Consumer medicine information

APO-Tibolone Tablets

Tibolone

BRAND INFORMATION

Brand name

APO-Tibolone

Active ingredient

Tibolone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Tibolone Tablets.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

APO-Tibolone tablets contain the active ingredient tibolone, which is a synthetic steroid medicine used for hormone replacement therapy (HRT). It mimics the activity of the female sex hormones in the body.

APO-Tibolone contains tibolone, a substance that has favourable effects on different tissues in the body, such as brain, vagina and bone. APO-Tibolone is used in postmenopausal women at least 12 months since their last natural period.

APO-Tibolone is used for:

Relief of symptoms occurring after menopause

During the menopause, the amount of estrogen produced by a woman's body drops. This can cause symptoms such as hot face, neck and chest ("hot flushes"). APO-Tibolone alleviates these symptoms after menopause. You will only be prescribed APO-Tibolone 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 take APO-Tibolone to prevent osteoporosis after menopause.

APO-Tibolone is not a contraceptive.

APO-Tibolone has no effect on alertness and concentration as far as is known.

A doctor's prescription is required to obtain this medicine.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Before you use this medicine

When you must not take it

Do not take this medicine if:

  • you are pregnant or think you may be pregnant
  • you are breastfeeding
  • you have or have ever had breast cancer, or if you are suspected of having it
  • you have cancer which is sensitive to estrogens, such as cancer of the womb lining (endometrium), or if you are suspected of having it
  • you have any unexplained vaginal bleeding
  • you have excessive thickening of the womb lining (endometrial hyperplasia) that is not being treated
  • 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)
  • you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
  • you have or recently have had a disease caused by blood clots in the arteries, such as a heart attack, stroke or angina
  • you have or have ever had liver disease and your liver function tests have not returned to normal
  • you have a rare blood problem called porphyria which is passed down in families (inherited)
  • you are allergic (hypersensitive) to tibolone or any of the ingredients of APO-Tibolone listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

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

Medical history and regular check-ups

As well as benefits, HRT or APO-Tibolone has some risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it.

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 APO-Tibolone may be different. Please talk to your doctor.

Before you start (or restart) HRT or APO-Tibolone, your doctor will ask you about your own and your family's medical history. Your doctor may decide to perform a physical examination. This may include an examination of your breasts and/or an internal examination, if necessary.

Once you have started on APO-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 APO-Tibolone.

Go for regular breast screening, as recommended by your doctor.

When to take special care with APO-Tibolone

Tell your doctor if you have ever had any of the following conditions before you start the treatment, as these may return or become worse during treatment with APO-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 estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
  • high blood pressure
  • a liver disorder, such as a benign liver tumour
  • diabetes
  • gallstones
  • migraine or severe headaches
  • a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
  • epilepsy
  • asthma
  • a disease affecting the eardrum and hearing (otosclerosis)
  • a very high level of fat in your blood (triglycerides)
  • fluid retention due to cardiac or kidney problems

Tell your doctor if you notice any change in your condition whilst using APO-Tibolone.

Stop taking APO-Tibolone and see a doctor immediately if you notice any of the following when taking HRT or APO-Tibolone:

  • any of the conditions mentioned in the "Do not take APO-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)"

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 and studies of an increased cell growth or cancer of the lining of the womb in women using APO-Tibolone. The risk of cancer of the lining of the womb increases with the duration of use.

Irregular bleeding

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

However, if the irregular bleeding:

  • Carries on for more than the first 6 months
  • starts after you have been taking APO-Tibolone for more than 6 months
  • carries on after you have stopped taking APO-Tibolone

see your doctor as soon as possible.

Breast Cancer

Taking estrogen, estrogen-progesterone combined HRT or APO-Tibolone for several years slightly increases the risk of breast cancer. The risk increases with the duration of HRT use and returns to normal within about 5 years after stopping HRT.

Women taking APO-Tibolone have a lower risk than women using combined HRT and a comparable risk with estrogen-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

Ovarian cancer

Ovarian cancer is rare. An increased risk of ovarian cancer has been reported in women taking HRT after 5 years of use.

For women aged 50 to 54 who are not taking HRT, on average 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 1 extra case per 2000 users. With use of APO-Tibolone, the increased risk of ovarian cancer for women taking APO-Tibolone for 5 years is 1 extra case per 2500 users.

Effects of HRT on heart or circulation

Heart disease (heart attack)
There is no evidence that HRT or APO-Tibolone will prevent a heart attack.

Women over the age of 60 who use estrogen-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 estrogen-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 APO-Tibolone is different to the risk of other HRT.

See a doctor as soon as possible and do not take any more APO-Tibolone if you get a pain in your chest that spreads to your arm or neck.

This pain could be a sign of heart disease.

Stroke
Recent research suggests that HRT and APO-Tibolone increases the risk of having a stroke. This increased risk has mainly been observed in elderly postmenopausal women above 60 years of age.

Looking at women in their 50s who are not taking APO-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 APO-Tibolone, the figure would be 7 in 1000 (i.e. an extra 4 cases).

Looking at women in their 60s who are not taking APO-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 APO-Tibolone, the figure would be 24 in 1000 (i.e. an extra 13 cases).

If you are worried about any of these things, or if you have had a stroke in the past, talk to your doctor to see if you should take APO-Tibolone.

See a doctor as soon as possible and do not take any more APO-Tibolone until your doctor says you can if you get any unexplained migraine-type headaches with or without disturbed vision. These headaches may be an early warning sign of a stroke.

Blood clots in a vein (Thrombosis)
Estrogen and estrogen-progestogen combined HRT may increase the risk of blood clots in the veins (also called deep vein thrombosis, or DVT), especially during the 1st year of taking it. It is unknown if APO-Tibolone increases the risk in the same way.

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 estrogens
  • you are unable to walk for a long time because of major surgery, injury or illness (see also "If you need to have surgery")
  • you are seriously overweight (BMI greater than 30kg per square metre)
  • 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, a disease of your immune system)
  • you have cancer

If any of these apply to you, talk to your doctor about whether you should use APO-Tibolone.

For signs of a blood clot, see "Stop taking APO-Tibolone and see a doctor immediately".

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 estrogen-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 APO-Tibolone, the increased risk of getting a blood clot in a vein is lower than with other types of HRT.

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.

Tell your doctor if you become pregnant or are breast-feeding. APO-Tibolone is for use in postmenopausal women only. If you are pregnant or breast-feeding or think you may be pregnant, do not take APO-Tibolone.

Tell your doctor if you react badly to lactose or milk before you start taking APO-Tibolone. APO-Tibolone tablets contain lactose.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with the effect of APO-Tibolone. This applies to the following medicines:

  • medicines against blood clotting (such as warfarin)
  • medicines for epilepsy (such as phenobarbitone, phenytoin and carbamazepine)
  • medicines for tuberculosis (such as rifampicin)
  • herbal remedies containing St John's Wort (hypericum perforatum)

Your doctor may need to adjust the dose of these medicines.

Ask your doctor or pharmacist for advice before taking any medicine.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the directions, ask your doctor or pharmacist for help.

When to start it

APO-Tibolone should not be taken until 12 months after your last natural menstrual bleed. If APO-Tibolone is taken sooner than this, the chance of irregular vaginal bleeding may be increased.

Women who have undergone premature menopause (surgical removal of ovaries) can start taking APO-Tibolone immediately.

If you are already using a different type of HRT, your doctor will advise you when to switch to APO-Tibolone.

How to take it

Take one tablet daily, at about the same time each day. Swallow the tablet with some water or other non- alcoholic drink.

The APO-Tibolone pack contains 28 white tablets. The strips with APO-Tibolone are marked with the days of the week. Start by taking the tablet marked with that day. For example, if it is a Monday, take a tablet marked Monday on the upper row of the strip. Follow the days of the week until the strip is empty. Start the next strip the next day.

Do not leave a break between strips or packs.

How long to take it

HRT should be prescribed at the lowest effective dose and for the shortest duration necessary. Your doctor can advise you how long you may need to take APO-Tibolone.

If you forget to take it

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, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Signs of an overdose may include feeling sick or vomiting. Vaginal bleeding may also occur after a few days.

If you need to have surgery

Tell your doctor and your surgeon that you are taking APO-Tibolone if you are going to have surgery. You may need to stop taking APO-Tibolone about 4-6 weeks before the operation to reduce the risk of a blood clot (see "Blood clots in a vein"). Ask your doctor when you can start taking APO-Tibolone again.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking this medicine.

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)
  • visual disturbances
  • 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

APO-Tibolone helps most women with menopausal symptoms, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Common side effects observed in clinical studies (occurring in 1-10% of the women using APO-Tibolone) were:

  • vaginal bleeding or spotting
  • abdominal pain
  • weight gain
  • breast pain
  • unnatural hair growth
  • vaginal symptoms, such as discharge, itching, and irritation

Uncommon side effects (occurring in 0.1-1% of the women using APO-Tibolone) were:

  • acne

Other side effects observed with APO-Tibolone in market use were:

  • dizziness, headache, migraine, depression
  • rash or itching
  • gastro-intestinal upset
  • fluid retention
  • joint pain, muscle pain
  • changes in liver function

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

Tell your doctor if vaginal bleeding or spotting occurs or if any of the above-mentioned side effects worry you or continue.

Please see "Medical history and regular check-ups" for conditions where APO-Tibolone should be stopped.

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)

Tell your doctor or pharmacist if you notice any side effects not mentioned in this leaflet.

After using this medicine

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store this medicine or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Packs contain 28 white round flat tablets with bevelled edges. The tablets are debossed with ‘TO’ above ‘2’ on one side and plain on other side.

Ingredients

APO-Tibolone tablet contains 2.5 mg of the active ingredient called tibolone. APO-Tibolone also contains the following inactive ingredients:

  • potato starch
  • lactose monohydrate
  • ascorbyl palmitate
  • lactose anhydrous
  • magnesium stearate

APO-Tibolone contains lactose.

Do not use the product if the blister pack or tablets are damaged or appear unusual.

Supplier

This medicine is supplied in Australia by:

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne, VIC 3121
www.arrotex.com.au

AUST R 283952

This leaflet was prepared in January 2023.

Published by MIMS February 2023

BRAND INFORMATION

Brand name

APO-Tibolone

Active ingredient

Tibolone

Schedule

S4

 

1 Name of Medicine

Tibolone.

2 Qualitative and Quantitative Composition

Each tablet contains 2.5 mg tibolone.

List of excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, uncoated.
APO-Tibolone 2.5 mg are white to off white, circular with flat face beveled edge, uncoated tablet debossed with 'TO' above '2' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term treatment of symptoms resulting from the natural or surgical menopause in postmenopausal women.
Second line therapy for the prevention of bone mineral density loss in postmenopausal women at high risk of future osteoporotic fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of bone mineral density loss.
After careful selection of users, APO-Tibolone should be prescribed for the shortest duration consistent with treatment goals. Review the need for continuation of treatment after 6 months, taking into account the risk-benefit ratio for the individual user at that moment (including cardiovascular disease and breast cancer, (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use). APO-Tibolone should only be continued for as long as the benefit outweighs the risks.

4.2 Dose and Method of Administration

Treatment of symptoms resulting from the natural or surgical menopause, more than one year after menopause.

The recommended dose is 2.5 mg once daily.

Prevention of post-menopausal bone mineral density loss.

The recommended dose is 2.5 mg once daily. No dose adjustment is necessary for the elderly.
The tablets should be swallowed with some water or other drink, preferably at the same time of day. Improvement of symptoms generally occurs within a few weeks, but optimal results are obtained when therapy is continued for at least 3 months.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see Section 4.4 Special Warnings and Precautions for Use) should be used. Review the need for continuation of treatment after 6 months, taking into account the risk-benefit ratio for the individual user at that moment.
A separate progestogen should not be added with APO-Tibolone treatment.

Starting APO-Tibolone.

Women experiencing a natural menopause should commence treatment with APO-Tibolone at least 12 months after their last natural bleed. In case of a surgical menopause, treatment with APO-Tibolone may commence immediately.
Any irregular/unscheduled vaginal bleeding, either on or off HRT, should be investigated to exclude malignancy before starting APO-Tibolone (see Section 4.3 Contraindications).

Switching from combined or estrogen only hormone replacement therapy (HRT).

In women with a uterus who change from an estrogen-only preparation, a withdrawal bleed should be induced before starting APO-Tibolone. If changing from a sequential HRT preparation, treatment with APO-Tibolone should start after the progestagen phase has been completed. If changing from a continuous-combined HRT preparation, treatment can start at any time. If abnormal vaginal bleeding is the reason for switching from combined HRT, it is advised to investigate the cause of bleeding before starting APO-Tibolone.

Missed tablets.

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.

Monitoring advice.

As for all steroids with hormonal activity, yearly medical examination particularly of the breasts and pelvic areas is advisable. Review the need for continuation of treatment after 6 months (see Section 4.4 Special Warnings and Precautions for Use; Section 4.1 Therapeutic Indications).
The occurrence of vaginal bleeding or spotting soon after starting treatment with APO-Tibolone may be due to the residual effects of endogenous or exogenous estrogens. Bleeding commencing after three months of treatment, or recurrent or persistent bleeding should be investigated.

4.3 Contraindications

Pregnancy and lactation.
Known, past or suspected breast cancer - tibolone increased the risk of breast cancer recurrence in a placebo-controlled trial.
Known or suspected estrogen-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 TIA).
Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal.
Known hypersensitivity to the active substance or to any of the excipients.
Porphyria.

4.4 Special Warnings and Precautions for Use

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.
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. The risks of stroke, breast cancer and, in women with an intact uterus, endometrial cancer (see below and see Section 4.8 Adverse Effects (Undesirable Effects)) 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 precautions for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including appropriate imaging tools e.g mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision.

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with tibolone, in particular: leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders (see below); risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer; hypertension; liver disorders (e.g. liver adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia (see below); epilepsy; asthma; otosclerosis.

Reasons for immediate withdrawal of therapy.

Therapy should be discontinued in case a contraindication is discovered and in the following situations:
Jaundice or deterioration in liver function.
Significant increase in blood pressure.
New onset of migraine-type headache.
Pregnancy.

Endometrial hyperplasia and carcinoma.

The available data from randomised controlled clinical trials are conflicting, however, observational studies have consistently shown that women who are prescribed tibolone in normal clinical practice are at an increased risk of having endometrial cancer diagnosed (see Section 4.8 Adverse Effects (Undesirable Effects)). In these studies the risk increases with increasing duration of use). Tibolone increases endometrial wall thickness, as measured by transvaginal ultrasound.
Break-through bleeding and spotting may occur during the first months of treatment (see Section 5.1 Pharmacodynamic Properties). 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 2.5 mg 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. However, a study using the General Practice Research Database (GPRD), did not show an increased risk (see Section 4.8 Adverse Effects (Undesirable Effects)). The THEBES study provided comparisons with continuous daily doses of conjugated estrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg risk (see Section 4.8 Adverse Effects (Undesirable Effects)).

Ovarian cancer.

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests an increased risk in women taking estrogen-only or combined estrogen-progestogen 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 use of combined HRTs may be associated with a similar risk (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.

Estrogen or estrogen-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 Adverse Effects (Undesirable Effects)). In an epidemiological study using a UK database, the risk of VTE in association with tibolone was lower than the risk associated with conventional HRT, but only a small proportion of women were current users of tibolone and a small increase in risk compared with non-use cannot be excluded. Patients with known thrombophilic states have an increased risk of VTE and HRT or tibolone may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3 Contraindications).
Generally recognised risk factors for VTE include a personal history or family history, use of estrogens, older age, major trauma or major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need 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. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT or tibolone is contraindicated.
Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT or tibolone.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD).

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

Ischaemic stroke.

Tibolone increases the risk of ischaemic stroke from the first year of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 dose-dependent decrease in HDL-cholesterol, total triglycerides and lipoprotein (a) levels. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged.
Estrogens 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 Estrogen replacement or HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
Treatment with tibolone results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Tibolone decreases the level of sex-hormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected.
HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.

Use in renal impairment.

No data available.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 estrogens and progestagens via CYP3A4. Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
Tibolone is contraindicated in women of reproductive potential including the women in the perimenopausal period. 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 that tibolone crosses the placenta in rabbits, and is teratogenic. Oral treatment of rats with tibolone during the period of organogenesis was associated with foetal microphthalmia (doses ≥ 0.7 mg/kg/day). In rabbits, a range of abnormalities were observed following oral maternal tibolone treatment (doses ≥ 0.7 mg/kg/day), including hydrocephaly, cleft palate, umbilical hernia, limb flexure and malrotation, bilateral microphthalmia and ocular opacity. A no-effect dose could not be demonstrated in either species. No evidence for teratogenic activity was observed in mice.
Systemic exposure to tibolone and its metabolites in the rat study (not measured in the rabbit or mouse study) was substantially lower than the anticipated human exposure. The potential risk for humans is unknown.
 Tibolone is contraindicated in lactating women (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

Tibolone is not known to have any effects on alertness and concentration. However, adverse effects of this medicine include dizziness, visual disturbance including blurred vision which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

See Table 1.
In market use, other undesirable effects that have been observed include dizziness, rash, pruritus, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), gastrointestinal upset, depression, oedema, effects on the musculoskeletal system such as arthralgia or myalgia and changes in liver function parameters.

Breast cancer risk.

An up to 2-fold increased risk of having breast cancer diagnosed was reported in the MWS in women taking combined estrogen-progestagen therapy for more than 5 years.
Any increased risk in users of estrogen-only and tibolone therapy is substantially lower than that seen in users of estrogen-progestagen combinations.
The level of risk is dependent on the duration of use (see Section 4.4 Special Warnings and Precautions for Use).
The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:
For women not using HRT or tibolone, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
For 1000 current or recent users of HRT, the number of additional cases compared to never users during the corresponding period will be:
For users of estrogen-only replacement therapy, between 0 and 3 (best estimate = 1.5) for 5 years' use between 3 and 7 (best estimate = 5) for 10 years' use.
For users of estrogen-progestogen combined HRT, between 5 and 7 (best estimate = 6) for 5 years' use between 18 and 20 (best estimate = 19) for 10 years' use.
For women who use tibolone the number of additional cases of breast cancer is comparable with that for estrogen-only use.
A GPRD study reported that, compared with never users, the rate of breast cancer was not elevated in subjects who exclusively used unopposed estrogens (RR 0.97: 95% CI: 0.86-1.09) or tibolone (RR 0.86: 95% CI: 0.65-1.13). However, the rate was significantly increased in subjects who used combined estrogen-progestogen HRT (adjusted rate ratio [RR] 1.33: 95% CI: 1.23-1.44), and further increased with longer duration of use.
For women who use tibolone the number of additional cases of breast cancer is comparable with that for estrogen-only use.
A GPRD study reported that, compared with never users, the rate of breast cancer was not elevated in subjects who exclusively used unopposed estrogens (RR 0.97: 95% CI: 0.86-1.09) or tibolone (RR 0.86: 95% CI: 0.65-1.13). However, the rate was significantly increased in subjects who used combined estrogen-progestogen HRT (adjusted rate ratio [RR] 1.33: 95% CI: 1.23-1.44), and further increased with longer duration of use.
In the THEBES study, a multi-national, multicentre, randomized, double blind, parallel group, active controlled, comparative study in which 807 healthy postmenopausal women, aged 45 to 65 years, were randomised to tibolone 1.25 mg, 816 to tibolone 2.5 mg and 1,617 to continuous CE/MPA (conjugated estrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg) to study various safety endpoints. Breast cancer was diagnosed more with tibolone than with CE/MPA: the tibolone 2.5 mg daily group 8 adjudicated cases, tibolone 1.25 mg daily had 2 cases and CE/MPA had 8 cases. Tibolone 2.5 mg tablet had a RR (95% CI) of 2.47 (0.88 to 7.19) compared with CE/MPA and 4.82 (1.03 to 45.21) compared with the 1.25 mg dosage form. The study cannot provide comparisons against no treatment as there was no placebo arm. The study was not specifically designed to provide these comparisons but these findings do underscore the need to observe the relevant precautions for use.

Endometrial cancer risk.

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT or tibolone.
In 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 cases of endometrial cancer in every 1000 women who used tibolone for one year in this study (see Section 4.4 Special Warnings and Precautions for Use).

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 Special Warnings and Precautions for Use).
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.
Other adverse effects have been reported in association with estrogen and estrogen-progestogen treatment.

Ovarian cancer.

Use of estrogen-only or combined estrogen-progestogen HRT has been associated with an increased risk of having ovarian cancer diagnosed (Section 4.4 Special Warnings and Precautions for Use). 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 50‐54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50‐54 years 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 (see Section 4.4 Special Warnings and Precautions for Use).

Venous thromboembolism risk.

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 (see Section 4.4 Special Warnings and Precautions for Use). Results of the WHI studies are presented in Table 2.

Coronary artery disease risk.

The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60 (see Section 4.4 Special Warnings and Precautions for Use). There is no evidence to suggest that the risk of myocardial infarction with tibolone is different to the risk with other HRT.
Estrogen-dependent neoplasms benign and malignant, e.g. endometrial carcinoma.
Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information, (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Myocardial infarction.
Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
Probable dementia over the age of 65 (see Section 4.4 Special Warnings and Precautions for Use).

Laboratory test finding.

No data available.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 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 withdrawal bleeding in females may develop. No specific antidote is known. Symptomatic treatment can be given if necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

After oral administration tibolone is rapidly metabolised into three compounds which all contribute to the pharmacological effects of tibolone. Two of these metabolites (the 3αOH and 3βOH metabolite) have predominantly estrogenic activity, a third metabolite (Δ4-isomer of tibolone) and the parent compound have predominantly progestagenic and androgenic activities.
Tibolone substitutes for the loss of estrogen production in postmenopausal women and alleviates menopausal symptoms. Tibolone prevents bone loss following menopause or ovariectomy.
Tibolone tablet has various tissue-specific effects. It has estrogenic effects on the vagina, on bone and on the thermoregulatory centres in the brain (hot flushes). Based on in vitro data, tibolone inhibits the sulphatase enzyme in cultured breast cancer cells thereby reducing the levels of active estrogens produced in those cells. Due to local conversion to the Δ4-isomer, the endometrial findings have been mainly atrophic or in some cases weakly proliferative, which can, in themselves, be considered normal endometrial states. Therefore, if vaginal bleeding occurs, this usually results from an atrophic endometrium. Tibolone also has androgenic effects on certain metabolic and haematological parameters such as a decrease in plasma high density lipoprotein cholesterol, triglycerides and lipoprotein (a), and may increase blood fibrinolytic activity. Tibolone improves vaginal dryness and vaginal atrophy. There are indications that tibolone has effects on mood and libido.

Clinical trials.

Relief of estrogen deficiency symptoms.

Two pivotal, multicentre, randomized, double-blind studies assessed the effects of tibolone on climacteric complaints. One of these studies was a placebo-controlled study and assessed the effects on hot flushes and sweats in groups of about 150 subjects after a 12-week treatment with various doses of tibolone and placebo. The 2.5 mg dose appeared to be the optimal dose for relieving hot flushes, sweats and other climacteric complaints. The other study was an active controlled study that compared the effects of a 48-week treatment of 2.5 mg tibolone with that of a continuous combined estradiol/norethisterone acetate combination in groups of about 220 post-menopausal subjects. Tibolone significantly relieved the climacteric symptoms (hot flushes, sweats, vaginal dryness and rating scores on well-being); the effects appeared to be similar to that of the continuous combined HT-preparation. The efficacy of tibolone on the climacteric symptoms was confirmed in three Organon-sponsored studies and in published studies. In addition to the positive effects on climacteric complaints, tibolone also has an effect on mood and libido.

Prevention of osteoporosis.

In two identical pivotal, multicentre, randomised, double-blind, placebo-controlled studies four doses of tibolone or placebo were given for 2 years to groups of about 75 women per dose and per study to assess the efficacy for preventing post-menopausal bone mineral density loss, safety and acceptability. In these studies, the bone mineral density measured with DEXA was significantly increased at all sites (spine, femoral neck, trochanter and Ward's, and distal radius) with the 2.5 mg dose compared to the placebo-groups. The results on BMD were confirmed by the results on the biochemical markers of bone turnover, showing that tibolone reduces the markers for bone resorption to a greater extent than the markers for bone formation. The efficacy of tibolone on bone was confirmed in 11 Organon-sponsored studies and many other studies published in literature.
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]. Because this study used only tibolone 1.25 mg daily versus placebo, its contribution to the risk: benefit profile of tibolone 2.5 mg daily in the prevention of osteoporosis is unknown.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, tibolone is rapidly and extensively absorbed. Due to rapid metabolism, the plasma levels of tibolone are very low.
The consumption of food has no significant effects on the extent of absorption.

Distribution.

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. See Table 3.

Metabolism.

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

Excretion.

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.

5.3 Preclinical Safety Data

Genotoxicity.

Tibolone did not show any evidence of genotoxicity in assays for gene mutations, chromosomal damage and DNA damage.

Carcinogenicity.

Tibolone treatment, similar to treatment with other sex hormones, in rodent studies demonstrated an association with the development of a range of tumours in long-term oral carcinogenicity studies. These included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet includes the following excipients: pregelatinised potato starch, lactose monohydrate, ascorbyl palmitate, lactose, magnesium stearate.

6.2 Incompatibilities

No incompatibilities have been found.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light. Protect from moisture.

6.5 Nature and Contents of Container

PVC/Al blister packs of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Tibolone exists as white to almost white crystals or crystalline powder. Tibolone is related to and derived from naturally occurring steroids. It is optically pure and has the D-configuration. It is practically insoluble in water, aqueous acid or alkali at 20°C.

Chemical structure.


Chemical name: (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5 (10)-en-20-yn-3-one.
Other name: 17α -ethynyl-17-hydroxy-7α-methyl-5(10)-estren-3-one.
Molecular formula C21H28O2.
Molecular mass 312.45.

CAS number.

5630-530-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes