Consumer medicine information

Zumenon

Estradiol

BRAND INFORMATION

Brand name

Zumenon

Active ingredient

Estradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zumenon.

SUMMARY CMI

ZUMENON®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. When you must not use ZUMENON?

Do not use ZUMENON or other estrogens, with or without progestogen to prevent heart attacks, stroke or dementia. Talk regularly with your doctor about whether you still need treatment with ZUMENON.

For more information, see Section 1. When you must not use ZUMENON? in the full CMI.

2. Why am I using ZUMENON?

ZUMENON contains the active ingredient estradiol hemihydrate. ZUMENON is a type of treatment called hormone replacement therapy (HRT) that helps to relieve the symptoms many women feel during and after menopause.

For more information, see Section 2. Why am I using ZUMENON? in the full CMI.

3. What should I know before I use ZUMENON?

Do not use if you have ever had an allergic reaction to any medicine containing estradiol or any of the ingredients listed at the end of this leaflet. HRT should only be used if you have been fully informed of the risks. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 3. What should I know before I use ZUMENON? in the full CMI.

4. What if I am taking other medicines?

Some medicines may interfere with ZUMENON and affect how it works.

A list of these medicines is in Section 4. What if I am taking other medicines? in the full CMI.

5. How do I use ZUMENON?

  • The usual dose is one tablet daily.
  • Swallow the tablet whole with a glass of water. Take ZUMENON at about the same time each day.

More instructions can be found in Section 5. How do I use ZUMENON? in the full CMI.

6. What should I know while using ZUMENON?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ZUMENON.
  • Tell your doctor that you are using ZUMENON well in advance of any expected hospitalisation or surgery. If you go to hospital unexpectedly, tell the doctor who admits you that you are using it.
  • Tell your doctor immediately if you have any sore veins or suspected blood clots, disturbances in vision, sudden onset of migraine, significant increase in blood pressure, or yellowing of the skin or eyes (jaundice) while taking ZUMENON tablets.
  • If you become pregnant while using ZUMENON, tell your doctor immediately.
  • Check your breasts each month and report any changes promptly to your doctor.
  • See your doctor at least once a year for a check-up.
Things you should not do
  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop taking ZUMENON, or change the dosage, without checking with your doctor.
Looking after your medicine
  • Keep the medicine in a cool, dry place where the temperature stays below 30°C.

For more information, see Section 6. What should I know while using ZUMENON? in the full CMI.

7. Are there any side effects?

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

For more information, including what to do if you have any side effects, see Section 7. Are there any side effects? in the full CMI.



FULL CMI

ZUMENON®

Active ingredient(s): estradiol hemihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZUMENON. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZUMENON.

Where to find information in this leaflet:

1. When you must not use ZUMENON?
2. Why am I using ZUMENON?
3. What should I know before I use ZUMENON?
4. What if I am taking other medicines?
5. How do I use ZUMENON?
6. What should I know while using ZUMENON?
7. Are there any side effects?
8. Product details

1. When you must not use ZUMENON

Do not use ZUMENON or other estrogens, with or without progestogen to prevent heart attacks, stroke or dementia.

A study called the Women's Health Initiative indicated increased risk of stroke, breast cancer, and blood clots in the legs or lungs in women receiving treatment with a product containing conjugated estrogens 0.625 mg and the progestogen medroxyprogesterone acetate (MPA). The researchers stopped the study after 5 years when it was determined the risks were greater than the benefits in this group.

This Women's Health Initiative also indicated increased risk of stroke, and blood clots in the legs or lungs in women receiving treatment with a product containing conjugated estrogens 0.625 mg alone. The researchers stopped the study after 7 years when it was determined the risks were greater than benefit in this group.

The Women's Health Initiative Memory Study indicated increased risk of dementia in women aged 65 years or older taking conjugated estrogens and MPA. Increased risk of dementia was also reported in women taking conjugated estrogens alone. There are no comparable data currently available for other doses of conjugated estrogens and MPA or other combinations of estrogens and progestogens. Therefore, you should assume the risks will be similar for other medicines containing estrogen and progestogen combinations.

Talk regularly with your doctor about whether you still need treatment with ZUMENON.

Treatment with estrogens, with or without progestogens should be used at the lowest effective dose and for the shortest period of time.

2. Why am I using ZUMENON?

ZUMENON is a type of treatment called hormone replacement therapy (HRT). ZUMENON tablets contain a hormone called estradiol.

