

Breast cancer
Evidence suggests that taking combined oestrogen-progestogen and possibly also oestrogen-only HRT increases the risk of breast cancer. The extra risk depends on how long you take HRT. The additional risk becomes clear within a few years. However, it returns to normal within a few years (at most 5) after stopping treatment.

Compare
Women taking Tibolone have a lower risk than women using combined HRT and a comparable risk with oestrogen-only HRT.

  • Regularly check your breasts. See your doctor if you notice any changes such as:
    • dimpling or sinking of the skin
    • changes in the nipple
    • any lumps you can see or feel
  • Make an appointment to see your doctor as soon as possible

Ovarian cancer
Ovarian cancer is rare – much rarer than breast cancer. The use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. For women who have been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case).

With use of Tibolone, the increased risk of ovarian cancer is similar to other types of HRT.

 Effect of HRT on heart and circulation
Blood clots in a vein (thrombosis)
The risk of blood clots in the veins is about 1.3 to 3-times higher in HRT users than in non-users, especially during the first year of taking it.
Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or even death.
You are more likely to get a blood clot in your veins as you get older and if any of the following applies to you. Inform your doctor if any of these situations apply to you:

  • you are pregnant or recently had a baby
  • you use oestrogens
  • you are unable to walk for a long time because of major surgery, injury or illness
  • you are seriously overweight (BMI >30 kg/m2)
  • you have any blood clotting problem that needs long-term treatment with a medicine used to prevent blood clots
  • if any of your close relatives has ever had a blood clot in the leg, lung or another organ
  • you have systemic lupus erythematosus (SLE)
  • you have cancer.
    For signs of a blood clot, see “Stop taking Tibolone and see a doctor immediately

Compare
Looking at women in their 50s who are not taking HRT, on average, over a 5 year period, 4 to 7 in 1000 would be expected to get a blood clot in a vein.
For women in their 50s who have been taking oestrogen-progestogen HRT for over 5 years, there will be 9 to 12 cases in 1000 users (i.e. an extra 5 cases).

  • With use of Tibolone, the increased risk of getting a blood clot in a vein is lower than with other types of HRT.

Heart disease (heart attack)
There is no evidence that HRT or Tibolone will prevent a heart attack.
Women over the age of 60 who use oestrogen-progestogen HRT are slightly more likely to develop heart disease than those not taking any HRT. As the risk of heart disease strongly depends on age, the number of extra cases of heart disease due to use of oestrogen-progestogen HRT is very low in healthy women close to menopause, but will rise with more advanced age.
There is no evidence to suggest that the risk of myocardial infarction with Tibolone is different to the risk of other HRT.

Stroke
Recent research suggests that HRT and Tibolone slightly increases the risk of having a stroke. The increased risk is seen mainly in women over 60 years old. Other things that can increase the risk of stroke include:

  • Getting older
  • High blood pressure
  • Smoking
  • Drinking too much alcohol
  • An irregular heartbeat

If you are worried about any of these things, talk to your doctor to see if you should take HRT

Compare
Looking at women in their 50s who are not taking Tibolone – on average, over a 5-year period, 3 in 1000 would be expected to have a stroke.
For women in their 50s who are taking Tibolone, the figure would be 7 in 1000 (i.e. an extra 4 cases).
Looking at women in their 60s who are not taking Tibolone – on average, over a 5-year period, 11 in 1000 would be expected to have a stroke.
For women in their 60s who are taking Tibolone, the figure would be 24 in 1000 (i.e. an extra 13 cases).

Other conditions
HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Speak to your doctor for advice.
Tibolone is not intended for contraceptive use.
Treatment with Tibolone results in a marked dose-dependent decrease in HDL cholesterol (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known.
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.

Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or Hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
Treatment with Tibolone results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Tibolone decreases the level of sex-hormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected.

Other medicines and Tibolone

Some medicines may interfere with the effect of Tibolone. This might lead to irregular bleeding. This applies to the following medicines:

  • Medicines against blood clotting (such as warfarin)
  • Medicines for epilepsy (such as phenobarbital, phenytoin and carbamazepin)
  • Medicines for tuberculosis (such as rifampicin)
  • Herbal remedies 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. This includes medicines obtained without a prescription, herbal medicines or other natural products.

Having an Operation
If you are going to have an operation
, make sure your doctor knows about it. You may need to stop taking HRT about 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start taking HRT again.

 

Tibolone with food and drink
You can eat or drink normally while you are taking Tibolone.

Pregnancy and breast-feeding
Tibolone is for use in postmenopausal women only. If you become pregnant, stop taking Tibolone and contact your doctor.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

 Driving and using machines
Tibolone has no known effect on the ability to drive or use machines.

 Tibolone contains Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before using Tibolone.
If you are worried about anything in this section, talk to your doctor about the risks and benefits of HRT.

  1. How to take Tibolone
    When can you start taking Tibolone
    Wait before taking Tibolone, If it is not yet 12 months since your last natural period

Start taking Tibolone straight away

  • If you are changing over from a period free HRT… (see note below)…
  • If you have never used HRT before
  • If you were prescribed HRT because you have had a hysterectomy
  • If you are being treated for endometriosis (a condition in which parts of the womb lining move around the body)…

Wait for your next period. Start taking Tibolone as soon as your period ends

  • If you are changing over from another type of HRT with which you have periods… (see the note below)…

If you are changing over from another type of HRT
There are several different types of HRT, such as tablets patches and gels. Most contain either oestrogen, or oestrogen and progestogen. With some you still have periods, and with some you don’t (these are called period-free HRT).

3)How to take Tibolone
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.


The recommended dose is one tablet every day.
Take this dose unless your doctor or pharmacist told you to do something different.
Press the tablet so that it comes through the foil. Swallow the tablet with some water or other drink, without chewing.

Take Tibolone at the same time each day.
The strips of tablets are marked with the days of the week. Start by taking a tablet marked with the current day. For example, if it is Monday, take a tablet marked Monday on the top row of the strip. Follow the arrows until the strip is empty. Start the next strip the next day. Do not leave a break between strips or packs.

Your doctor will aim to prescribe the lowest dose to treat your symptoms for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough.

 If you take more Tibolone than you should
It is unlikely that taking more than one tablet will do you any harm, but you may feel sick, be sick or have some vaginal bleeding.

 If you forget to take Tibolone
If you forget to take a tablet, take it as soon as you remember, unless you are more than 12 hours late. If you are more than 12 hours late, just skip it, and take your next tablet at the usual time. Don’t take a double dose.

If you need to have surgery
If you are going to have surgery, tell the surgeon that you are taking Tibolone. You may need to stop taking Tibolone about 4 to 6 weeks before the operation to reduce the risk of a blood clot.Ask your doctor when you can start taking Tibolone again.

  1. Possible side effects
    The following diseases are reported more often in women using HRT compared to women not using HRT:
  • breast cancer
  • abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer)
  • ovarian cancer
  • blood clots in the veins of the legs or lungs (venous thromboembolism)
  • heart disease
  • stroke
  • probable memory loss if HRT is started over the age of 65

For more information about these side effects.Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are mild.

  • Tell your doctor or pharmacist if you are worried about any side effects which you think may be due to Tibolone
    Serious side effects – see a doctor straight away
    If you think you may have signs of a serious side effect, see a doctor straight away.
    You may need to stop taking Tibolone:
  • If your blood pressure rises
  • If your skin or the whites of your eyes go yellow (jaundice)
  • If you suddenly have migraine-type headaches
  • If you have signs of a blood clot

Other side effects
Common (may affect up to 1 in 10 women):

  • breast pain
  • stomach or pelvic pain
  • unusual hair growth
  • vaginal bleeding or spotting.
    This is usually nothing to worry about in the first few months of taking HRT.
  • If bleeding continues, or starts after you have been on HRT vaginal problems such as more secretions, itching, irritation and thrush
  • thickening of the lining of the womb or the lining of the cervix
    weight gain.

Uncommon (may affect up to 1 in 100 women):

  • swollen hands, ankles or feet – a sign of fluid retention
  • stomach upset
  • acne
  • painful nipples or breasts feeling uncomfortable
  • vaginal infections

Rare (may affect up to 1 in 1000 women):

  • itchy skin

Some women taking Tibolone have also reported:

  • depression, dizziness, headache
  • joint pain or muscle pain
  • skin problems such as rash or itching
  • loss of vision or blurred vision
  • changes in liver tests

There have been reports of breast cancer and of an increased cell growth or cancer of the lining of the womb in women using Tibolone.

  • Tell your doctor if any of the above mentioned side effects continues or becomes troublesome.

The following side effects have been reported with other HRTs:

  • gall bladder disease
  • various skin disorders:
    • discolouration of the skin especially of the face or neck known as “pregnancy patches” (chloasma)
    • painful reddish skin nodules (erythema nodosum)
    • rash with target-shaped reddening or sores (erythema multiforme)
  • eporting of side effects
  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side affects you can help provide more information on the safety of this medicine.
  • United Kingdom: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
  • Malta: ADR Reporting at: www.medicinesauthority.gov.mt/adrportal
  1. How to store Tibolone
    Keep this medicine out of the sight and reach of children.
    Do not use this medicine after the expiry date which is stated on the carton after ‘EXP’. The expiry date refers to the last day of that month.
    Store below 25°C. Do not refrigerate. Store in the original package. Keep the blister in the outer carton, in order to protect from light and moisture.
    Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
  2. Contents of the pack and other information

What Tibolone contains
The active substance is tibolone.
The other ingredients are potato starch, lactose monohydrate, ascorbyl palmitate and magnesium stearate.

What Tibolone looks like and the contents of the pack
Tibolone tablets are white, and marked Organon* on one side, and “MK2” on the other side.
They come in packs of one or three strips of 28 tablets.

The Marketing Authorisation Holder is:

Merck Sharp & Dohme Limited
Hertford Road
Hoddesdon
Hertfordshire
EN11 9BU
UK

Manufactured by:
Taj Pharmaceuticals Limited
220, Mahagujarat Ind. Estate, Moraiya, Tal. Sanand, Dist. Ahmedabad, Gujarat, INDIA

Marketing Authorization Holder:
Regal sun co., Ltd.Myanmar

More about Tibolone
The most important natural sex hormones in women are oestrogens and progesterone.
These hormones are produced in the ovaries. They are needed for normal sexual development and control the menstrual cycle.
The menopause is the time (usually around the age of 50) when the ovaries gradually stop producing oestrogens. If the ovaries are removed surgically before the menopause, the decrease in hormone production occurs very quickly. The decrease in hormone production often leads to symptoms such as hot flushes and night sweats. The shortage of sex hormones may also cause the lining of the vagina to become thin and dry. So sexual intercourse may be painful and vaginal infections may occur more frequently. Some women also experience mood changes, nervousness, depression, irritability and loss of sexual desire.

Oestrogens are also important for bone formation. Bone is built up during youth, and peak bone mass is reached between the age of 20 and 30. After that, bone mass decreases, at first slowly, but later in life more quickly, especially after the menopause. Gradually, the bones become brittle and may easily break (osteoporosis), especially in your spine, hip and wrists. Osteoporosis may also cause back pain, loss of height and a curved back.
Tibolone contains tibolone, a substance that has beneficial effects on different tissues in the body, such as the brain, vagina and bone. This results in the relief of symptoms such as hot flushes and night sweats, and an improvement in the lining of the vagina, mood and sexual desire. Tibolone can also stop the process of bone loss that occurs in your spine, hip and wrists after the menopause. Unlike some hormone replacement therapies, Tibolone does not stimulate the lining of the womb. So treatment with Tibolone does not cause monthly vaginal bleeding.

 

 

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