This medicine helps to relieve the symptoms many women feel during and after menopause. ZUMENON may be used by women who still have a uterus (womb). Menopause may be natural or occur after surgery or medical treatment.

Women with an intact womb should generally be prescribed ZUMENON and another medicine, a progestogen, to protect the lining of the uterus from over stimulation.

HRT should not be used for the long-term maintenance of general health or to prevent heart disease or dementia.

ZUMENON is not suitable for birth control and it will not restore fertility.

How it works

Estradiol is a natural female sex hormone called an estrogen. It is the same hormone that your ovaries were producing before the menopause.

Menopause generally occurs between the ages of 45 and 55, because your body's production of estrogen decreases. It may happen sooner if the ovaries are removed by surgery (e.g. total hysterectomy). This can cause unpleasant symptoms such as a feeling of warmth in the face, neck and chest, "hot flushes" (sudden intense feelings of heat and sweating throughout the body), sleep problems, irritability and depression. Some women also have problems with urine control or with dryness of the vagina causing discomfort during or after sex. Estrogens can be given to reduce or eliminate these symptoms.

Ask your doctor if you have any questions about why it has been prescribed for you.

Your doctor may have prescribed it for another purpose.

This medicine is not addictive.

3. What should I know before I use ZUMENON?

Warnings

HRT should only be used if you have been fully informed of the risks.

The decision to use HRT should be based on your symptoms and health, and made after a careful medical evaluation.

Do not use ZUMENON if:

  • you are allergic to any medicine containing estradiol or any of the ingredients listed at the end of this leaflet
    - Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.
  • If you have or have had:
    - Cancer of the breast or uterus (endometrium) or any other estrogen dependent cancer
    - Blood clots. Painful inflammation of the veins or blockage of a blood vessel in the legs, lungs, brain or heart
    - Any condition that increases the tendency for you to get blood clots
    - Abnormal vaginal bleeding
    - Severe liver disease
    - A condition called porphyria
    - Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

If you are not sure whether any of the above conditions apply to you, your doctor can advise you.

You must stop taking ZUMENON 4 weeks before certain types of surgery.

Do not take it after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering.

If it has expired or is damaged return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor or pharmacist if you have any allergies to any other medicines, foods, preservatives or dyes.

You must have a through medical check-up before starting HRT for the first time or recommencing HRT.

Tell your doctor if you have or have had any of the following medical conditions:

  • a family history of breast cancer
  • nodules, lumps or cysts in your breasts or any other benign breast condition (not cancerous)
  • fibroids or other benign tumours of the uterus (not cancerous)
  • ovarian cancer
  • unusual or irregular bleeding or spotting from the vagina
  • endometriosis
  • liver problems, including yellowing of the skin and whites of the eyes and a condition called porphyria
  • cholestatic jaundice (obstruction of the bile duct)
  • kidney problems
  • high blood pressure
  • heart problems
  • diabetes
  • migraine or severe headaches
  • asthma
  • epilepsy
  • gall bladder disease
  • a high level of triglycerides (fats) in the blood
  • high or low levels of calcium in the blood
  • abnormal vision
  • hypothyroidism
  • hearing loss due to a problem with the bones in the ear called otosclerosis
  • hereditary angioedema or acquired angioedema

Tell your doctor if you are likely to have an increased risk of developing blood clots in your blood vessels.

The risk increases as you get older and it may also be increased if:

  • anyone in your immediate family has ever had blood clots in the blood vessels of the legs or lungs
  • you are overweight
  • you have varicose veins
  • you have a disorder called systemic lupus erythematosus

If you have not told your doctor about any of the above, tell them before you take ZUMENON.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 7. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant. Discuss with your doctor if you are planning on becoming pregnant.

Do not breastfeed if you are taking this medicine.

Special Warning

Treatment with estrogens alone over a prolonged period may expose women with an intact womb to an increased risk of cancer of the lining of the womb.

4. What if I am taking other medicines?

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

Some medicines and ZUMENON may interfere with each other. These include:

  • herbal medicines containing St John's Wort
  • some medicines used to treat epilepsy, e.g. lamotrigine
  • some antibiotic and anti-infective medicines
  • some medicines which require precise dosing e.g. tacrolimus, ciclosporin, fentanyl and theophylline
  • the hepatitis C treatment combination regimen of ombitasvir/paritaprevir/ritonavir with and without dasabuvir

These medicines may be affected by ZUMENON, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking ZUMENON.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZUMENON.

5. How do I use ZUMENON?

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 instructions on the box, ask your doctor or pharmacist for help.

How much to take

  • The usual dose is one tablet daily.
  • If you have not had a period for twelve months or more or if you have had a hysterectomy, you can start ZUMENON immediately.
  • If you are having irregular periods, start taking ZUMENON on day 5 of the menstrual cycle.
  • If your uterus is still intact your doctor will generally prescribe another medicine (progesterone) to take with ZUMENON during part of your menstrual cycle.

How much to take

  • Swallow the tablet whole with a glass of water.

When to take ZUMENON

  • Take ZUMENON at about the same time each day.
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • The pack is labelled with the days of the week to help you with taking your tablets every day.
  • You should start each new pack the day after you have finished the current pack. Do not leave a gap between packs.

How long to take it

Your doctor can advise you how long you may need to take ZUMENON.

Your doctor can discuss the risks and benefits of long-term treatment with HRT. Some recent studies have shown that women using HRT have a small increase in breast cancer risk after several years of use. The risk increases with the length of HRT use.

Recent studies have also shown that HRT is associated with a small increase in the risk of heart attacks, strokes, blood clots, including clots in the lungs. However, the risk of hip fractures and bowel cancer may be reduced.

Another study has shown that in women older than 65 years, HRT is associated with a small increase is the risk of dementia, including Alzheimer's disease. It is not known if this finding applies to younger women.

Continue taking ZUMENON for as long as your doctor recommends.

If you forget to take ZUMENON

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of getting an unwanted side effect.

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

If you have trouble remembering when to take your medicine, ask your pharmacist for advice.

If you take too much ZUMENON

If you think that you have used too much ZUMENON, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

6. What should I know while using ZUMENON?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ZUMENON.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

Tell your doctor that you are using ZUMENON well in advance of any expected hospitalisation or surgery. If you go to hospital unexpectedly, tell the doctor who admits you that you are using it.

The risk of developing blood clots in your blood vessels may be temporarily increased after surgery, serious injury or having to stay in bed for a long period of time. If possible, ZUMENON should be stopped at least 4 weeks before surgery and it should not be restarted until you are fully mobile.

Tell your doctor immediately if you have any sore veins or suspected blood clots, disturbances in vision, sudden onset of migraine, significant increase in blood pressure, or yellowing of the skin or eyes (jaundice) while taking ZUMENON tablets.

If you are still having periods of any kind, you should continue to use non-hormonal contraceptive methods (such as a condom) to prevent pregnancy.

If you become pregnant while using ZUMENON, tell your doctor immediately.

ZUMENON should not be used while you are pregnant.

Check your breasts each month and report any changes promptly to your doctor. Particularly if you have breast lumps or a family history of breast cancer.

See your doctor at least once a year for a check-up. Some women will need to go more often. Your doctor may:

  • check your breasts and order a mammogram at regular intervals
  • check your uterus and cervix and do a pap smear at regular intervals
  • check your blood pressure and cholesterol level.

Things you should not do

Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not stop taking ZUMENON, or change the dosage, without checking with your doctor.

Looking after your medicine

  • Keep the medicine in a cool, dry place where the temperature stays below 30°C.
  • Keep your tablets in the pack until it is time to take them.
    - If you take the tablets out of the box or the blister pack they may not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

7. Are there any side effects?

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

All medicines have some unwanted side effects. Sometimes they are serious but most of the time they are not. You may need medical attention if you get some of the side-effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • irregular vaginal bleeding or spotting (if bleeding is heavy, check with your doctor as soon as possible)
  • tender, painful or swollen breasts
  • period-like pain
  • vaginal itching, inflammation or discharge
  • swelling of the lower legs, ankles, fingers or abdomen due to fluid retention
  • nausea (feeling sick), abdominal pain or tenderness, vomiting, heartburn, bloating, diarrhoea
  • headache, migraine
  • rise in blood pressure, palpitations
  • fatigue or dizziness
  • depression, anxiety
  • back pain, muscle cramps
  • change in sex drive
  • weight change
  • acne, itchy or dry skin, skin discolouration
  • unusually excessive hair growth
  • vision changes
  • contact lens intolerance
Tell your doctor or pharmacist if you notice any of these common side effects. They are usually mild however tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Serious side effects

Serious side effectsWhat to do
  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing
  • signs that blood clots may have formed, such as sudden severe headache, loss of coordination, blurred or loss of vision, slurred speech, numbness or tingling, painful swelling in the calves or thighs, chest pain, coughing blood
  • pain or tenderness in the abdomen, which may be accompanied by fever, loss of appetite, nausea and vomiting
  • chest pain
  • difficulty breathing
  • new onset migraine-like headache
  • a yellow colour to the skin or eyes, itching, dark coloured urine or light-coloured bowel motions.
  • sudden loss of vision

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects. These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

8. Product details

This medicine is only available with a doctor's prescription.

What ZUMENON contains

Active ingredient
(main ingredient)		2 mg of estradiol (as hemihydrate)
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • hypromellose
  • maize starch
  • colloidal anhydrous silica
  • magnesium stearate
  • Opadry complete film coating system OY-6957 Pink (ARTG PI No: 4158)
Potential allergensZUMENON tablets contain sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What ZUMENON looks like

ZUMENON tablets are round, biconvex, brick-red, film-coated tablets of 7 mm diameter each containing 2 mg estradiol bearing the inscription "379" on one side. (AUST R 75888).

ZUMENON is available in boxes of 56 tablets.

ZUMENON is made in the Netherlands.

Who distributes ZUMENON

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

ZUMENON® is a Viatris company trade mark

This leaflet was prepared in November 2023.

ZUMENON_cmi\Nov23/00

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Zumenon

Active ingredient

Estradiol

Schedule

S4

 

1 Name of Medicine

Estradiol hemihydrate.

2 Qualitative and Quantitative Composition

Zumenon tablets are immediate-release, film-coated tablets for oral use containing 2 mg of micronised estradiol (equivalent to 2.06 mg estradiol hemihydrate).

Excipients with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Round, biconvex, brick red, film-coated tablets of 7 mm diameter each containing 2 mg estradiol bearing the inscription "379" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of estrogen deficiency due to natural or surgical menopause in hysterectomised postmenopausal women.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used with the goal being short-term use (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).
In women with intact uteri, use of opposed therapy must be considered.

4.2 Dose and Method of Administration

One tablet administered orally daily without interruption (see Section 4.1 Therapeutic Indications; Section 4.4 Special Warnings and Precautions for Use for treatment duration advice).
Treatment of hysterectomised women and postmenopausal women may be started on any convenient day. In oligomenorrhoea, treatment is to commence on day 5 of the withdrawal bleed.
In order to counteract endometrial hyperplasia, which occurs with estrogen monotherapy, it is recommended that a progestogen be given for at least ten days per calendar month in women with intact uteri.
If a dose has been forgotten, it should be taken as soon as possible. If more than 12 hours have elapsed, treatment should be continued with the next tablet without taking the forgotten tablet.

4.3 Contraindications

Nonhysterectomised women without opposing progestogen.
Known, suspected or past history of carcinoma of the breast, endometrium or other estrogen dependent neoplasia.
Acute or chronic liver disease or a history of liver disease where the liver function tests have failed to return to normal.
Vaginal bleeding of unknown aetiology in women with intact uteri.
Untreated endometrial hyperplasia.
Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) or cerebrovascular accident.
Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, see Section 4.4 Special Warnings and Precautions for Use).
Active or recurrent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Porphyria.
Known or suspected pregnancy.
Lactation.
Known hypersensitivity to any ingredients contained in Zumenon tablets.

4.4 Special Warnings and Precautions for Use

The benefits and risks of estrogen/ progestogen therapy must always be carefully weighed including consideration of the emergence of risks as therapy continues.

Medical examination/follow-up.

Before initiating therapy, a complete medical and family history should be taken and a physical examination performed. Pretreatment and subsequent physical examinations should include special reference to blood pressure, breasts, abdomen and pelvic organs. Women should be advised that changes in their breasts should be reported to their doctor or nurse (see Breast cancer). Mammography is advisable. Patients who are being, or have previously been treated with unopposed estrogens should be examined with special care to exclude endometrial stimulation before commencing Zumenon therapy.
As a general rule, hormone replacement therapy (HRT) should not be prescribed for longer than one year without another physical examination including gynaecological examination being performed. Women on HRT should have regular breast examination and regular mammography (every 1-2 years). In all cases of undiagnosed, persistent or recurring abnormal vaginal bleeding, adequate diagnostic measures, including endometrial sampling, should be undertaken to rule out malignancy. The benefits and risks of HRT should be carefully considered. HRT should be dosed at the lowest effective dose to relieve symptoms and for the shortest duration for control of symptoms.
If estradiol is administered in women with an intact uterus it has to be opposed by a progestogen. The contraindications and precautions relating to combined HRT should be regarded carefully. A careful appraisal of the risks and benefits should be undertaken over time in women treated with hormone replacement therapy. HRT should be dosed at the lowest effective dose to relieve symptoms and for the shortest duration for control of symptoms.
Patients in the perimenopausal phase should be advised to use nonhormonal contraceptive methods.

Cardiovascular disorders.

Estrogen and estrogen/ progestogen therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogen/ progestogen therapy should be discontinued immediately.
Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolaemia, and obesity) and/or venous thromboembolism (e.g. personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Coronary heart disease and stroke.

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of stroke was observed in women receiving conjugated estrogens (CE) 0.625 mg per day compared to women receiving placebo (44 vs 32 per 10,000 women years). The increase in risk was observed in year one and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the estrogen plus progestogen substudy of the Women's Health Initiative (WHI) study, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE plus MPA (conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day) compared to women receiving placebo (37 vs 30 per 10,000 women years). The increase in risk was observed in year one and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the same substudy of WHI, an increased risk of stroke was observed in women receiving estrogen plus progestogen compared to women receiving placebo (29 vs 21 per 10,000 women years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/ progestin Replacement Study; HERS) treatment with CE plus MPA demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the estrogen/ progestogen treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen/ progestogen treated group and the placebo group in HERS, HERS II and overall.

Venous thromboembolism (VTE).

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving CE compared to placebo (21 vs 15 per 10,000 women years). The increase in VTE risk was observed during the first year (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients with known thrombophilic states have an increased risk of VTE, and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3 Contraindications).
Generally recognised risk factors for VTE include use of estrogens, older age, major surgery, obesity (BMI > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE), and cancer.
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 is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit/risk of use of HRT.
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).
In the estrogen plus progestogen substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE plus MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women years in the estrogen plus progestogen treated group compared to 16 per 10,000 women years in the placebo group. The increase in VTE risk was observed during the first year and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilisation.

Endometrial cancer.

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogens users with an intact uterus is about 2 to 12-fold greater than in nonusers and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15 to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/ progestogen combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Addition of a progestogen when a woman has not had a hysterectomy.

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestogens with estrogens compared with estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of glucose tolerance. Clinical surveillance of all women taking estrogen/progestogen combinations is important. Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Breast cancer.

The use of estrogen-only HRT and combined estrogen-progestogen by women has been shown to increase the risk of breast cancer, that is dependent on the duration of taking HRT.

Combined estrogen-progestogen therapy.

The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8 Adverse Effects (Undesirable Effects)).

Estrogen-only therapy.

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations (see Section 4.8 Adverse Effects (Undesirable Effects)).
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of estrogens alone or estrogens plus progestogens compared to never users, while the estrogen plus progestogen substudy of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years.
The use of estrogen plus progestogen has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
HRT, especially estrogen/ progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Dementia.

HRT use does not improve cognitive function. In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomised women aged 65 to 79 years was randomised to conjugated estrogens (CE) 0.625 mg/day or placebo. In the estrogen plus progestogen WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomised to CE + MPA or placebo.
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE alone versus placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone versus placebo was 37 versus 25 cases per 10,000 women years.
In the estrogen plus progestogen substudy, after an average follow-up of 4 years, 40 women in the estrogen plus progestogen group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestogen versus placebo was 45 versus 22 cases per 10,000 women years.
Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Gallbladder disease.

A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Hypercalcaemia.

Estrogen administration may lead to severe hypercalcaemia in patients with breast cancer and bone metastases. If hypercalcaemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Visual abnormalities.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilloedema or retinal vascular lesions, estrogens should be discontinued.

Elevated blood pressure.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomised, placebo controlled clinical trial, a generalised effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

Hypertriglyceridaemia.

In patients with pre-existing hypertriglyceridaemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

Impaired liver function and past history of cholestatic jaundice.

Estrogens may be poorly metabolised in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and, in the case of recurrence, medication should be discontinued.

Hypothyroidism.

Estrogen administration leads to increased thyroid binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid retention.

Because estrogens/ progestogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

Hypocalcaemia.

Estrogens should be used with caution in individuals with severe hypocalcaemia.

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 estrogen only or combined estrogen/ progestogen HRT, which becomes apparent within 5 years of use and diminished over time after stopping. Some other studies, including the WHI trial, suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk (see Section 4.8 Adverse Effects (Undesirable Effects)).

Exacerbation of endometriosis.

Endometriosis may be exacerbated with administration of estrogen therapy. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progesterone should be considered.

Exacerbation of other conditions.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic haemangiomas and should be used with caution in women with these conditions.
Zumenon is not an oral contraceptive and will not restore fertility.
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 Zumenon, in particular: leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders (see Section 4.4 Special Warnings and Precautions for Use, Venous thromboembolism (VTE)); 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 Section 4.4 Special Warnings and Precautions for Use, Endometrial cancer); epilepsy; asthma; otosclerosis.
Reasons for immediate withdrawal of therapy. Therapy should be discontinued on discovery of a contraindication and in the following situations:
jaundice or deterioration in liver function;
significant increase in blood pressure;
new onset of migraine type headache, diplopia, sudden partial or complete loss of vision or a sudden onset of proptosis;
pregnancy.
It is advisable to withdraw treatment with Zumenon at least four weeks before elective surgery of the type associated with increased risk of thromboembolism or during periods of prolonged immobilisation.
When estrogens are given to hypertensive women, supervision is necessary and blood pressure should be monitored at regular intervals.
Other conditions. Estrogens may cause fluid retention and, therefore, patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Zumenon is increased.
Estrogens can influence carbohydrate metabolism. This has not been observed with hormone replacement therapy involving natural estrogens.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

ALT elevations.

During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Use in the elderly.

Of the total number of subjects in the estrogen plus progestogen substudy of the Women's Health Initiative study, 44% (n = 7,320) were 65 years and over, while 6.6% (n = 1,095) were 75 years and over (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 women aged 65 to 79 years was randomised to a continuous combined regimen of conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day or placebo. A population of 2,947 hysterectomised women, aged 65 to 79 years, was randomised to conjugated estrogens (CE 0.625 mg) alone or placebo. In the planned analysis, pooling the events in women receiving CE or CE plus MPA in comparison to those in women on placebo, the overall relative risk (RR) for probable dementia was 1.76 (95% CI 1.19-2.60). In the estrogen alone group, after an average follow-up of 5.2 years a RR of 1.49 (95% CI 0.83-2.66) for probable dementia was observed compared to placebo. In the estrogen plus progestogen group, after an average follow-up of 4 years, a RR of 2.05 (95% CI 1.21-3.48) for probable dementia was observed compared to placebo. Since this study was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Dementia).
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilising estrogens and progestogens to determine whether those over 65 years of age differ from younger subjects in their response to estrogens and progestogens.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.
The concomitant use of drugs known to induce drug metabolising enzymes, specifically cytochrome P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, carbamazepine, phenytoin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) may increase the metabolism of estrogen resulting in decreased estrogenic activity.
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St. John's wort (Hypericum perforatum) may induce the metabolism of estrogens.

Other interactions.

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see Section 4.4 Special Warnings and Precautions for Use).

Estrogens might interfere with the metabolism of other drugs.

Estrogens may inhibit CYP450 drug metabolizing enzymes via competitive inhibition. This is in particular to be considered for substances with a narrow therapeutic index, such as tacrolimus and ciclosporin, fentanyl, theophylline.
Clinically this may lead to a plasma increase of the affected substances up to toxic levels. Thus, careful drug monitoring for an extended period of time might be necessary and a dosage decrease of tacrolimus, fentanyl, ciclosporin and theophylline may be necessary.

Effect of HRT with oestrogens on other medicinal products.

Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Zumenon is not an oral contraceptive and will not restore fertility.
(Category B1)
Estrogens are contraindicated during known or suspected pregnancy.
 Zumenon should not be taken by lactating mothers. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of milk. Detectable amounts of estrogen have been found in breast milk receiving these compounds, but the effect on the breastfed infant has not been determined.

4.7 Effects on Ability to Drive and Use Machines

Zumenon does not cause drowsiness. Zumenon has no or negligible influence on the ability to drive and use machines. However, adverse effects of Zumenon include dizziness and visual disturbances which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Side effects, if they occur, are more common in the first months of treatment. Breast tenderness and breakthrough bleeding may occur. Nausea, headache and oedema may occur but symptoms are normally transient. Skin reactions have also been reported. For the most serious adverse reactions associated with hormone replacement therapy (see Section 4.4 Special Warnings and Precautions for Use). See Table 1.
The following adverse effects have also been reported (frequency unknown):

Neoplasms benign, malignant and unspecified (incl. cysts and polyps).

Breast cancers; estrogen dependent neoplasms benign and malignant, e.g. endometrial cancer, ovarian cancer; increase in size of leiomyoma.

Immune system disorders.

Systemic lupus erythematosus.

Metabolism and nutrition disorders.

Change in carbohydrate metabolism; hypertriglyceridaemia.

Nervous system disorders.

Probable dementia (see Section 4.4 Special Warnings and Precautions for Use), chorea, exacerbation of epilepsy.

Eye disorders.

Steepening of corneal curvature.

Cardiac disorders.

Myocardial infarction.

Vascular disorders.

Stroke; arterial thromboembolism, i.e. angina and myocardial infarction (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use); venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Pancreatitis (in women with pre-existing hypertriglyceridaemia); gastro-oesophageal reflux disease; abdominal cramps.

Hepatobiliary disorders.

Hepatic function abnormal, sometimes with jaundice, asthenia or malaise.

Skin and subcutaneous tissue disorders.

Angioedema; erythema multiforme, vascular purpura; chloasma or melasma which may persist when drug is discontinued; allergic skin reactions (e.g. rash, pruritus, urticaria).

Renal and urinary disorders.

Urinary incontinence; cystitis-like symptoms.

Reproductive system and breast disorders.

Breakthrough bleeding, change in cervical erosion and degree of cervical secretion; fibrocystic breast changes.

Congenital, familial and genetic disorders.

Aggravation of porphyria.

Investigations.

Increase or decrease in weight; total thyroid hormones increased.

Breast cancer.

For estrogen only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which > 80% of HRT use was estrogen only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95% CI 1.21-1.49) and 1.30 (95% CI 1.21-1.40), respectively. The increased risk in users of estrogen-only therapy is lower than that seen in users of estrogen-progestogen combinations. The MWS reported that, compared to never users, the use of various types of estrogen/ progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95% CI 1.88-2.12) than use of estrogens alone (RR = 1.30, 95% CI 1.21-1.40) or use of tibolone (RR = 1.45, 95% CI 1.25-1.68).
The absolute risk estimations based on the results of the largest meta-analysis of prospective epidemiological studies, and the WHI trials are presented in Tables 2, 3 and 4.

Endometrial cancer.

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens (see Section 4.4 Special Warnings and Precautions for Use).

Ovarian cancer risk.

Use of estrogen only or combined estrogen/ progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see 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 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50-54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5 year period.

Risk of venous thromboembolism.

HRT is associated with an increased 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 HT (see Section 4.4 Special Warnings and Precautions for Use).

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 (see Section 4.4 Special Warnings and Precautions for Use).

Risk of ischaemic stroke.

The use of estrogen only and estrogen/ progestogen therapy is associated with an increased relative risk of ischaemic stroke.
This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.4 Special Warnings and Precautions for Use).

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

Symptoms.

Acute toxicity studies did not indicate a risk of acute adverse effects in case of inadvertent overdosage of estradiol.
Nausea, vomiting, sleepiness, dizziness and withdrawal bleeding may occur in some women. There is no specific antidote and treatment should be symptomatic.

Treatment.

There are no specific therapeutic recommendations for the management of overdosage. In the event of a large overdose, gastric lavage can be undertaken and further treatment should be symptomatic.
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.

Estradiol is chemically and biologically identical to endogenous human estradiol and has pharmacological actions similar to the physiological effects of the endogenous hormone. Estradiol is the primary estrogen and the most active of the ovarian hormones.
Zumenon restores plasma estrogen levels and thus relieves or decreases estrogen deficiency symptoms. It suppresses gonadotrophin secretion (FSH/LH) and improves vaginal cytology in postmenopausal women. It has a positive effect on the symptoms of the urogenital estrogen deficiency syndrome including lower urinary tract dysfunction and atrophic vaginitis. Estradiol is known to decrease LDL-C and increase HDL-C and triglycerides.

Clinical trials.

Women's health initiative studies.

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral conjugated estrogens (CE) 0.625 mg/day alone or the use of a continuous combined regimen of conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day (CE + MPA) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture or death due to other cause. The study did not evaluate the effects of CE alone or CE + MPA on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% white, 15% Black, 6.1% Hispanic), after an average follow-up of 6.8 years are presented in Table 5.
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women years in the group treated with CEE alone were 12 more strokes while the absolute risk reduction per 10,000 women years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women years. There was no difference between the groups in terms of all cause mortality. (See Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use.)
The estrogen plus progestogen substudy was also stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". Results of the estrogen plus progestogen substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 6.
For those outcomes included in the WHI "global index", the absolute excess risks per 10,000 women years in the group treated with CE + MPA were 7 more CHD events, 8 more strokes, 8 more PEs and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women years. There was no difference between the groups in terms of all cause mortality (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use).

Women's health initiative memory study.

The estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were age 65 to 69 years, 36% were 70 to 74 years and 19% were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE) 0.625 mg/day alone on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women years) and 19 in the placebo group (25 per 10,000 women years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95% CI, 0.83 to 2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).
WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE plus MPA on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/ progestogen group (45 per 10,000 women years) and 21 in the placebo group (22 per 10,000 women years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).

5.2 Pharmacokinetic Properties

Absorption.

Micronised estradiol is rapidly and efficiently absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations of estradiol occur 4-6 hours after tablet ingestion. Thereafter elimination is slow and estradiol levels are maintained above baseline for 24 hours. The steady-state plasma level of estradiol ranges between 70-100 picogram/mL. Estradiol has a half-life of approximately 14-16 hours.

Distribution.

In the bloodstream more than 90% of estradiol is bound to plasma proteins.

Metabolism.

Some estradiol is converted to estrone in the intestinal mucosa before absorption into the portal vein. During passage through the liver a significant proportion of estradiol is metabolised to estrone. Estradiol and hydroxyestrones are also produced as well as sulfate and glucuronate conjugates. Circulating estrone sulphate may be reconverted to estrone and estradiol in extrahepatic organs like the uterus.

Excretion.

Estrogens are excreted into the bile and undergo significant enterohepatic cycling. Biologically inactive glucuronide and sulphate conjugates are excreted in the urine (90 to 95%) and unconjugated estrogen metabolites appear in the faeces (5 to 10%). Estrogens are also secreted in the milk of nursing mothers.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Supraphysiological doses of estradiol have been associated with the induction of tumours in estrogen dependent target organs in all rodent species tested. The relevance of these findings with respect to humans has not been established.
Unopposed estrogen therapy by women with intact uteri is associated with an increase in endometrial carcinoma, particularly with prolonged use. Adjunctive progestogen use for a minimum of ten days reduces the risk of endometrial hyperplasia. Endometrial hyperplasia (atypical or adenomatous) often precedes endometrial cancer.
There has been concern about the possible risk of breast cancer in estrogen treated women. Although many studies have failed to disclose an increased incidence of breast cancer, some have shown a small increase upon prolonged therapy (e.g. 10 years or longer). It is not known whether concurrent progestogen use influences the risk of breast cancer although recent studies suggest no reduction of the risk when progestogens are added to estrogens. Epidemiological surveys have disclosed no increase in breast cancer mortality among estrogen treated women.
Women who are on long-term therapy or have breast nodules or fibrocystic disease should have regular breast examinations and should be instructed in self breast examination. Regular mammographic investigations should be conducted where considered appropriate. There is a need for caution when prescribing estrogens in women who have a history of, or known, breast nodules or fibrocystic disease. Breast status should be closely monitored, supported by regular mammography.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, hypromellose, maize starch, colloidal anhydrous silica, magnesium stearate. The colour used in the coating is Opadry complete film coating system OY-6957 Pink (ARTG PI No: 4158).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 30°C.

6.5 Nature and Contents of Container

Zumenon 2 mg tablets are available in PVC/aluminium blister packs containing 7, 28, 56 or 84 tablets.
Some pack sizes may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 75888 - Zumenon estradiol (as hemihydrate) 2 mg tablet blister pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Estradiol hemihydrate has the chemical name: Estra-1,3,5,(10)-triene- 3,17β-diol. Chemical formula: C19H24O2.½H2O; Molecular weight = 281.4. It has the following chemical structure:
It is a white or almost white, crystalline powder or colourless crystals and is practically insoluble in water.

CAS number.

Estradiol hemihydrate: 35380-71-3.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes